A 61-year-old Hispanic man with past medical history of benign prostatic hyperplasia (BPH) treated with transurethral resection of the prostate the preceding year presented to our emergency room with a nonhealing wound on his right thigh. He reported that he sustained a laceration to his right thigh during work with machinery one week prior to presentation and had visited the nearest urgent care. Despite suture placement at the urgent care, he continued to bleed. In addition, he reported multiple ecchymoses on his lower abdomen and extremities and severe pain in his left hip and leg. The patient had a temperature of 36.5°C, a heart rate of 101 beats per minute, a blood pressure of 138/87 mm Hg, a respiratory rate of 18 breaths per minute, and an oxygen saturation of 98% on room air. Physical exam revealed skin pallor along with diffuse ecchymoses of the abdomen, thighs, and extremities. No lymphadenopathy was noted. Labs revealed a WBC of 7.9 (normal 3.4–10.4 1000/μL), hemoglobin 8.2 (normal 13.5–17.5 g/dL), hematocrit 24.8 (normal 40.0–51.0%), platelet counts of 76 (normal 150–425 1000/μL), INR 1.8 (normal 0.8–1.1), PT 20.9 (normal 11.9–15.0 seconds), PTT 46.9 (normal 22.6–35.5 seconds), fibrinogen 40 (normal 200–430 mg/dL), alkaline phosphatase 1193 (normal 40–150 IU/L), and D-dimer >20.0 (normal <0.5 μg/mL). The patient was started on 4 units of fresh frozen plasma and 1 unit of cryoprecipitate, and a DIC panel was obtained every 6 hours.
An X-ray of the left hip and femur demonstrated extensive metastatic lesions of the left ilium, ischium, and pubic bones including involvement of the acetabulum. A contrast-enhanced chest CT revealed focal periosteal reaction in the left posteromedial 6th, 7th, and 8th ribs along with nonhomogenous mixed sclerotic and lytic appearance in the spine. An abdominal MRI with and without contrast demonstrated diffuse osseous metastatic disease but no evidence of primary malignancy in the abdomen. Nuclear medicine whole body bone scan revealed diffuse osseous metastatic disease involving the axial and proximal appendicular skeleton along with bilateral involvement of the femurs. Spinal MRI with and without contrast demonstrated diffuse osseous metastatic disease involving the cervical, thoracic, lumbar spine, and sacrum. The MRI also demonstrated an unusual finding of extensive metastatic epidural tumor deposits along the thoracic and lumbosacral spine resulting in spinal canal stenosis (). The patient required transfusions of cryoprecipitate (CP), fresh frozen plasma (FFP), platelets (PLTs), and red blood cells (PRBCs) pending workup (Figures and ). Prostate serum antigen (PSA) and α2-antiplasmin (AAP) levels were ordered and revealed PSA and AAP levels of 673.17 (normal 0.0–4.0 ng/mL) and 42 (normal 88–120%), respectively. The significantly decreased fibrinogen and AAP levels in conjunction with high PSA indicated PC with DIC XFL as the diagnosis. A prostate biopsy was not attempted given the high risk of bleeding. The patient received two subcutaneous injections of degarelix 120 mg on each side of his abdomen (total 240 mg), followed immediately by cold compresses to both areas to prevent bleeding. Over the next 7 days, he was transfused with CP, PRBCs, PLTs, and FFP. He also received Vitamin K 5 mg daily. Coagulopathy marker goals were fibrinogen level > 100 mg/dL, hemoglobin > 8 g/dL, and platelet count > 50,000/μL. Ten days after admission, his coagulopathy improved obviating the need for transfusions (Figures and ).
The patient was observed an additional two days and did not require supportive transfusions and was discharged on day 13 after admission. Over the course of his encounter, he received a total of 70 units of CP, 8 units of FFP, 4 units of PRBCs, and 3 units of PLTs. His lab values upon discharge were platelets 139,000/μL, INR 1.1, PT 14.4 sec, PTT 22.4 sec, fibrinogen 141 mg/dL, alkaline phosphatase 600 IU/L, and PSA 125.70 ng/mL.
During an outpatient followup, the patient was stable and his labs revealed no coagulopathy and his D-dimer remained persistently elevated. He decided against pursuing a prostate biopsy given his concerns of bleeding and low likelihood that results will change management. MRI of the spine one month after starting testicular suppression revealed complete resolution of the epidural deposits (). After 3 months of treatment with degarelix his PSA decreased to 26 and he achieved a very good partial response by imaging. Six months after starting hormonal therapy he developed urinary retention requiring hospitalization and urinary catheter placement. His PSA increased to 555 and a bone scan and an MRI of the spine, abdomen, and pelvis revealed extensive bone metastasis in thoracic and lumbar spine, femur, ribs, and pelvis. Bicalutamide was added; however, his disease progressed with a PSA level of 1361 and an alkaline phosphatase level of 1247 (normal 40–150 IU/L). He was started on docetaxel and received 3 cycles of therapy. His PSA remained elevated at 1200 and his performance status worsened significantly (Karnofsky performance status of 60%) necessitating admission to a rehab center. The patient shortly after decided on comfort care.


A 28-year-old woman experienced sudden-onset abdominal pain with associated nausea and vomiting during the night. She was transferred to our hospital complaining of severe epigastralgia. The patient’s medical history was unremarkable. Her blood pressure was 104/66 mmHg, her heart rate was 107 beats/min, and her body temperature was 37.7 °C. On physical examination, she had severe tenderness to palpation around the umbilicus with no signs of diffuse peritonitis. Laboratory results were as follows: white blood cell count, 13.3 × 109/L; hemoglobin, 14.6 g/dL; aspartate aminotransaminase, 623 IU/L; alanine aminotransaminase, 431 IU/L; total bilirubin, 4.9 mg/dL; alkaline phosphatase, 1007 IU/L; gamma-glutamyl transpeptidase, 939 IU/L; and C-reactive protein, 3.7 mg/dL.
Urgent contrast-enhanced abdominal computed tomography (CT) revealed remarkable dilatation of the CBD. It also demonstrated fluid collection around the CBD, mainly in the retroperitoneal space, and suspicion of a perforated cyst wall (Fig. ). Endoscopic retrograde cholangiopancreatography (ERCP) was performed for further evaluation and biliary drainage, with a presumed diagnosis of perforated CC. ERCP revealed APBDU and biliary leakage out of the CC (Fig. ). The concentration of amylase in the bile was 2040 IU/L. After an endoscopic nasal biliary drainage (ENBD) tube was placed, the general condition of the patient improved. Before the definitive surgery, additional multimodal examinations, including cholangiography taken by the ENBD tube (Fig. ), CT, magnetic resonance cholangiopancreatography, ultrasonography, and pathology tests, revealed a congenital type IVa CC, according to Todani’s classification [], but no signs of malignancy.
Twenty-two days after endoscopic biliary drainage, laparotomy was performed. Operative findings showed the bile duct was extremely dilated from the porta hepatis to the lower part of the CBD. A single free perforation site was observed at the right-side wall of the CBD, near the confluence of the cystic duct. The other organs had no evidence of perforation. Because inflammation around the pancreas head was severe, it was difficult to dissect the dilated intrapancreatic bile duct safely. For complete resection of the cystic mass, subtotal stomach-preserving pancreatoduodenectomy was performed, and the Traverso technique was employed for reconstruction. The postoperative course was uneventful, and the patient was discharged on the 29th postoperative day. Pathologic examination of a specimen revealed no malignancy, and the patient has remained well during the 3-year follow-up.
CC, or bile duct cyst—a congenital dilation of the biliary tract—is commonly seen in women, East Asians, and children. The incidence of CC in Western populations ranges from 1 in 100,000 to 1 in 150,000 live births [], which is thought to be lower than that in Asian countries. In Japan, the total number of admissions to children’s hospitals for CC has been estimated to be as high as 1 in 1000 [], although, it has been reported to be 1 in 13,500 in the USA [] and 1 in 15,000 in Australia []. Biliary cysts can be divided into five subgroups according to Todani’s modification of the Alonso-Lej classification []. It has been reported that APBDU, which is seen in almost all cases of CC [, ], predisposes the patient to risk of carcinoma. Incidence of carcinogenesis associated with CC ranges from 4 % to 30 %, and increases with age [, , –]. Given the high risk of malignant conversion, surgical resection of the cyst, especially the extrahepatic bile duct, has been recommended for type IV CCs [, ].
Perforation of CC is a rare, but important, condition in children [, ]. Spontaneous perforation of CC in adults is extremely rare [, ]. Surgical management, especially two-stage biliary reconstruction, commonly has been performed for bile peritonitis [–]. There are several reasons why two-stage surgery has been strongly recommended. First, the cyst wall is so friable due to severe inflammation that anastomosis in primary closure would be disrupted. This is why T-tube drainage is recommended in the first surgery []. Second, because of bile staining and severe inflammation, a definitive procedure can be difficult to perform during emergency exploratory laparotomy. Therefore, it is safer to perform the definitive surgery when the patient recovers from the inflammatory state.
However, in adult cases with no signs of diffuse peritonitis, it might be possible to perform transient biliary drainage using an endoscopic or percutaneous approach. This strategy is not common, but it has several advantages. First, this strategy can be used as a less invasive alternative to emergency drainage by laparotomy for patients in bad general condition. Using endoscopic or percutaneous biliary drainage as a bridging procedure, definitive single-stage surgery can be performed when inflammation has improved and the patient is in better condition. The second advantage is that additional examinations can be performed before the definitive surgery while the patient recovers from the inflammatory state. These examinations could make the preoperative evaluation and diagnosis more precise, including assessment of malignant potential. Endoscopic or intraductal ultrasonography, for example, might be effective for preoperative diagnosis due to their high diagnostic accuracy [, ]. Bile cytology also could be helpful for diagnosis. Cholangiography taken by the cyst drainage tube would be extremely helpful to plan the optimal definitive surgery. If any signs of malignancy are indicated, R0 surgery and additional lymphadenectomy should be considered. In our case, owing to biliary drainage, multimodal examinations enabled precise evaluation, and helped to simulate the optimal definitive surgery.
There are some considerations to bear for this strategy. In our case, there were no evident indicators of histologic improvement from the inflammatory state. Rapid recovery from the acute phase and sufficient biliary drainage for almost 3 weeks allowed us to suspect improvement from the inflammatory state. However, the definitive surgery was complicated by residual inflammation around the pancreas head. Therefore, it can be difficult to determine proper timing of the definitive surgery following transient biliary drainage. It is easy to understand that biomarkers of inflammation, such as white blood cell count or serum C-reactive protein level, and patients’ symptoms indicate clinical improvement from the inflammatory state. However, these criteria do not always indicate histological improvement. As in the management of other inflammatory diseases, a sufficient interval might be needed for safe operation. An interval appendectomy for acute appendicitis in children is generally planned 2 or 3 months after conservative management []. Histological findings suggest that the adhesion around the appendix improves about 2 months after the disappearance of symptoms []. On the other hand, early cholecystectomy following biliary drainage for acute cholecystitis is reported to be preferable if the patient’s condition improves, because surgery is easy to perform when the inflammation has improved and the adhesion is still soft and fresh [, ]. Based on these findings, with regard to histological tissue inflammation, it might be better to plan elective surgery either within 72 h or over 2 months after the onset of symptoms. However, malignancy might be difficult to rule out within 72 h after the onset of symptoms. Therefore, in clinical practice, it might be recommended to perform elective surgery over 2 months after the onset and disappearance of symptoms if biliary drainage is carefully managed. Our patient required continuous biliary drainage due to extreme narrowing of the lower biliary tract; therefore, ENBD was thought to be a better intervention for biliary drainage than endoscopic biliary stenting (EBS). This is because ENBD can detect nonfunctioning of the biliary drainage system much earlier and because exchanging an ENBD tube for an EBS tube might be a challenging procedure with a high risk of re-perforation in this case. Our patient could not wait more than 2 months for elective surgery because of social issues; therefore, she underwent definitive surgery 3 weeks after the onset of symptoms.
If malignancy is suspected, endoscopic biliary drainage might be performed using a percutaneous approach with regard to peritoneal dissemination. Both endoscopic and percutaneous approaches are appropriate for biliary drainage near the CBD. On the other hand, it would be better to employ a percutaneous approach when bile collection is distant from the bile duct. If necessary, a combination of these approaches can be considered for better management.
In a PubMed database search, we found 10 cases in eight English articles addressing management of spontaneously perforated CC in adults [, –, , ]. We summarize the features and clinical course of these 10 cases in Table . In most of these cases, patients were aged in their twenties, from East or South Asian countries, and presented with bile peritonitis. All 10 cases were either a type I or IVa CC, according to Todani’s classification, and had no signs of malignancy. Preoperative abdominal paracentesis confirmed biliary leakage in six cases. Two-stage surgery comprising T-tube choledochocystostomy and peritoneal lavage as the first surgery, and cyst excision and hepaticojejunostomy as the second surgery was performed in six cases. Single-stage surgery was performed in the other four cases; preoperative percutaneous biliary drainage was performed in three of them. The interval from diagnosis to definite surgery varied from case to case. Almost all of the cases managed by two-stage surgery might have been treated by single-stage surgery with preoperative biliary drainage, if they had no manifestation of diffuse peritonitis. Although it is difficult to clearly define the criteria for single-stage surgery for perforated CC, the lack of clinical signs of diffuse peritonitis or malignancy at initial assessment might be helpful factors for planning this elective surgery. It is controversial whether to plan single-stage or two-stage surgery. However, if the clinical outcomes for both strategies are the same, single-stage surgery would be better because it is potentially more cost-effective and safe. In addition to the two advantages described above, elective surgery when the patient’s condition has improved can have better results and avoid a possible emergency operation.


A previously healthy 4-year-old girl exhibited butterfly like rash, heliotrope rash, Gottron’s papules, mild proximal muscle weakness, muscle grasping pain, and serum creatine kinase (CK) levels and erythrocyte sedimentation rate were elevated. This patient fulfilled the diagnostic criteria for dermatomyositis []. To fulfill the criteria, patients must meet more than 4 findings among 8 (1. proximal muscle weakness, 2. muscle grasping and spontaneous pain, 3. nondestructive arthritis or arthralgia, 4. elevated CK or aldolase level, 5. presence of systemic inflammatory signs (fever, elevated C-reactive protein, or elevated erythrocyte sedimentation rate), 6. myogenic changes on electromyogram, 7. anti Jo-1 antibody positive, 8. pathologic findings compatible with inflammatory myositis) with having shown the characteristic skin findings (heliotrope rash or Gottron’s papules). She was treated with high-dose oral prednisolone (PSL) followed by 2 courses of methylprednisolone pulse therapy (MPT). Subsequently, the skin rash and myositis gradually improved, and low-dose oral PSL was continued. Three months after MPT, she was emergently admitted to our hospital because of dyspnea, high fever, erythema, hepatosplenomegaly, cytopenia, liver dysfunction and coagulopathy. Hypoxemia, high Krebs von den Lungen-6 (KL-6) levels, and diagnostic imagings indicated progressive IP (Fig. , ). Results of hematological examinations were as follows: leukocytes, 2.56 × 109/L; hemoglobin, 13.4 g/dL; platelet count, 119 × 109/L; D-dimer, 120.0 mg/L (reference range [rr]: 0–1 mg/L); alanine aminotransferase (ALT), 596 IU/L (rr: 5–43 IU/L); aspartate aminotransferase (AST), 1,154 U/L (rr: 12–34 IU/L); ferritin, 8,062 ng/mL (rr: 25–280 ng/mL); lactate dehydrogenase (LDH), 2,267 IU/L (rr: 115–217 IU/L); CK, 40 IU/L (rr: 41–123 IU/L); KL-6, 1,106 U/mL (rr: 0–499 U/dL). The urinary β2-microglobulin (U-β2MG) levels were elevated, 8.06 mg/L (rr: <0.29 mg/L). The tests for antinuclear antibody (1:80; speckle) and anti-melanoma differentiation-associated gene 5 (MDA5) antibody were positive. Anti-Jo-1 antibody and Epstein–Barr virus (EBV) DNA were negative. Bone marrow aspiration showed activated macrophages phagocytosing hematopoietic elements. She was diagnosed as having JDM-MAS, and progressive IP. Heparinization, dexamethasone palmitate (DP) and cyclosporine (CsA) therapy appreciably controlled the disease activity. Six days later, the flare-up of MAS such as decrease of platelet count and elevation of serum ferritin and U- β2MG levels required MPT for 3 consecutive days, and then successfully subsided (Fig. ). The following intravenous cyclophosphamide (IVCY) therapy led to a clinical and radiological remission of IP (Fig. , ).
We studied serum cytokine profiles in this patient during the acute (days 4, 6), subacute (day 12) or convalescent phase (day 50) of JDM-MAS with IP. Multi-target streaming protein quantitative technology (BD-Pharmingen Cytometric Bead Array; BD Biosciences, Franklin Lakes, NJ, USA) was used to detect the serum cytokine levels of interleukin (IL)-2,4,6,10, tumor necrosis factor-α (TNF- α), and interferon-γ (IFN- γ), following the manufacturer's instructions. The lower detection limits for IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ were 2.6, 2.6, 2.5, 2.8, 2.8, and 7.1 pg/mL, respectively. Serum levels of IL-18 were determined using enzyme-linked immunosorbent assay (ELISA) kits (Medical & Biological Laboratories, Co., Ltd., Nagoya, Aichi, Japan) according to the manufacturer's protocols. The lower detection limit was 12.5 pg/mL.
The clinical courses and the results of cytokine expressions in our patient with JDM-MAS and IP are shown in Fig. , . There was hypercytokinemia before the treatment and during the acute phase of JDM-MAS with IP. IL-6 and IL-18 were at prominent high levels compared with the elevated levels of IL-10, TNF-α and IFN- γ. IL-6 levels promptly decreased after the initial therapy. IL-18 levels sustained to be high after the start of effective treatments during the acute and subacute phases of JDM-MAS. On the other hand, the IL-18 levels decreased after IVCY therapy, in concert with the declining KL-6 levels and the clinical and radiographical improvement of IP (Fig. ).


A 45-year-old never-smoking male of Danish origin, without any medical history, was referred acutely to our emergency department with abdominal pain, vomiting, and jaundice. He denied alcohol use and had no predisposition to cancer, pulmonary, or gastrointestinal (GI) diseases. As a gardener, he had no relevant occupational exposures. During the last 4 weeks, he had suffered from a lack of appetite, dull pain in the right upper abdominal quadrant, and had an unintended weight loss of 10 kg. He denied any respiratory symptoms, change in bowel habits, melena, or fever.
At physical examination, he was chronically ill with a body mass index of 18, jaundice and abdominal pain on palpation of the upper abdominal quadrant. Pulmonary and cardiac auscultation was normal and no exanthema was present.
Laboratory tests showed leucopenia of 2.50×109/L (3.50–8.80×109/L) and increased liver enzymes tests with alanine transaminase of 441 IU/L (10–70 IU/L), alkaline phosphatase of 194 IU/L (35–105 IU/L), bilirubin of 196 µmol/l (5–25 µmol/L), and lactate dehydrogenase of 218 U/L (105–205 U/L). Pancreas amylase, gamma-glutamyl transferase, C-reactive protein, haemoglobin, thrombocyte concentration, calcium, and creatinine were within normal limits. Because of the liver involvement, hepatitis was suspected, but serology test for Hepatitis A, B, C, HIV, and Leptospirosis were negative. There were normal immunoglobulin subgroups and autoimmunological tests, including anti-nuclear and anti-neutrophil cytoplasmic antibodies, which were negative. However, an increased blood angiotensin-converting enzyme (ACE) above 88 U/L (8–53 U/L) was observed.
Lung function tests showed normal ventilation and diffusion parameters with forced expiratory volume in 1 second (FEV1) of 4.4l, corresponding to 102% of predicted; forced vital capacity (FVC) of 5.7l, corresponding to 105% of predicted; and lung diffusion of carbon monoxide (DLCO) corresponding to 85% of predicted. Total lung capacity was not measured.
Because of the biochemical signs of hepatitis, an abdominal sonography was performed, uncovering lymphadenopathy in the lever hilus. The patient underwent computer tomography (CT) of thorax and abdomen, which revealed lesions in the pancreas, bilateral pulmonary nodular infiltrates, as well as mediastinal and intraabdominal lymphadenopathy (–).
As metastatic cancer was suspected, a whole-body 18 flour-deoxyglucose positron emission tomography (18-FDG PET) scanning was performed, presenting multiple pathological lesions in lungs, pancreas, lymph nodes, and bones ().
A sonography-guided lever biopsy showed non-caseating granulomatous inflammation. The patient underwent further invasive procedures: bronchoscopy with transbronchial biopsy (TBB), bronchoalveolar lavage (BAL) with flowcytometry, endobronchial ultrasound (EBUS) with transbronchial needle aspiration (TBNAB) biopsy, and a bone marrow biopsy. None of the pathological tests revealed any malignant findings. Bronchoscopy was without any macroscopic abnormalities. BAL flowcytometry uncovered an overall lymphocytic inflammation with a proportion of 51%, an increased CD4/CD8 ratio of 5.4 without any eosinofilia or neutrofilia. Pathological evaluation of the samples from the TBBs demonstrated non-caseating granulomas and EBUS-TBNAB from the mediastinal lymph nodes showed unspecific fibrosis. Microbiological tests from the bronchoscopy specimens did not reveal any respiratory infection (no growth of bacteria in cultivation, negative tuberculosis tests including cultivation, negative PCR tests concerning Legionella pneumophila, Mycoplasma pneumonia, Chlamydia psittaci et pneumoniae, and Pneumocystis jirovecii).
We considered the following differential diagnoses: metastatic malignancy with unknown primary tumour, liver diseases (hepatitis, both infectious and autoimmune, biliary cirrhosis, and primary sclerosing cholangitis), infectious diseases (leptospirosis, AIDS, and tuberculosis), and autoimmune systemic diseases.
Based on the composite findings (increased blood ACE, various FDG metabolic active lesions in the PET-scanning, non-caseating inflammation in liver biopsy and TBBs, lymphocytic inflammation with increased CD4/CD8 ratio in BAL) and exclusion of other diseases capable of producing a similar pathological and clinical picture, a diagnosis of systemic sarcoidosis was well established.
The patient was treated with systemic prednisolone (0.5 mg/kg/day=37.5 mg/day), slowly tapering every third week (25 mg/day for 3 weeks, then 12.5 mg for 3 weeks), until a fixed dose of 7.5 mg prednisolone/day was reached. Three weeks into the treatment, blood tests showed normalised ACE and liver function parameters. At present we follow him in our respiratory outpatient clinic and plan to fully taper steroids according to the disease activity.


The patient was a 53-year-old woman who had migrated to São Paulo city, Brazil from Arapiraca, Alagoas in the Northeast of Brazil. She visited the dermatology outpatient department of the University of São Paulo Medical School Hospital (HCFMUSP) with complaints of fever and skin lesions that had persisted for over a year and had worsened during the last 3 months. She mentioned that she had been treated for leprosy (MDT-MB) for 14 months, which had ended 3 months earlier. She had used prednisone intermittently for over a year during outbreaks of reactions.
Dermatological examination showed a Cushingoid face, widespread erythematous and edematous, some painful plaques and nodules some of which with central necrosis. This led us to establish the diagnosis of sub-polar lepromatous leprosy (LLsp) with a necrotizing erythema nodosum leprosum (ENL) reaction (type-2 leprosy reaction) (Fig. ).
She was many times hospitalized during the 3 years after MDT-MB and once in a critical condition with fever, tachycardia and hypotension. Prednisone 40 mg/day and thalidomide 300 mg/day were prescribed at the intensive care unit for treating the reaction. During hospitalization, the patient developed a septic shock. The skin was considered the most likely focus and she was treated with oxacillin.
After 6 days, despite general clinical improvement, the skin lesions worsened, but no other focus of infection was found. Histopathological examinations of the skin, one from a biopsy of the right cavum plantaris and one from a biopsy of the left arm were conducted. Both of them showed multi-bacillary leprosy with a regressive response and fragmented acid-fast bacilli (2+/6+).
After a few days, the patient had new fever attacks, swelling of the abdomen, generalized edema and worsening of the necrotizing ENL. She had elevated levels of liver enzymes, pancytopenia with progressive hypotension, hepatic and hematologic failure. Empirical antibiotic therapy with vancomycin and imipenem indicated by the infectious disease department was started. Liposomal amphotericin B was also introduced to cover the possibility of fungemia or candidemia (the patient had an esophageal candidiasis diagnosed by endoscopy, supposedly due to the long-term corticosteroid therapy).
Three days later, a new investigation at the emergency department showed hepatosplenomegaly and ascites. VL was diagnosed based on the parasitology of the bone marrow (Fig. ), the gold standard for diagnosis of VL and on blood examinations, which showed numerous intracellular and extracellular Leishmania parasites; using rk39 (39 amino acid repeats of a kinesin-like gene found in L. chagasi), a rapid immunochromatographic test specific for the Leishmania donovani complex [] and by molecular tests (kDNA-PCR = kinetoplast target DNA for PCR and ITS1-DNA-PCR = Internal Transcribed Spacer 1 target DNA for PCR). In addition, after ITS1-RFLP (PCR amplification of the Internal Transcribed Spacer 1 genes (ITS1) and Restriction Fragment Length Polymorphism) (Fig. ), fitted-in with the diagnosis of VL, it was demonstrated definitively that L. (L.) infantum chagasi was the etiologic agent, because it presented 184 bp (base pair), 72 and 55 bp fragments [].
Liposomal amphotericin B (4 mg/kg/day for 5 days) was now continued for the treatment of VL (kala-azar). This also led to a significant clinical improvement of her ENL skin lesions. Secondary prophylaxis with amphotericin B (3 mg/kg/day for 21 days each month during 6 months) was introduced by the infectious diseases physicians. During the last dose only the kDNA-PCR with her blood was positive.
Around 6 months after the treatment for VL and free of necrotizing ENL for 1 year and an occasional nodule of ENL, she developed a few hypochromic papules on her forehead (Fig. ). Histopathological examination of a biopsy of such a papular lesion showed a granulomatous inflammatory infiltrate throughout the dermis and superficially in the sub-cutis consisting of epithelioid histiocytes, lymphocytes and many plasma cells (Fig. ). Leishman bodies were seen within macrophages (Fig. ). The presence of Leishmania was further confirmed by immunohistochemistry (Fig. ) using a peroxidase-anti-peroxidase technique and a polyclonal antibody to Leishmania produced in rabbits []. At this time, there was no hepatosplenomegaly and the bone marrow did not show Leishmania parasites. A revision of all previous skin biopsies with immunohistochemistry for Leishmania was performed, but the results were all negative. At that moment, the diagnosis of post-kala-azar dermal leishmaniasis (PKDL) was established and liposomal amphotericin B (3 mg/kg/day for 7 days) was re-introduced resulting in a clinical regression of the skin lesions that was confirmed by histopathological examinations. About 2 years after the treatment of PKDL the patient is still free of PKDL lesions.


A 42-year-old woman presented with a right breast lump, lower back pain, loss of height, marked kyphosis and hepatomegaly. Core biopsies from the breast lump showed ductal carcinoma in situ (sample labelled P1.1; and ). An additional biopsy from an ipsilateral axillary lymph node (P1.2) revealed metastatic ductal adenocarcinoma (ER+ (8/8) and HER2+ (3+)). Computed tomography scan revealed widespread metastatic disease in bones, pleura and liver ( and ). The patient was started on treatment with trastuzumab and taxane-based chemotherapy, with a significant partial response (). After induction chemotherapy, she was maintained on tamoxifen and trastuzumab. After 19 months on treatment, she presented with seizures and head computed tomography revealed a large metastasis in the left frontal lobe (), which was resected (M2.1). Therapy with tamoxifen and trastuzumab was continued and collection of plasma samples was initiated (samples T1–T9). Four months after surgery, she had enlarging liver lesions and a new metastatic deposit in the left ovary (). Treatment was switched to a combination of lapatinib and capecitabine, resulting in stable disease for 12 months (). General deterioration then occurred, with disease progression in the chest (new pulmonary nodules, bilateral pleural effusions and posterior chest wall mass, ; Eastern Cooperative Oncology Group performance status 2–3). Treatment was stopped and the patient died ∼4 months later.
Tumour samples were obtained at diagnosis from the primary breast site (P1.1) and an axillary lymph node (P1.2); after 19 months from the brain metastasis area (M2.1); and at autopsy after 3 years on treatment (from the primary breast site, and from metastatic deposits in the chest, liver, ovary and vertebrae, labelled P3.1 and M3.1–M3.4, respectively). Serial plasma samples were obtained over the last 500 days of clinical follow-up (T1–T9). Tumour and plasma samples collected and the clinical course are summarized in .


A 48-year-old man, predisposed to thromboembolic events by smoking, hypertension, hypercholesterolemia, and family history, debuted in 2008 with 5 CT verified cerebral strokes. The patient was treated with platelet inhibitors, antihypertensive, and cholesterol lowering drugs. Due to side effects, the patient stopped all medication after one year. In 2012 and 2014 the patient suffered from strokes again and had a work-up including testing for infectious focus, coronary angiography, and thrombophilia screening. All were negative. Atheromatosis without significant stenosis was found by ultrasound of the carotid arteries. A Transesophageal Echocardiography (TEE) was performed and a thread-like frond was found on the aortic valve (see ). The excrescence was interpreted as a fibroelastoma and this was thought to explain the strokes. The patient was therefore planned for surgical valve resection. During the anaesthesia a TEE was performed but now the tumour/excrescence was no longer visible. The surgery was therefore aborted. At a TEE performed 3 weeks later it was still not recognized nor was paradox embolism. After reviewing all the TEE data it was concluded that the most likely diagnosis was Lambl excrescence (see ).


A 63-year-old female presented for a right hemicolectomy and umbilical hernia repair for a large transverse colon polyp found on screening colonoscopy. She received 1.0 gram of ertapenem preoperatively. On postoperative day four she developed abdominal pain and distention, nausea, vomiting, and diarrhea. A nasogastric tube was placed which drained two liters of fluid. Computed tomography () demonstrated dilated small bowel loops with a small amount of gas in the colon consistent with an ileus. She developed hypotension, tachycardia, and reduced oxygen saturation and was transferred to the surgical intensive care unit (SICU) on mechanical ventilation and vasopressor support. She developed acute kidney failure. She was started on continuous venovenous hemodialysis to assist in metabolite and volume control and empiric broad spectrum antibiotics. On postoperative day five she was taken to the operating room for exploratory laparotomy. At the time of reexploration there was no acute intra-abdominal process noted, and her anastomosis was intact. She was transferred back to the SICU where she required increasing vasopressor support and continued mechanical ventilation. Flexible sigmoidoscopy was performed to the descending colon, showing no pseudomembrane formation nor other abnormalities. On postoperative day seven she had a cardiac arrest and expired despite attempted resuscitation. An autopsy was performed which demonstrated pseudomembranous enteritis throughout her small bowel with patchy transmural inflammation and hemorrhage and focal areas of necrosis. Opening of the small bowel demonstrated pseudomembranous exudates, which filled the lumen. The colon did not show pseudomembranes. The pathology of the resected mass demonstrated well-differentiated adenocarcinoma of the colon.


A 63-year-old female presented with pelvic abscess and rectovaginal fistula several months after undergoing a low anterior resection at another institution complicated by intra-abdominal sepsis from dehiscence of her anastomosis. This had been treated with diverting loop ileostomy and closure of her abdominal fascia with biologic mesh. Since that time she had developed purulent drainage from her vagina and rectum. She had been started on per oral amoxicillin-clavulanate. She was taken to the operating room for low anterior resection with coloanal anastomosis, small bowel resection, primary repair of parastomal hernia with mesh, and drain placement. The patient was on broad spectrum antibiotics at the time of surgery. Specific preoperative antibiotics were not given. On postoperative day three she developed nausea and vomiting. On postoperative day four she developed hypotension. A nasogastric tube was placed with return of bilious output. She became hypotensive and was transferred to the surgical intensive care unit (SICU) for fluid resuscitation. She was afebrile, with moderate abdominal tenderness, reduced urine output, and elevated creatinine. The decision was made to proceed to the operating room. At the time of reoperation her anastomoses were intact, but the abdomen could not be closed. An ABThera Open Abdomen Negative Pressure Wound Therapy System was placed and she was returned to the SICU where she was started on intravenous metronidazole and oral vancomycin due to concern for small bowel C. difficile enteritis after pseudomembranes were noted on the ileostomy. A C. difficile toxin assay was positive at that time. Red rubber catheters were placed in both sides of her ileostomy and her rectum taking care not to disrupt her coloanal anastomosis. 500 mg of vancomycin was placed in each of these tubes and down her nasogastric tube every 6 hours.
Her hospital course was further complicated by ventricular tachycardia, heart failure intolerance of enteral feeds, cholestatic jaundice, need for reoperation for placement of absorbable mesh for closure of the abdominal cavity, leukocytosis, need for total parenteral nutrition (TPN), tracheostomy, development of enterocutaneous fistula, multiple intraabdominal abscesses, a repeat episode of C. difficile enteritis, atrial fibrillation with rapid ventricular rate, and a urinary tract infection. She remained in the hospital for two months.
At the time of discharge, her tracheostomy had been removed; she was tolerating snacks of thickened liquids, had a nasoenteric feeding tube in place, and was receiving TPN and intravenous metronidazole. A wound manager was being used to control her fistula output. The fistula subsequently closed, and she remains healthy but with a large ventral hernia.


A 62-year-old woman, gravida 2 para 2, presented with abdominal pain. Gastrointestinal endoscopy showed superficial gastric erosions and histopathological examination of endoscopic biopsy specimens revealed poorly differentiated adenocarcinoma. Staging computed tomography (CT) scan demonstrated thickening of the gastric sinus wall, peritoneal dissemination, and 9 cm diameter solid pelvic mass. Based on these findings, the patient was diagnosed as having advanced (stage IV) gastric cancer and treated with TS-1/cisplatin (CDDP) chemotherapy. After 16 courses of TS-1/CDDP chemotherapy, gastroscopy showed complete resolution of the ulcerous lesion and CT demonstrated significant reduction in peritoneal dissemination. However, the pelvic tumor had not changed in size and had developed a cystic component. The patient was referred to our hospital for evaluation of the pelvic tumor.
At the first visit to our hospital, the patient's general condition was good and her medical and family histories unremarkable. On pelvic examination, a firm, nontender, approximately 10 cm diameter mass was palpated in the right lower abdomen. Transvaginal ultrasonography and computed tomography (CT) revealed a 10 cm diameter pelvic mass (Figures and ). Magnetic resonance imaging (MRI) demonstrated a tumor with mixed low- and high-signal intensities on both T1- and T2-weighted images (Figures and ). Moreover, fatty elements were identified in the tumor on fat-saturated T1-weighted images (). Smear cytology of the endometrium was negative. Laboratory data, including serum concentrations of cancer antigens 125 and 19-9, carcinoembryonic antigen, and squamous cell carcinoma antigen, were within normal limits. We therefore suspected a benign right ovarian tumor, such as a mature cystic teratoma, and elected to follow the patient up closely without further treatment. Three months later, transvaginal ultrasonography demonstrated a multilocular cystic mass that differed markedly from that seen on referral to our hospital. Contrast-enhanced CT revealed a 10 cm sized multilocular cystic mass with heterogeneous enhancement (Figures and ). However, the peritoneal dissemination was stable and no new metastatic lesions were detected. As malignancy, including primary or metastatic ovarian tumor could not be excluded by the imaging studies, diagnostic laparotomy was performed. Examination of the pelvic cavity revealed a subserosal uterine tumor extending into the right broad ligament and total abdominal hysterectomy and bilateral salpingo-oophorectomy was performed.
The subserosal uterine tumor measured 10 cm in diameter and had a yellow-white cut surface; the cysts contained yellow serous fluid (). No areas of necrosis or hemorrhage were detected (). The endometrium was atrophic. Both ovaries and fallopian tubes were macroscopically normal. On histological examination, the uterine tumor showed features of lipoleiomyoma with a mixture of mature fat and fascicles of muscle fibers (Figures and ). It was infiltrated by well- to moderately differentiated carcinoma cells (Figures –), which on immunohistochemical staining were found to be positive for cytokeratin (CK) 7, CK20, and CDX2, but negative for estrogen and progesterone receptors (Figures and ). These features are compatible with metastatic adenocarcinoma of the previous gastric cancer, but not endometrial cancer infiltrating uterine myometrium (). Additionally, lymphatic permeation was detected in the body of the uterus. Peritoneal washing cytology analysis did not reveal any malignant cells.
The patient's postoperative course was uneventful, and she was discharged on the seventh day. The TS-1/CDDP chemotherapy was resumed and she remained alive with disseminated metastases 14 months after the surgery.


A 70-year-old man was admitted to our hospital for ileus and uncontrollable high blood pressure. His systolic blood pressure exceeded 160 mmHg, and oral diltiazem and amilodipin were initiated 5 days before the onset of ileus. Computed tomography showed a left adrenal mass and ileus (Fig. ). His consciousness level was low with incoherent speech. His body temperature was 37.4 °C, pulse rate was 126 bpm, blood pressure was 210/146 mmHg, and SpO2 was 98 % on room air. He appeared to be sweating profusely, with cold moist peripheries. Electrocardiogram showed sinus rhythm tachycardia and short PQ, high voltage, mitral P, and negative T on V4–6. Abdominal radiography showed large intestine expansion due to gas. Initial laboratory data showed low thrombocyte count (74,000/μL), normal white blood cell count (6000/μL), high levels of hemoglobin (16.3 g/dL), C-reactive protein (9.30 mg/dL), serum glucose (201 mg/dL), and blood urea nitrogen (48 mg/dL), and normal level of serum creatinine (1.05 mg/dL). Amino-terminal pro-brain natriuretic peptide was extremely high at 13,938.0 ng/mL.
We suspected pheochromocytoma on the basis of his computed tomography findings and clinical features. Doxazosin (2 mg/day orally), nicardipine (1.5 μg/kg/h i.v.), and landiolol (200 mg/day i.v.) were administered for blood pressure control. Because of the high fever, we suspected necrotizing enteritis due to ileus. Therefore, intravenous antibiotics were administered. Moreover, creatinine kinase and lactose dehydrogenase increased rapidly to 7066 and 609 IU/L, respectively. At that time, his body temperature was 40.1 °C. His respiratory state was aggravated after 3 days in the hospital, and oxygen was started. Laboratory tests showed that renal and liver functions were deteriorating. Five days after hospitalization, tracheal intubation was performed in the intensive care unit. Artificial ventilation and continuous hemodiafiltration were started.
The patient was diagnosed with PMC on the basis of the clinical course and radiological findings, without considering serum catecholamine levels. We performed emergency left adrenalectomy despite his critical condition, as he showed poor control and was refractory to medical treatment. Intraoperatively, the anesthesiologist used several types of antihypertensive drugs including doxazosin, landiolol hydrochloride, and diltiazem as necessary. Although temporary blood pressure was reduced to 80/46 mmHg after removal of the adrenal gland, the patient’s vital signs stabilized quickly after catecholamine infusion.
Postoperatively, the patient’s blood catecholamine levels intraoperatively were: epinephrine 10,351 (normal range ≤100 ng/mL), norepinephrine 27,654 ng/mL (normal range 100–450 ng/mL), and dopamine 209,500 ng/mL (normal range ≤20 ng/mL). The patient recovered rapidly postoperatively. One day postoperatively, his body temperature normalized. Furthermore, lactose dehydrogenase, creatinine kinase, liver function, respiratory status, and consciousness began to improve. He was weaned from ventilatory support at 2 days postoperatively, and from continuous hemodiafiltration and catecholamine administration at 3 days postoperatively. He was discharged 37 days postoperatively. Various imaging examinations including computed tomography and magnetic resonance imaging were performed during hospitalization to reconfirm the absence of metastatic mass. He has had no tumor recurrence or metastasis for 2 years.
The resected tumor was 12 × 11 × 8 cm in size and weighed 530 g, with prominent central necrosis and internal bleeding (Fig. ). Histologically, the tumor had a capsule and was comprised of basophilic granular cells with polygonal features (Fig. ). On immunohistochemistry, the specimen stained positive for chromogranin A, NCAM, and S100. Therefore, the tumor was identified as a pheochromocytoma. The cell proliferation index measured using an anti-Ki-67 antibody was 9.7 % (Fig. ).


A fifty-five-year-old female came into our department in November 2013, suffering from left PT, synchronous with her heartbeat, and CHL on the same side, from two years, with a sudden onset. General examination was normal. Otoscopy and neck evaluation were normal and lateral rotation of the head to the right or left had no effect on the tinnitus, although a mild digital compression over the internal jugular vein was able to eliminate it. Pure tone audiometry showed left-sided CHL, in the low frequencies tones. Immittance measurement showed bilateral type A tympanograms, with the presence of acoustic reflexes. Due to the fact that the patient reported an improvement in hearing during voluntary mastoid compression, we repeated the pure tone audiometry with a thumb placed on the left mastoid causing compression and, surprisingly, this resulted in a temporary normal hearing.
We also carried out a careful evaluation of tinnitus that included both evaluation by questionnaires for psychometric assessment and hyperacusis, as well as psychoacoustic assessment. Our protocol included (1) a through history with detailed interview; (2) questionnaire for hyperacusis [] and tinnitus handicap inventory (THI) []; and (3) our tinnitus test battery: tinnitus loudness and pitch matching, minimal masking levels (MMLs), and loudness discomfort levels (LDLs) []. The result was a monolateral, pulsatile tinnitus, with pitch over 3 kHz. LDLs did not show the presence of loudness sensitivity problems; psychometric test (THI) showed that tinnitus was easily masked by environmental sounds and easily forgotten with activities, but that it interferes with sleep. There were no significant results on other tests.
The patient underwent a MRI of the brain, which detected a vascular malformation in the left occipitotemporal region (). Angiography showed a type II DAVF of the left lateral sinus, according to Cognard classification [], composed of meningeal branches of middle meningeal artery and of anastomotic branches of left occipital artery (). The venous drainage was towards sigmoid sinus, left lateral sinus, and petrous sinus, against the stream of flow. The selective injection of the right internal carotid artery showed a 3 cm diameter supraclinoid internal carotid artery aneurysm. At the same time, the patient was taken up for neuroradiological intervention, where the fistula was treated with endovascular embolization wherein all the meningeal branches that fed fistula were occluded using Onyx glue, in the same session. Following this, there was a dramatic disappearance of the tinnitus. Moreover, pure tone audiometry showed a recovery of the CHL on the left side. The follow-up angiography (), after three months, showed a regression of the fistula and, at one year, the patient is completely asymptomatic and cured of tinnitus and the hearing threshold was stable.


A 42-year-old white man had a history of kidney cancer from 2005. At that time, his right kidney was removed, and RCC was concluded on the basis of histology. The disease was staged as T3apN0M0 (TNM-Union for International Cancer Control, TNM-UICC, 2010). The cancer was regarded as localized and no further investigation was undertaken at the time. In the winter of 2013, the patient consulted his general practitioner for increasing right-sided lateral chest pain. Computed tomography (CT) of his thorax revealed a lateral mass destructing his third rib, without penetrating through the pleural cavity. Several biopsies were obtained and the tumor was confirmed as clear cell RCC. However, the pathologist responsible had doubts about the correct histology and consulted experts in the field for a second opinion abroad. Techniques including Sanger sequencing of the candidate translocation region and fluorescence in situ hybridization (FISH) confirmed a translocation including TFEB (t6;11), which is diagnostic of RCC. Immunohistochemistry was positive for cathepsin K and Melan-A, which supported the diagnosis.
Further investigation of the patient with magnetic resonance imaging (MRI; Fig. ) of his vertebral column showed small lesions in his lower lumbar spine, suspicious of tumor spreading to his skeleton. This clinical picture, and the first immunohistochemical results showing intensive staining of cathepsin K, pointed to dysfunctional activity in osteoclasts, and linked therapeutic choices to autophagy and metabolism. He was referred to surgical resection of the part of his chest wall afflicted by a tumor mass, which was conducted at the University Hospital Oslo in September 2013. Postoperatively, he received irradiation to the tumor bed, 3 Gy per fraction to a total dose of 30 Gy.
Today, there is no commonly accepted treatment recommendation for non-RCC. Pending the final histology report, while having the clinicopathological suspicion of translocational RCC, several therapeutical strategies were discussed. In the light of no available standard treatment for patients with translocational RCC, a mammalian target of rapamycin (mTOR) inhibitor (everolimus 10 mg daily) counteracting phosphorylation of TFEB by mTOR complex 1 (mTORC1) [] and denosumab (120 mg subcutaneously every fourth week), a monoclonal antibody regulating osteoclast activity by targeting the RANK ligand, were both applied during and after postsurgical radiotherapy. This therapeutic strategy aimed to counteract the dysfunctional signaling effect in catabolism and bone reabsorption as described for TFEB tumors. In addition, the formerly nephrectomized patient had moderately reduced kidney function after the operation, and needed self-catheterization. Often tyrosine kinase inhibitors (TKIs) affect kidney function, supporting an mTOR pharmacological treatment instead of TKI for this patient. Unfortunately, everolimus led to thrombocytopenia and had to be reduced to 7.5 mg per day taken orally. During the next 2 months, the patient’s health deteriorated, and the mTOR-inhibitor therapy was eventually interrupted.
A new series of MRI (Fig. ) confirmed progression, with multiple additional bony lesions. The patient was treated with a broadly acting TKI, pazopanib (800 mg once daily) as second-line medical treatment, interfering with platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) pathways. At the same time, neither anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid (18F-FACBC) positron emission tomography (PET)/CT nor 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) PET/CT scans detected tumor spreading.
Acknowledging the difficulty in identifying a rational therapeutic approach, the patient consented to serial biopsies taken in February and June 2014, preceding the choice of a new treatment due to a major lesion in his sacrum. Both samples were then assessed molecularly by Agilent SureSelect exome capture with Illumina sequencing, and expression profiling using bead arrays from Illumina.
Ribonucleic acid (RNA) extraction from the tumor taken at the first time point was split in two parts and a TissueLyser (Qiagen) was used to disrupt the sample. RNA from both parts was extracted using a GenElute Mammalian Total RNA Miniprep Kit (Sigma-Aldrich), according to the manufacturer’s instructions. DNA was extracted from the tumor taken at the second time point, using the NucleoSpin Tissue Kit (Macherey-Nagel), according to the manufacturer’s protocol. Normal DNA was extracted from ethylenediaminetetraacetic acid (EDTA) blood using the NucleoSpin Blood Midi Kit (Macherey-Nagel), according to the manufacturer’s protocol. Normal and tumor DNA was subjected to whole exome sequencing using the SureSelect whole exome v5 and Illumina sequencing by synthesis technology (HiSeq 2500) following the supplier’s protocol. The resulting FASTQ files were further analyzed using an in-house developed pipeline for somatic event detection. Reads of the tumor and its matched control sample were separately mapped with BWA-MEM [] to human reference genome (build b37) with an added decoy contig, obtained from []. Sample-wise sorting and duplicate marking was performed on the initial alignments with Picard tools []. Genome Analysis Toolkit (GATK) tools [] were subsequently used for two-step local realignment around indels (in this step, both samples were processed together). Each sample’s pair-end read information was then checked for inconsistencies with Picard, and base-quality recalibration was performed by GATK.
Somatic variant calling on the sample pair was done with MuTect [] (somatic single nucleotide variant, SNV, detection), Strelka [] (somatic SNV and INDEL detection), DELLY [] (large-scale variation – deletions, duplications, translocations and inversions – detection) and VarScan2 [] (somatic copy number variation, CNV, analysis).
GATK tools were used for computing coverage statistics based on the recalibrated alignment files.
Most of the analysis (starting with the local realignment step) was limited to exome regions, defined by Agilent sequencing probes (for further details, see Additional file ).
One translocation was identified through sequencing, involving positions chr11:65,267,772 and chr6:41,659,234, involving the expected TFEB translocation previously described for this patient.
We identified 23 somatic single SNVs, and three insertion/deletion events. Among these, one mutated gene was located in the tumor necrosis factor (TNF) receptor pathway (MAP3K7, G110V), a pathway previously implicated in clear cell RCC []. However, no obvious candidate therapeutic target genes were identified as mutated.
A DNA copy number plot is shown in Fig. . Gain of a region of 1q including the gene KIF14 has previously been associated with fatal progression, and KIF14 was among the genes reported to be overexpressed in tumors with 1q []. We did identify a somatic mutation for this gene (H849Y), but the tumorigenic potential remains unclear. Other chromosome arm scale events with more or less clear breaks could be seen on chromosomes 1, 3, 18 and 22. Some chromosomes (9, 13, 19) appeared to be generally underrepresented by sequencing reads in the tumor, while some other chromosomes (for example 2 and 7) seemed to be affected by many smaller events.
Transcriptome analysis was performed using the TruSeq Stranded Total RNA with Ribo-Zero Gold from Illumina according to the manufacturer’s instructions. The RNAa-Seq library was sequenced using a HiSeq 2500 with a paired-end 2×100 base pair (bp) approach. The sequencing reads were mapped with TopHat2 [] to human reference genome/transcriptome (build hg19) and subsequently processed by the Cufflinks2 tools [] (cufflinks, cuffmerge, cuffdiff) in order to generate a gene-wise fragments per kilobase of transcript per million mapped reads (FPKM) expression (Table ).
A plot of normalized transcript counts is shown in Fig. . In order to estimate upregulation of transcription compared to a normal kidney, we obtained transcript counts from the RNA-Seq Atlas [] (Fig. ). In order to evaluate whether there was an expression effect of TFEB being overexpressed, we examined whether genes that previously had been reported as upregulated in transiently TFEB-overexpressed HeLa cells were also affected in the tumor (Fig. , TFEB curve). A marked curve shift towards higher transcript levels, compared to the full list of genes, was observed, indicating that the high TFEB level observed in the tumor also increased expression of the reported target genes. We also examined whether a previously reported gene set for coordinated lysosomal expression and regulation (CLEAR) was upregulated in the tumor, and this could also be observed. Moreover, TFEB expression is very high in the tumor, compared to TFEB expression levels observed otherwise in normal kidney tissues [, ].
The transcriptional profile confirmed the clinical suspicion of highly upregulated macro-autophagy and dysfunctional pathway activity in c-MET, MAPK, TSC2 and S100A9, and downregulation of mTOR, as previously reported relevant for this type of tumor (Fig. ). Treatment with an autophagy-inhibiting agent, hydrochloroquine 200 mg twice a day, was therefore started and subsequently increased to 400 mg twice a day, but stopped when progression was observed in July 2014.
Unfortunately, 5 months after the start of pazopanib, the CT and MRI evaluation confirmed progression, and the treatment was switched to another broad-acting TKI, sunitinib dose 37.5 mg per day, as third-line therapy.
In the wake of the genetic results and the approval of checkpoint inhibitor therapy, a second course of palliative radiotherapy was planned in late July 2014 (see Fig. ).
The second biopsy results gained from DNA pointed to enhanced autophagy gene signature and MAPK and AKT pathways downstream. On histological examination, cathepsin K and Melan-A were highly positive. Due to local pain in the patient’s chest wall, a second course of three-dimensional CT conformal radiotherapy encompassing pleural metastases (3 Gy per fraction, 5 days per week) was planned 4 weeks later, and sunitinib treatment was halted prior to radiotherapy. Acute pleural bleeding confirmed with a CT scan showed tumor growth after 8 fractions of radiotherapy, and further irradiation was abolished. Sunitinib treatment was discontinued.
In view of the young age of the patient and the specific staining for Melan-A expressing tumor cells [] (Fig. ), he was finally accepted for ipilimumab, targeting CTLA-4, activating the immune system, combined with third-line sorafenib treatment, a kinase inhibitor used in the treatment of renal cancer. Ipilimumab was withdrawn rapidly, due to controversies around combined treatment in the physicians group, exaggerated by temporary health deterioration of the patient. At last follow-up, 16 months after the diagnosis of translocational RCC, the patient’s sorafenib treatment stopped due to disease progression and he died shortly afterwards.
Attempts of cell culture of excess cell material from the bone biopsy in medium were unsuccessful.


A 53-year-old woman, resident in Germany, was admitted to the emergency department because of confusion, aphasia and agitation. Her partner reported that she had complained about neck pain for a few weeks which had been interpreted as being related to a herniated cervical disk in an X-ray examination seven days ago and treated with analgesics. Furthermore, the patient had suffered from unspecific flu-like symptoms in the previous week and intermittent diarrhea during the previous two months. Her past medical history revealed a chronic obstructive pulmonary disease based on nicotine addiction, a chronic pain syndrome following repeated vertebral disk herniation, obesity, and appendectomy as well as surgical repair of an epigastric and umbilical hernia six years ago. Because of the chronic lumbar pain, she had been under long-term morphine treatment with suspicion of morphine addiction, but had not received intraspinal steroid/analgesics injections for several months.
On physical examination, she had a body temperature of 38.6 °C; pulse rate and blood pressure were within the normal range. In the examination of respiratory system, cardiovascular system, and abdomen, no abnormalities were detected. The neurological examination also showed no abnormalities, especially no meningism and no neurological deficits, apart from the confusion, aphasia and agitation. Laboratory analysis at admission (Table ) revealed a pronounced leukocytosis with an increase mainly in the neutrophil granulocytes, and a strongly elevated serum C-reactive protein level, indicating an infectious cause of the patient’s symptoms. Furthermore, a rise of lactate dehydrogenase, liver enzymes and cholestasis parameters, and a hyponatremia were observed. In the emergency department, a magnetic resonance tomography of the brain was performed, but demonstrated no abnormalities apart from first signs of a subcortical arteriosclerotic encephalopathy.
An immediate lumbar puncture was not successful because of the patient’s agitation, but was conducted on the second day of admission, when nuchal rigidity emerged. Because of strongly suspected bacterial meningitis, antimicrobial treatment with ceftriaxone (4 g daily in two divided doses) and ampicillin (12 g daily in six divided doses) was started. Analysis of the cerebrospinal fluid (Table ) was consistent with bacterial meningitis, showing 1,657 leukocytes per μl, increased protein, undetectable glucose and increased lactate. Cerebrospinal fluid was also subjected to microscopic Gram stain examination and routine culture: The Gram stain revealed a high number of Gram-negative rods, and Escherichia coli grew on the culture plates. Species identification was performed by Matrix-Assisted Laser Desorption / Ionization (MALDI) Time of Flight (TOF) Mass Spectrometry (Bruker Daltonics, Bremen, Germany), and antimicrobial susceptibility testing was done by microdilution in accordance with European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommendations [], using pre-configured microtiter plates (MERLIN Diagnostika GmbH, Bornheim-Hersel, Germany). The Escherichia coli strain exhibited elevated minimum inhibitory concentrations (MICs) for aminopenicillins (amoxicillin: >128 mg/l, amoxicillin/clavulanic acid: 128/2 mg/l), oxyimino-cephalosporins (cefotaxime: 16 mg/l, ceftazidime: 2 mg/l), fourth-generation cephalosporins (cefepime: 64 mg/l) and monobactams (aztreonam: 16 mg/l), a synergy phenomenon in the double-disk synergy test with amoxicillin/clavulanic acid consistent with an ESBL, and a positive polymerase chain reaction (PCR) for blaCTX-M-9 group. In contrast, it showed low MICs to piperacillin/tazobactam (≤1/4 mg/l), carbapenems (imipenem: 0.0625 mg/l, meropenem: ≤0.03125 mg/l, ertapenem: ≤0.0625 mg/l, doripenem: ≤0.03125 mg/l) and fluoroquinolones (ciprofloxacin: ≤0.015625 mg/l, levofloxacin: ≤0.0625 mg/l), and was also susceptible to several other types of antibiotics such as aminoglycosides, trimethoprim/sulfamethoxazole, tigecycline, colistin and fosfomycin. In multilocus sequence typing (MLST), the strain was assigned to ST73. On the second day after admission, the initially taken blood cultures also flagged positive for ESBL-producing Escherichia coli. Of note, the patient’s ESBL carriage was not previously known. The antimicrobial therapy was switched to meropenem (6 g daily in three divided doses).
After pathogen identification, additional diagnostics was performed to exclude a primary focus of infection: Although a urine culture yielded an Escherichia coli strain having the same antimicrobial susceptibility pattern, the patient’s past medical history was negative for urinary tract infection symptoms. Furthermore, chest X-ray, abdominal ultrasound and transesophageal echocardiography conducted at admission and / or during the further hospital stay merely showed degenerative changes in the spine and an early-stage atherosclerosis, but did not reveal a primary focus. Thus, a magnetic resonance tomography of the spine was added in consideration of the patient’s neck pain even though that pain had already been attributed to a herniated cervical disk. However, magnetic resonance tomography showed a large descending retropharyngeal abscess with a cervical spondylodiscitis at C2-C3 down to C4-C5 and a secondary spinal canal stenosis (Fig. ). Additionally, multiple disk protrusions were found, especially in the lumbar spine. Thus, the search for a source of meningitis, initiated because of the unexpected pathogen identification, led to diagnosis of previously unrecognized retropharyngeal abscess and cervical spondylodiscitis. In addition to continued meropenem treatment, the patient was immediately subjected to neurosurgery: The abscess was evacuated including polymethylmethacrylate-assisted ventral diskectomy. Intraoperative swabs also yielded the ESBL-producing Escherichia coli.
Initially, therapy was complicated by morphine withdrawal delirium requiring sedation of the patient. Then, the patient’s condition rapidly improved, and she had fully recovered without any neurological sequelae when meropenem treatment was stopped after 21 days (14 days after source-control surgery). Control computer tomography and magnetic resonance tomography three weeks and two months after admission, respectively, both proved complete remission of the retropharyngeal abscess and the spondylodiscitis. Nevertheless, hospitalization was prolonged because of secondary complications including prolonged dysphagia subsequent to the retropharyngeal abscess and several hospital-acquired infections. Specifically, the patient required mechanical ventilation in the course of two hospital-acquired pneumonia episodes, the first episode empirically treated with 7 days ceftriaxone and erythromycin, the second with 7 days imipenem. Then, she received 7 days vancomycin for treatment of Enterococcus faecium bacteremia. In addition, she developed bilateral trochanteric decubitus ulcers due to being bedridden for weeks. ESBL-producing Escherichia coli was isolated from those decubitus which were subsequently treated surgically and with 10 days ciprofloxacin. Finally, the patient received 12 days caspofungin because of candidemia. Of the antimicrobials used for therapy of the hospital-acquired infections, imipenem and ciprofloxacin also had in vitro activity against the meningitis-causing Escherichia coli strain. However, neither clinical nor radiological signs of a meningitis relapse occurred after cessation of meropenem, which may indicate that the meningitis had already been cured at the time-point of meropenem cessation. After all, the patient was discharged from hospital in good health three months after admission.


A 45 year old Hispanic woman presented with fever, vomiting and abdominal distention for 5 days. Vital signs revealed hypertension and tachycardia. Physical examination revealed abdominal distention and tenderness with a palpable mass in the right lower quadrant. The abdominal CT on admission revealed a partial small bowel obstruction and a right colonic mass. She underwent an exploratory laparotomy with a right hemicolectomy with ileotransverse colon anastomosis. Pathological findings discovered extensive amebic colitis with perforation, necrosis, acute and chronic inflammation with abscess formation and peritonitis in the terminal ileum and right colon. Microscopic examination of the terminal ileum and right colon revealed multiple flask shaped ulcers and numerous E. histolytica trophozoites. One week later she developed peritonitis secondary to an anastomotic leak that required another exploratory laparotomy with resection of the ileotransverse anastomosis and creation of an ileostomy. She was subsequently discharged on metronidazole therapy. Five months later she was readmitted for ileostomy takedown and ileocolonic anastomosis. Nine months after her first admission, she presented complained of diarrhea and hematochezia for 6 months. An upper endoscopy found an extraluminal mass close to the fundus of the stomach. Abdominal CT revealed an amebic liver abscess. She was treated with metronidazole for 2 weeks followed by paromomycin for 1 week.


An 83 year old Hispanic woman presented with weakness, diarrhea, abdominal cramps, tenesmus for 2 weeks. Her concurrent medical problems included hypertension, diabetes and a stroke. Vital signs revealed hypotension. Significant physical examination included abdominal distention and hypoactive bowel sounds. Laboratory findings were significant for anemia, leukocytosis with a bandemia, hyponatremia and hyperglycemia. A colonoscopy was done 2 days later and revealed multiple ulcers throughout the entire colon and rectum. Histopathology of the biopsy specimens revealed amebiasis with deep ulcerations in the distal transverse, proximal descending and rectum. She was treated with metronidazole for 2 weeks followed by paromomycin for 1 week.


A 38 year old Hispanic man presented with fever, chills, weakness, nausea, vomiting, loss of appetite and watery diarrhea for 1 week. His concurrent medical problems included hepatitis C. Vital signs revealed a high grade fever and tachycardia. Physical examination was significant for diffuse abdominal tenderness. Laboratory findings were significant for leukocytosis and hyponatremia. Stool studies revealed E. histolytica trophozoites. Five days after admission, a colonoscopy revealed rectosigmoid ulcerations with histopathology showing acute and chronic colitis. He was discharged on a 10 day course of metronidazole and paromomycin. Seven days after being discharged, the patient was readmitted for right upper quadrant pain and shortness of breath. Abdominal CT revealed two large liver abscesses that were subsequently drained by interventional radiology and found to be positive for E. histolytica. He was subsequently discharged and retreated with a 10 day course of metronidazole followed by paromomycin for another 10 days.


A 46 year old Hispanic man presented with watery diarrhea for 1 month that became bloody within the last 2 weeks. Vital signs revealed tachycardia. Physical examination findings were significant for abdominal distention and diffuse tenderness to palpation and guarding. Laboratory findings were significant for leukocytosis, anemia, hyponatremia, hypokalemia and hyperglycemia. Stool studies revealed E. histolytica trophozoites. One day after admission, a colonoscopy revealed rectosigmoid colitis and ulceration with histopathology revealing surface ulcerations covered by fibrinous exudate containing hemophagocytic amebic trophozoites (Figs. , a, b). He was subsequently discharged with a 2 week course of metronidazole followed by paromomycin for another 20 days.


A 70 year old Hispanic man presented with abdominal pain and watery diarrhea for 10 days. Concurrent medical problems included diabetes mellitus. Physical examination findings included abdominal tenderness to palpation at the left lower quadrant. Laboratory findings were significant for leukocytosis with a bandemia, anemia, hyponatremia and hyperglycemia. Stool studies revealed E. histolytica trophozoites. Amebic serology was positive. One day after admission, a colonoscopy revealed pancolitis with multiple ulcerations throughout the entire colon with histopathology revealing mucosal edema, ulcerations and necrosis with fibrinous exudate containing hemophagocytic amebic trophozoites. He was subsequently discharged with a 2 week course of metronidazole.


A 60 year old Hispanic woman presented with watery diarrhea and abdominal pain for 2 weeks. Concurrent medical problems included ulcerative colitis for more than 20 years, currently being treated with prednisone and sulfasalazine. Physical examination findings included diffuse abdominal tenderness. Laboratory findings were significant for leukocytosis and anemia. Stool studies revealed E. histolytica trophozoites. Amebic serology was positive. One day after admission, a colonoscopy revealed diffuse inflammation and multiple pseudopolyps. Histopathologic examination was consistent with acute and chronic colitis with superficial erosions, focal liquefactive necrosis and amebic trophozoites. The patient was subsequently discharged with a 2 week course of metronidazole followed by 10 days of paromomycin.


A 45 year old Hispanic man presented with hematochezia and rectal pain for 2 weeks. Vital signs were significant for hypotension. Physical examination findings of the abdomen were unremarkable. However, rectal examination was positive for occult blood but no masses were felt in the rectal vault. Laboratory findings were significant for leukocytosis, severe anemia, hyponatremia and hypokalemia. One day after admission, a colonoscopy revealed pancolitis with severe proctitis and perirectal ulcerations (Fig. ). Histopathologic examination was consistent with acute colitis with amebic trophozoites (Fig. a, b). The patient was subsequently discharged with a 2 week course of metronidazole followed by 20 days of iodoquinol.


A 44 year old Hispanic man presented with diarrhea for 7 days prior to admission followed by constipation, rectal discomfort, and melena. Past medical history was significant for hepatitis C infection. Physical examination findings included diffuse abdominal tenderness. Lab results were significant for elevated transaminases and total serum bilirubin of 1.2 mg/dL. Stool examination was positive for Clostridium difficile toxin. An abdominal and pelvic CT scan showed thickening of the rectal wall. A subsequent colonoscopy showed a normal terminal ileum, with congested, erythematous, eroded, granular mucosa throughout the colon and rectum. No areas of ulceration or erosions were present. Biopsies revealed focal active colitis and microorganisms compatible with E. histolytica. Amebic serology was positive. He was treated with metronidazole for 14 days, for C. difficile infection and invasive amebiasis.


A 76 year old Hispanic man presented with intermittent hematochezia for 6 months and a 20 pound weight loss. Physical examination of the abdomen was unremarkable. Lab results were significant for anemia. Abdominal CT showed soft tissue densities of the sigmoid colon with extra colonic invasion and associated perilesional adenopathy and liver metastases. A subsequent colonoscopy revealed two fungating and ulcerated partially obstructive masses in the distal sigmoid colon and distal descending colon. Pathological findings confirmed a sigmoid adenocarcinoma, with positive amoeba on PAS stain. Liver biopsy showed metastatic poorly differentiated adenocarcinoma. An amebic serology was positive at a titer of 1:256. Due to persistent hematochezia, a sigmoid resection followed by formation of a colostomy was performed. Pathology of the sigmoid colon mass from the segmental colectomy showed invasive adenocarcinoma of the sigmoid colon, with the tumor invading the entire thickness of the colonic wall, pericolic soft tissue, and directly invading an adjacent segment of colon with direct extension into the mucosa forming a secondary mucosal ulcerated mass. The original ulcerated tumor bed was invaded by trophozoites of E. histolytica with organisms present in the necrotic and inflammatory debris and infiltrating the tumor parenchyma. In our case this was an adenocarcinoma infiltrated by amebic trophozoites and not an ameboma. Treatment was with metronidazole IV for 14 days followed by paromomycin for 7 days.


A 25-year-old white woman with a documented history of TA and total occlusion of her left main coronary artery received a CABG (LITA-LAD) in 2004. In 2012, two episodes of angina, due to graft failure, were treated by percutaneous coronary interventions using a Xience Prime drug-eluting stent. Unfortunately she was referred back to our hospital with signs of unstable angina after an initial symptom-free period of 4 months. During this period she received two platelet inhibitors (ticagrelor 90 mg, orally twice a day and Ascal (carbasalate calcium) 80 mg once a day), metoprolol 150 mg, ramipril 2.5 mg, simvastatin 40 mg, isosorbide mononitrate 60 mg twice a day and one dose of methotrexate (2 mg) every week in combination with folic acid. A clinical examination showed no abnormalities, besides a significant difference in blood pressure to the prejudice of the left side with absent radial pulsations. Her chest X-ray showed a normal heart size. A 12-lead electrocardiogram showed T-wave depression in the precordial and lateral leads. Blood biochemical and hematological parameters, including cardiac enzymes, were within normal range. A computed tomography angiogram was performed revealing a thickened aortic wall at the level of the aortic arch with a normal diameter and occlusion of her left subclavian and left pulmonary artery. The coronary angiogram revealed a total occlusion of her left main coronary artery and recurrent graft failure, with significant double in-stent restenosis of 99 % in the LITA-LAD. Her left coronary system was filled by collaterals from the right, dominant, system (Fig. ).
In consultation with the patient we decided on a re-CABG using a Dacron (Vascutek®, Renfrewshire) patch on her aorta for the proximal anastomosis which was performed on 6 September 2012. Intraoperatively we encountered a thickened and inflamed aortic wall, in which the left lateral side was severely affected. We performed redo CABG using a SVG to the anterolateral, first diagonal and LAD. For the proximal anastomosis an oval Dacron (Vascutek®, Renfrewshire) patch was tailor-made by the surgeon and attached to her side-clamped aorta. Subsequently, the venous graft was sutured into the patch using prolene. Biopsies from the ascending aortic wall and the LITA proximal to the stent were taken. Histological examination of the aortic wall specimen demonstrated extensive changes including significant intima proliferation without calcification and a nonspecific chronic inflammatory response with widespread fibrosis (Fig. ). The LITA specimen showed some reactive changes but no specific inflammatory characteristics. Both the intraoperative and postoperative courses were uneventful and the patient was discharged 5 days after surgery. Fraxiparine (nadroparin) injections (0.3 ml) were added to the medical regimen and Ascal (carbasalate calcium) dosage was increased to a 100 mg once a day.
Since then, the patient routinely visits the cardiology out-patient clinic. Her last examination (October 2015) revealed no signs of recurrent coronary perfusion problems: she reported no angina complaints during exercise, an electrocardiogram revealed no abnormalities and echocardiography showed no signs of left ventricular dysfunction or wall-motion abnormalities. Since December 2014 she stopped taking methotrexate because of an active pregnancy wish. Despite the withdrawal of immunosuppressive medication her TA is still in remission to date.


A 52-year-old woman was referred to a nephrologist for work-up of proteinuria and slightly increased serum creatinine levels found during a routine health examination. The patient had been aware of her proteinuria for 2 years. However, she had not undergone further evaluation or treatment. The patient had no other relevant medical history.
The laboratory results of complete blood count and blood chemistry assay were represented in Table . Urinalysis revealed 1+ protein with normal pH, and the results were negative for glucose. Random urine chemistry showed a state of glomerular proteinuria as the results revealed creatinine level of 1847.56 μmol/L (20.9 mg/dL), microalbumin level of 0.04869 g/dL (486.9 mg/L), and an albumin/creatinine ratio of 2329.7 mg/g. The protein level in the 24-h urine sample was elevated to 2.62 g. The patient was then found to have a monoclonal protein concentration of 5.2 g/L in serum and 0.01 g/L in urine. The serum and urine monoclonal protein fractions were found to represent IgG and kappa in immune fixation electrophoresis. The free kappa and lambda light-chain levels in the serum were 571.6 mg/L and 23.3 mg/L, respectively, and the serum free light-chain ratio was 24.53 (0.26 − 1.65). There was no evidence suggesting hepatitis B or C virus or human immunodeficiency virus infection on serologic tests.
An ultrasound-guided kidney biopsy was performed; the final pathologic diagnosis was FSGS. Among 16 glomeruli, seven showed global sclerosis and two showed segmental glomerulosclerosis (Fig. ). Mild tubular atrophy, mild interstitial fibrosis, and focal tubular necrosis were observed. Interestingly, proximal tubular epithelial cells contained some crystalline structures (Fig. ). Congo red staining also produced negative results. Interstitial inflammation with mild infiltration of lymphocytes was noted. Immunofluorescence microscopy showed a linear pattern with trace intensity for IgG and a granular pattern for complement component C3 (++), C1q (+), and fibrinogen (trace) in the glomerulus (Fig. ). However, there was no significant positive staining for IgA, IgM, or C4. On performing immunofluorescent staining, the mesangium, tubules, interstitium, and vessels were negative for staining. However, many of the tubular cells showed stronger positivity for the kappa light chain than for the lambda light chain on immunohistochemical staining.
Electron microscopic examination revealed diffuse effacement of foot processes and electron-dense deposits, with some crystalline structures in the cytoplasm of visceral glomerular epithelial cells. Furthermore, similar electron-dense crystalline deposits found in podocytes were observed throughout the cytoplasm of proximal tubular cells (Fig. and ). These showed diverse morphology with a needle shape or a rhomboid shape and variable size ranging from 0.2 × 1 to 0.5 × 2.8 μm2. However, no pathologic abnormalities were noted within the glomerular basement membrane, mesangium, or glomerular endothelium.
A BM examination was performed to investigate for the presence of plasma-cell neoplasms. The BM aspirate smears were stained with Wright’s stain. The plasma cells with fine needle-shaped intracellular crystalline depositions were found to have increased in number, representing up to 10.4 % of the total nucleated cells counted (Fig. ). Typical plasma cells were rarely observed. All of the cells with intracellular cytoplasmic crystalline inclusions were negative for α-naphthyl acetate esterase (ANBE) staining, suggesting that macrophages such as histiocytes were not involved. The paraffin-embedded BM biopsy and clot sections were stained with hematoxylin and eosin. The cellularity of the BM was 30–40 %, that is, she had normocellular marrow for her age. Cells with red-colored cytoplasmic inclusions and eccentric mononucleosis, which seemed to be malignant plasma cells, were frequently seen in the clot sections (Fig. ). Immunohistochemical staining was performed on the BM clot sections with antibodies against CD138, kappa light-chain, and lambda light-chain. Plasma cells stained with CD138 were seen in these sections more frequently than in the aspiration smear. The plasma cells showed strongly positive staining for kappa light-chains (Fig. ). However, a few of the plasma cells were positive for lambda light-chain staining. Masson’s trichrome staining was performed on clot sections to evaluate the characteristic features of the crystalline deposits. The plasma cells had deep-red-colored cytoplasmic inclusions with fine needle-shaped structures (Fig. ). These cells were negative in periodic acid-Schiff staining.
The complex karyotype of 44,X,-X,-6,-21,+mar[2]/46,XX[53] was determined by conventional karyotyping using the BM specimen. The fluorescence in situ hybridization studies for detecting cytogenetic abnormalities such as TP53 deletion, 13q14 (RB1) deletion, 1q trisomy, and rearrangement of IgH/MAF - t(14;16), IgH/FGFR3 - t(4;14), IGH/CCND1 - t(11;14) were found to be negative.


A 53-year old man presented in the emergency room because of suddenly onset of chest pain, nausea and then syncope for several minutes. Previous medical history included neurodermitis for which ebastine and ketotifen were given but proven ineffective, so thalidomide (150 mg/d) therapy was initiated 2 weeks before; medical history also included hypercholesterolemia and simvastatin taking. No other medication including corticosteroids was reported and electrocardiography (ECG) in the past was almost normal (Fig. ). The patient did not exhibit any other established risk factors for coronary artery disease, such as obesity, diabetes, hypertension or family history, with the exception of current smoking. Physical examination on admission revealed a heart rate of 47 bpm, blood pressure of 96/61 mmHg and normal SpO2 (98 % without oxygen). The 12-lead ECG showed sinus rhythm with a first-degree AV block and complete right bundle branch block (CRBBB), and I, aVL, V2-4 leads ST segment elevation (Fig. ); about 1 h later repeated ECG showed third-degree AV block but no ST-T dynamic change (Fig. ). So the diagnosis of acute coronary syndrome was suspected. The treatment of aspirin and clopidogrel was initiated for anti-platelet after which patient’s chest pain relieved partially, but intravenous nitroglycerin was avoided because of relatively low blood pressure and slow heart rate. 1 h after presentation, emergency coronary angiography was conducted and demonstrated no flow-limiting lesions in coronary arteries except minor atherosclerosis (Fig. ), and meanwhile temporary pacemaker was implanted (Fig. ). Hours later the patient was admitted into cardiac care unit, blood tests showed LDL-C level 2.23 mmol/L and cardiac troponin I (cTnI) level elevated significantly (maximum 50.83 μg/L reached at 24 h after symptoms onset, normal upper limit was 0.04 μg/L; Fig. ). And echocardiography only showed hypokinesis of middle and inferior segment of anterior wall with normal ejaculation fraction (EF) of 53 %, without tricuspid regurgitation or pulmonary hypertension, and no evidence of left or right-sided heart thrombi or right-left shunt was found; 99mTc-MIBI myocardial perfusion single photon emission computed tomography showed reduced perfusion in the middle anterior wall of left ventricle; and further cardiac magnetic resonance imaging (MRI) showed thinning of apical anterior wall of left ventricle and subendocardial late gadolinium enhancement (Fig. ). So it was likely that acute coronary event had happened. In CCU we continued aspirin for anti-platelet, but 2 days later patient’s SpO2 fell to 95 % at 10 L/min oxygen with reservoir mask, and D-dimer level elevated significantly (3.06 mg/L, normal range within 0.55 mg/L). Further ultrasound examination found no thrombi in deep veins of both lower limbs, but computed tomography pulmonary angiography (CTPA) revealed scattered embolism of subsegmental pulmonary arteries of both sides (Fig. ). Tests for hypercoagulability was ordered and demonstrated normal coagulation parameters (also including factor V Leiden mutation and levels of protein C, protein S and anti-thrombin III), normal homocysteine level, negative anti-nuclear antibodies, anti-cardiolipin antibodies, lupus anticoagulant and tumor markers. So thalidomide was thought to be the cause of hypercoagulability, and this medication was ceased immediately; therapeutic low molecule weight heparin was initiated and then switched to warfarin with a target INR of 2 ~ 3, and nifedipine was given for coronary spasm. The patient reported no symptoms after therapy modification and SpO2 rose up to normal (97 % without oxygen) gradually, and third degree AV block also disappeared during hospitalization with temporary pacemaker removed (Fig. ). After discharge, patient was followed up over a period of 12 months, and warfarin was continued for 3 months with appropriate INR. No further recurrences of chronotropic or ischemic cardiac symptoms were reported.


A 41-year-old man with a background of hereditary spastic paraplegia was not tolerating the side effects of oral baclofen and underwent ITB pump placement subcutaneously in the right lower quadrant of the abdomen. He regularly competes as an international power canoeist, and has a muscular build.
Ten months following ITB placement, he attended clinic with a history of pump site discomfort. On examination, the implanted pump had eroded a substantial amount of subcutaneous adipose tissue and the overlying skin was erythematous and tender. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were both within normal range. Whilst the overlying skin was intact on presentation, computed tomography demonstrated a fluid collection posterior to the pump. The fluid was aspirated with a needle, and was confirmed sterile on Gram stain microscopy and culture; this fluid was sampled for microbiological analysis and determined to be sterile. Twelve weeks later, the pump was re-sited to the right medial thigh. Intraoperatively, the pump was disconnected and removed from the original site. There was no evidence of infection in the pump cavity. A medial mid-thigh transverse incision was made and a subcutaneous pouch was created, into which the original pump was inserted. A new catheter was connected to the pump. It was first tunnelled out through an intermediate proximal thigh incision, in which the tubing was anchored to the muscle fascia (Fig. ). Subsequently, the same catheter was tunnelled to the original abdominal pouch, where it was connected to the original distal spinal catheter with a straight connector. The pouch was irrigated with gentamicin solution and closed in layers.
Eight months later, the patient presented to his general practitioner complaining of swelling around the revised placement site. For the next 6 months he described intermittent episodes of warmth and erythema at the pump site that worsened during his physical training regime. Towards the end of this period we reviewed the patient in clinic and concluded that this swelling was likely precipitated by exercise. Ten days subsequent to this clinic visit, he was admitted due to increased swelling, pain and ulceration at the pump site. CRP, ESR and white blood cell count (WBC) were all normal. He underwent further surgery: the lateral part of the wound was reopened and thin, inflamed skin edges excised. The wound was washed and closed. Microbiological assessment of the excised skin edges revealed no evidence of infection.
At 1-month post-operative follow-up, evidence of dehiscence was still present along with underlying haematoma formation. Thinning of skin and small discharging vesicles were noted lateral to the scar. The patient underwent further surgery under the plastic surgery and neurosurgery team. The wound was debrided and washed out. A new proximal pocket was developed superficial to the deep fascia anterior to the thigh and the pump was re-sited for a second time. At post-operative follow-up, the patient was well and the wound was well healed. Six months later, there was no collection surrounding the pump, the patient was receiving regular ITB pump refills and is able to train without difficulty.


A 30-year-old man with a background of cerebral palsy and spastic diplegia had a right flank ITB pump inserted 7 years previously. During a routine follow-up clinic, the ITB pump was visibly protruding through the subcutaneous tissue of the abdominal wall (Fig. ). This complication occurred following a period of significant weight loss after his recent move to university. Otherwise, the patient was apyrexial and there was no erythema, purulent discharge or raised temperature in the skin. WBC and CRP were normal.
Six days later, the patient underwent a re-siting procedure. The old transverse wound was opened and the original pump was dissected from its capsule. It was then inserted into the potential space developed between the superior rectus abdominus and the posterior rectus sheath. The pump was anchored to the posterior rectus sheath with polyester suture. A new proximal catheter was attached to the pump and brought out superficial to the superficial linea alba, where it was connected to the old distal catheter using a straight connector (Fig. ). The wound was closed in layers.
The patient was monitored in the ITB pump clinic, where he received regular refills. Twelve months later, the pump was stable and the wound remained intact.


A 62-year-old male presented to the hospital’s emergency department with right-sided mild hemiataxia and mild hemiparesis. Fourteen days prior to admission, the patient had noticed numbness of the fourth and fifth finger of the right hand, which continued to spread up the entire arm. The medical history included hypertension with a prescription of ramipril 5 mg daily.
Initial physical examination revealed a mild hemiparesis with hemiataxia and choreiform movements of the right leg. His left extremities showed increased reflexes-levels as well as a right-sided positive Babinski sign. Otherwise he was in good medical condition. Blood pressure was 140/90 mmHg.
Initial sonographic studies showed a right-sided pulsatile Doppler-signal in the common and internal carotid arteries, suggestive of distal stenosis. In addition, there was moderate increase in flow velocities in the basilar-artery. In contrast the Doppler-spectrum in the intracranial vessels indicated widespread obliteration. Numerous arterial vessels suggestive of leptomeningeal and lenticulostriate collateral arteries revealed a strong collateral flow (Figs. and ). These findings were interpreted as evidence of moyamoya-syndrome. MRI-angiography (3 Tesla) also suggested the suspected disorder; both middle cerebral arteries were obliterated (Fig. ). The diagnosis was eventually verified using conventional angiography, which revealed severe stenoses of the internal carotid arteries in the siphon portion, the obliterated vessels of the circle of Willis and the extended collateral leptomeningeal and lenticulostriate network (Figs. and ).
Further diagnostic including brain imaging revealed the disease burden caused by the vasculopathy. A hypodense lesion dorsolateral to the left-sided caudate nucleus, measuring 15 × 7mm, was detected in the CT scan. Magnetic resonance imaging (diffusion weighted imaging on MRI) showed bilateral water shed ischemic lesions at various stages of development suggesting a haemodynamic infarction mechanism (Fig. ). MRI findings also indicated previous old haemorrhage in the left-sided putamen.
A cardiac workup revealed a persistent foramen ovale without any indication for deep venous thrombosis or pulmonary embolism. Holter-ECG provided no evidence for an arrhythmia such as atrial fibrillation. An etiological workup ruled out autoimmune disorders and the cerebrospinal fluid showed no abnormalities. As no cause was found, the patient was diagnosed with moyamoya disease.
The patient was prescribed a medication with aspirin and simvastatin. Due to recurrent symptoms during hospitalization (dysarthria, worsening of hemiparesis) clopidogrel was added to the treatment plan for 3 months. At discharge, the patient only suffered from mild hemiparesis. On subsequent follow-up, the vascular status did not change and clinically the patient recovered entirely. After 3 months, the secondary prevention treatment plan was reduced to aspirin as single therapy.


A 41-year-old Hispanic male was brought to our hospital ED after having a witnessed tonic-clonic seizure on the street. His past medical history was significant for polysubstance abuse (heroin, cocaine, benzodiazepines, and methadone) and chronic liver disease (hepatitis C). He had history of multiple admissions to our institution for opiates detoxification. On arrival to ED his vital signs were as follows: blood pressure of 98/63 mmHg, heart rate of 118 beats/minute, respiratory rate of 48 breaths/minute, temperature of 37.5°C, and an oxygen saturation of 90% while receiving oxygen by a non-rebreather mask. Emergency Medical Services (EMS) staffing reported finding a bag of K2 at the scene. Physical examination was remarkable for bilateral rales on lung auscultation. Old needle puncture areas were found over his arms and legs, without erythema. Pupils were equal with positive light reflex. While in ED, he was combative and developed another tonic-clonic seizure episode. Endotracheal intubation was performed and he was placed on mechanical ventilation. Remarkable laboratory findings included a white blood cell (WBC) count of 29.5 K/mm3 (4.8–10.8), a bicarbonate level of 15 mmol/L (24–31), a lactic acid level of 4.4 mmol/L (0.5–2.2), and a urine toxicology screen positive for opiates, benzodiazepines, and methadone. Creatine kinase (CK) level was 5,590 U/L (25–215), and troponins were mildly elevated at 1.45 ng/mL (<0.1). Creatinine, coagulation, and liver function profiles were within normal limits. Arterial blood gas (ABG) while on mechanical ventilation and receiving FIO2 of 100% showed a pH of 7.14 (7.35–7.45), a pCO2 level of 79 mmHg (34–45), and a paO2 level of 77 mmHg (80–100). Initial chest X-ray (CXR) showed bilateral infiltrates (). Electrocardiogram (ECG) showed sinus tachycardia without ST-segment or T-wave abnormalities ().
He was admitted to the intensive care unit (ICU) with the diagnosis of acute hypoxemic/hypercapnic respiratory failure presumptively secondary to drug overdose. He required propofol, fentanyl, and midazolam to achieve adequate sedation and ventilatory synchrony. Empiric intravenous antimicrobial therapy consisting of piperacillin/tazobactam (3.375 grams every 6 hours) was initiated for the possibility of aspiration pneumonitis. While in ICU, CK and troponin levels continued to increase to 18,589 U/L and 8.76 ng/mL, respectively. A new transthoracic echocardiogram (TTE) showed markedly decreased left ventricular ejection fraction of 30% (55–65), with severe global and segmental hypokinesis and no vegetations or valvular dysfunction. Given the echocardiographic and CXR findings as well as the elevated troponin levels, therapy for acute congestive heart failure probably secondary to a non-ST-segment elevation MI was initiated with low-molecular weight heparin, β-blockers, aspirin, clopidogrel, diuretics, statins, and angiotensin-converting enzyme (ACE) inhibitors. Repeated CXR after 24 hours showed near resolution of bilateral infiltrates (). Blood, urine, and respiratory cultures were negative and antimicrobials were discontinued. He was extubated on day 4 of ICU admission but required reintubation because of severe agitation and hypoxemia, which were thought to be a clinical component of a possible withdrawal syndrome. His ICU course was further complicated by fevers, new bilateral infiltrates on CXR, and persistently elevated FIO2 requirements. TTE was repeated, showing a remarkable improvement of left ventricular ejection fraction (63%), with a complete resolution of wall motion abnormalities. He was successfully extubated on day 11 of ICU admission, after being treated for acute respiratory distress syndrome (ARDS) secondary to ventilator-associated pneumonia.