A 69 year old Hispanic female with a past medical history significant for hypertension, diabetes mellitus, coronary artery disease status post revascularization, ischemic cardiomyopathy and chronic kidney disease had presented to our hospital for further evaluation and care. For the past few months the patient had suffered weight loss (approximately 30–35 lb), generalized malaise, low grade fevers (99.9 F), non-productive cough, myalgias and arthralgias. She did not endorse any night sweats or recent travel history, and there were no sick contacts at home. Prior to admission to our institution the patient was at an outside hospital and was being treated for sepsis with combinations of antibiotics including intravenous vancomycin, meropenem, echinocandin, metronidazole, and piperacillin tazobactam for 2 to 3 weeks duration as she was developing fevers and productive cough.
The physical exam yielded a thin and chronically ill appearing female patient.
Vital signs at the time of admission were notable for hypertension (186/79 mmHg). Her eyes did not show any conjunctival hemorrhaging or icterus, however there was conjunctival pallor. Oropharynx did not show any active exudates or ulcerative lesions. Her cardiac exam did not reveal any murmurs and her airways were clear to auscultation. Abdominal exam revealed palpable splenomegaly. Examination of the extremities did not show nail deformities including splinter hemorrhages or nail pitting. Her skin had no evidence of skin nodularities or other lesions. There was a 1 cm non tender, movable left axillary lymph node. The rest of the physical examination was unremarkable.
Initial laboratory work revealed that the patient had pancytopenia. White blood cell count (WBC) was stated at 2.4 K/uL, absolute neutrophil count (ANC) 1.92 K/uL, hemoglobin (Hgb) of 11.6, and platelet count of 39,000/uL. B2-microglobulin was seen elevated at 9.2 mg/L. Basic metabolic panel obtained showed sodium 134 mEq/L, Potassium 3.5 mEq/L, Chloride 103 mEq/L, Bicarbonate 26 mEq/L, Blood urea nitrogen 30 mg/dl, Creatinine 0.90 mg/dl, glucose 220 mg/dl. Liver function panel showed Albumin 2.2 g/dl, normal transaminases, total bilirubin 0.8 mg/dl, direct bilirubin 0.4 mg/dl. Urine analysis showed 200 mg/dl of protein and occasional amorphous crystals.
Initial computed tomography (CT) scan of the abdomen and pelvis during hospital admission showed a 15 cm spleen which was heterogenous and micronodular, as well as scattered abdominal and pelvic lymphadenopathy (Fig. ). No imaging signs of portal hypertension were noted.
During the hospitalization our patient was noted to become more confused and agitated, and there was concern that the patient was having seizures as she was seen numerous times to lose consciousness and awaken, with occasional loss of bladder function. A brain magnetic resonance imaging (MRI) showed subcortical non enhancing FLAIR hyper intense foci in the bilateral posterior occipital lobes.
Lumbar puncture and cerebral spinal fluid (CSF) studies were further performed for further analysis, and showed: WBC 1; no red blood cells; protein 62 mg/dL; glucose 35 mg/dL; and, lactate dehydrogenase 234 mIU/mL. Most notable negative findings in the CSF included no detectable viral cultures for cytomegalovirus, adenovirus, herpes virus, and varicella zoster virus, negative cryptococcal antigen serology and negative bacterial and fungal cultures.
Electroencephalogram studies showed triphasic morphology waves with and without sharp negative component at 2–3 hertz. These were seen in continuum mostly with subtle waxing and waning features. To 0.5 mg intravenous alprazolam, above discharges had slowly resolved, replaced by organized background that consists of 6 hertz rhythms. Importantly, there was a clinical improvement after alprazolam; suggesting a nonconvulsive seizures responding to benzodiazepine.
Two weeks later after the initial CT imaging and after the patient was more stable from the neurological perspective in order to attempt a lymph node excisional biopsy, a PET-CT imaging was performed and showed complete resolution of the previously detected lymphadenopathy and splenomegaly. (Fig. ).
Additional serologies for viral hepatitis and autoimmune etiology work up were performed. A bone marrow biopsy was performed and additional serum erythropoietin level, iron profile; cobalamin and folate level were determined.
The patient returned to the benign hematology clinic after discharged from the hospital. During her follow up appointment she appeared in better spirits and recovering well. Physical examination was notable for an absence of lymphadenopathy particularly in the cervical and axillary region, as well as no palpable organomegaly in the abdomen. It was further revealed that her antinuclear antibody (ANA) titer was highly positive (1:640), ESR 108 mm/hr with a CRP 6.74 mg/L. Negative viral hepatitis B, C and Human Immunodeficiency virus serologies.
Serum quantitative immunoglobulin showed a mildly elevated Ig A and Ig G level, without other abnormalities. Serum and urine protein electrophoresis did not reveal a monoclonal gammopathy. Serum free light chain levels showed kappa 96.3 mg/L and lambda 60.06 mg/dL with a normal ratio 1.6 in a patient with chronic kidney disease.
Complement C3 level was normal with a slightly elevated C4 at 46 mg/dL.
Bone marrow aspirate yielded a predominance of CD3 positive polytypical small T cells and a population of polyclonal B-cells by flow cytometry and negative for lymphoma or other malignant process. A focal lymphohistiocytic aggregate with granuloma formation was noted; occasional larger cells with prominent nucleolus identified; eosinophils were increased mildly in the vicinity of this aggregate. Acid fast bacilli and fungal stains were attempted; however the focal granuloma could not be appreciated at subsequent sections.
The patient’s pancytopenia was thought to be likely secondary to systemic lupus erythematosus and she was thus referred to rheumatology for further work up, and further testing included anti-double-stranded DNA, anti-RNP, anti-CCP antibody, ANCA vasculitis panel, direct antiglobulin test, lupus anticoagulant, anticardiolipin antibody, anti-double-stranded DNA antibody, and anti-SSA and anti-SSB. All these tests were negative, thus ruling out systemic erythematous lupus, rheumatoid arthritis, and other connective tissue disorders.
The interval improvement and self-limited clinical course in our case led us to believe that her elevated ANA titers, her bone marrow granuloma were secondary to an EBV infection-related syndrome. Monospot test was not performed and at that point we evaluated for EBV PCR and EBER staining in the bone marrow. Initial EBV PCR results were positive (960 copies/mL), while Epstein–Barr virus-encoded small RNAs staining in the bone marrow was negative. Our in situ hybridization stain is validated to work on decalcified bone marrow trephine biopsies and all stains include an on-slide positive control. As such, the likelihood of a false negative result is low. A possible explanation includes a sampling factor with lack of infected B-cells in the bone marrow despite the presence of viremia.
Her follow up labs during subsequent clinic visits showed WBC 5.3 K/uL, ANC 3.15 K/uL, Hgb 7.4 g/dL, calculated reticulocyte index of 1.1 and platelets 172 K/uL. Iron was 68 ug/dL, transferrin 124.1 mg/dL, ferritin 2952 ng/mL and serum erythropoietin levels were 31.7 mIU/mL. Serum cobalamin was 394 pg/mL and serum folate 12.3 ng/mL. Since there was spontaneous interval resolution of her neutropenia and her thrombocytopenia our diagnosis at that point was cytopenias secondary to infectious mononucleosis and anemia of chronic kidney disease related to diabetes.
Our patient presented 7 weeks later at the emergency room with a recurrent febrile syndrome with diffuse cervical and axillary lymphadenopathy and splenomegaly (Fig. ) and worsening cytopenias: WBC 1800/uL, ANC 1480/uL, Hgb 8.3 gr/dL, platelet count 20,000/uL; a repeat EBV titer revealed 6580 copies/mL. CT imaging with contrast found bilateral axillary, mediastinal and hilar lymphadenopathy. Low volume retroperitoneal and pelvic lymphadenopathy, hepatosplenomegaly with numerous small ill-defined hypodense lesions was in the spleen and probably also within the liver (Fig. ). At this time a repeat bone marrow biopsy and an excisional lymph node biopsy were performed and reviewed. The bone marrow specimen showed a solitary large cell positive for CD30 identified in the clot. No atypical cells are identified in core biopsy as assessed by IHC for CD30 and Pax-5. EBER was positive in few and scattered cells. The lymph node sections demonstrated near-total effacement of the lymph node architecture by a neoplasm comprised of neoplastic cells with Hodgkin-Reed-Sternberg morphology. The neoplastic cells were positive for CD15, CD30, PAX5 (weak), and MUM1. They were negative for CD3, CD20, CD45, ALK, and EMA. The findings were diagnostic of classical Hodgkin lymphoma, best subtyped as lymphocyte-depleted. (Fig. ). The expression of PAX5 with weak intensity coupled with MUM1 expression by the neoplastic cells is diagnostic of classical Hodgkin lymphoma. The expression of PAX5, a gene encoding a B-cell-specific transcription factor, excluded T-cell lymphoma as a diagnostic consideration. It is worth noting also that flow cytometry done on a bone marrow sample with involvement by lymphoma showed no evidence of T-cell or B-cell immunophenotypic aberrancies.
The patient was started on ABVD chemotherapy regime, bleomycin was held secondary to patient’s history of cardiomyopathy. She received three cycles of chemotherapy with complete clinical remission. Additional cycles of chemotherapy were not completed given prolonged and severe chemotherapy-induced cytopenias that eventually recovered over the following months. A bone marrow biopsy at completion of treatment revealed no morphologic evidence of residual Hodgkin lymphoma. Her most recent surveillance PET-CT imaging, nine months from completion of treatment, showed no hypermetabolic lymphoma and continuing complete metabolic response to therapy.


In September 2015, a 36-year-old, emaciated, Hungarian man presented with a 3-month history of widespread, red, rust-colored papules and nodules partially erosive and crusted as well as a 4 cm wide, prominent, skin-colored, subcutaneous tumor at the left zygomatic arch (Fig. ). The oral mucosa was free of lesions. The patient was occasionally homeless in Austria, his travel history was unremarkable and he reported intravenous drug use. The latter comorbidity and the clinical presentation prompted HIV rapid testing, which provided a positive result.
HIV infection was confirmed by Western blot and quantitative HIV PCR (4.70 log copies/mL). The CD4+ cell count was 47 cells/μL (CD4+/CD8+ ratio: 0.06), indicative for severe immunosuppression. In addition, the patient was HCV positive and the viral load was 2.62 ×106 copies/mL (genotype 1a). The white blood cell count was within normal range, and the patient was subfebrile.
Related to the rust-colored papules, BA, vascular tumors-like multiple pyogenic granulomata (PG), and HIV-associated Kaposi sarcoma were suspected. A biopsy of the nodular skin lesions from the dorsum revealed solid, abundant telangiectatic vessels in the upper dermis with prominent endothelial cells surrounded by neutrophils and lymphocytes, compatible with BA and PG. Immunohistochemical staining for human herpes virus 8 was negative. The Warthin–Starry stain showed clusters of microorganisms. High levels of serum IgG antibodies against B henselae and B quintana were detected in an indirect immunofluorescence assay (Euroimmun, Lübeck, Germany) strongly suggesting BA.
For direct pathogen identification, an EDTA blood sample and tissue samples of the nodular skin lesions were analyzed in PCR assays. DNA was extracted and processed from both samples using a peqGOLD Tissue DNA Mini Kit (Peqlab) according to the manufacturer's protocol. DNA isolates were amplified with a real-time PCR targeting the ssrA gene of Bartonella spp.[ An ABI7900 cycler (Applied Biosystems, Foster City, CA, USA) was used with a thermal profile of initial enzyme activation at 95°C for 2 minutes, 45 cycles of denaturation at 95°C for 15 seconds, followed by annealing and elongation at 61°C for 1 minute. Bartonella spp. DNA was detected in all samples. Amplicons for sequence analysis were generated in conventional PCR. The PCR products were loaded onto a 1% agarose gel and amplicons of size 301 bp were purified using the QIAquick Gel Extraction Kit (Qiagen, Austria). DNA sequencing was carried out by Eurofins Genomics DNA sequencing service (Eurofins Genomics GmbH, Ebersberg, Germany). The forward and reverse DNA sequences obtained were used for homology searches in the National Center for Biotechnology Information (NCBI) database BLAST search program ().
The skin tissue was further cultured on Columbia blood agar plates (Biomerieux, Vienna, Austria) at 37°C in an atmosphere of 5% CO2 and 95% humidity. After 4 weeks of culture, microbial growth was detected by clinical characteristics and selected colonies were propagated by culture via dilution streak plating. Single colonies were then picked and sub-cultured, and the DNA was purified and tested by a Bartonella-specific PCR assay.[4] Sequencing (BLAST analysis) demonstrated a clearly positive result for B quintana.
Contrast-enhanced computed tomography (CT) scans of the head, chest, and abdomen (Fig. ) revealed hepatosplenomegaly and several abscesses located in lung, stomach wall, pancreatic tail, subcutaneous tissue, and the large lesion (4.5 × 2.8 cm) at left zygomatic arch already eroding the adjacent bone. No pathological findings were seen on x-ray of the long bones or on echocardiography.
In order to exclude a different pathology of the facial subcutaneous mass, such as Burkitt lymphoma, a biopsy was performed. Histology revealed neutrophil infiltrations with no evidence for a malignant process. In addition, DNA was extracted from the paraffin-embedded tissue for broad spectrum fungal PCR (MycoRealFungi, Ingenetix, Vienna, Austria) and no pathogens could be identified. The same tissue was tested for B quintana by PCR as described above and the result was positive. Silver impregnation staining showed bacilli.
In view of the advanced immunosuppression, a screening for other opportunistic infections was performed. Atypical and typical mycobacterial infections were excluded by negative cultures from blood, urine, and skin biopsies. The TBC-specific interferon-gamma release assay and Cryptococcus neoformans antigen were also negative. Among several blood cultures from venous blood only one was positive for Staphylococcus epidermidis.
After 23 days of treatment with doxycycline 100 mg bid, an improvement of the skin lesions, partial regression of the facial tumor and resolution of fever were observed. The HIV viral load had decreased to 2.02 log c/mL after initiation of antiretroviral therapy with emtricitabine/tenofovir 200/245 mg qd and dolutegravir 50 mg qd. A follow-up CT scan could not be performed, because the patient abandoned the hospital and was lost for follow-up.


A 40-year-old woman in the 27th week of her fourth pregnancy was referred to our rheumatology clinic because of a three-week history of a skin rash, arthralgia, and weak positive anti-nuclear antibody test by immunofluorescence assay (ANA-IFA). Her previous three pregnancies were uneventful. She did not have a history of recent infections nor a potential exposure to toxic or medical agents. Physical examination on admission revealed bilateral periorbital edema and erythema on her eyelids (heliotrope rash) as well as diffuse rash on the face (). She had bilateral erythematous macules on the extensor surfaces of the metacarpophalangeal and proximal interphalangeal joints (Gottron's sign). There was also symmetrical and proximal muscle weakness in the upper and lower extremities. Other physical examination findings were unremarkable. Laboratory findings were as follows: serum creatine kinase (CK): 2138 U/L (normal: 29–200), lactate dehydrogenase: 520 U/L (normal: 140–280), aspartate aminotransferase: 113 U/L (normal: <35), and alanine aminotransferase: 58 U/L (normal: <35). ANA-IFA was weakly positive at 1/100 titration (homogenous pattern). Anti-Ro52 was positive, but antibodies to Jo-1 or other extractable nuclear antigens were negative. Serum anti-double stranded DNA, rheumatoid factor, and complement levels were within normal ranges. Serum creatinine level and urine analysis were normal. Erythrocyte sedimentation rate was 31 mm/h and serum C-reactive protein level was 17.9 mg/L (normal 0–5). Electromyography of the right deltoid muscle revealed fibrillations and small polyphasic motor unit action potentials. Magnetic resonance imaging showed diffuse edema in thigh muscles (). She declined muscle biopsy. Investigations for occult malignancies including breast ultrasound, pelvic and abdominal ultrasound, peripheral blood smear, and fecal occult blood test were all negative. Serum CA-125 level was 6.5 U/mL (normal 0–35). She was diagnosed with dermatomyositis according to Bohan and Peter's criteria [, ] and started on methylprednisolone 32 mg/day orally. Five weeks later, however, no improvement was noted in muscle strength, skin rash, or serum CK level. Her blood pressure was 180/120 mmHg and she had developed bilateral pretibial edema. She was diagnosed as having preeclampsia and her pregnancy was terminated by an emergency caesarean section at the 32nd week of the gestation. She gave birth to a 1800 g male infant with no apparent congenital malformation. In postpartum period, we searched the mother for the presence of anti-phospholipid antibodies. Anti-cardiolipin and anti-β2 glycoprotein-1 antibodies (immunoglobulin G and M isotypes) were found to be negative. Lupus anticoagulant test could not be performed due to technical limitations.
After delivery, her muscle strength and rash improved rapidly. The dosage of methylprednisolone was tapered off. At postpartum 6th week, she was on methylprednisolone 8 mg/day and serum CK levels were within normal limits. There was only mild facial rash left, but heliotrope rash and Gottron's sign had completely resolved.


An 85 year-old Caucasian gentleman with hypertension, paroxysmal atrial fibrillation, hypothyroidism, stage 3 chronic kidney disease, mixed ischemic and non-ischemic cardiomyopathy, severe biventricular systolic dysfunction, secondary prevention cardiac resynchronization therapy device implant with defibrillator function, and frequent monomorphic VT presents with VT storm. Heart failure medical therapy was optimized and included beta-blockade. A prior trial of sotalol therapy provided no arrhythmia suppression. Amiodarone therapy provided some relief, particularly when augmented by mexilitine therapy, however drug-related lung and neurologic toxicities limited amiodarone use. Transvenous catheter VT ablation was attempted however the arrhythmia recurred a month later.
On presentation, the patient had recurrent VT at 215 beats per minute. 12-lead electrocardiography revealed a monomorphic wide complex tachycardia with left bundle branch block like morphology, inferior axis, and late precordial transition. His arrhythmia precipitated frequent appropriate implantable cardioverter defibrillator anti-tachycardia pacing and shocks therapies. There was no evidence of ongoing reversible myocardial ischemia or metabolic and electrolyte abnormalities.
Given his severe biventricular failure, prior sotalol and mexilitine failure, and drug-toxicities with amiodarone, antiarrhythmic options were limited. The patient was not a good candidate for a repeat ablation procedure or cardiac transplantation given his age and frail status. Having exhausted antiarrhythmic options, dronedarone therapy was considered for off-label use. After discussing potential benefits and risks regarding dronedarone use in the treatment of VT based on the limited data available in the scientific literature, the patient consented to an off-label trial of the agent at 400 mg twice daily. After only three doses, it was discontinued due to severe nausea and the development of multisystem organ failure including acute severe hepatotoxicity. This brief trial of dronedarone therapy had no appreciable effect of the patient’s VT burden. The duration of the VT episodes was brief and not felt to be the cause of the patient’s multi-organ failure that was temporally associated with the initiation of dronedarone therapy. Five days prior to dronedarone administration, the patient’s serum alanine transaminase was measured at 59 U/L (normal 11–63 U/L), serum creatinine at 135 umol/L (normal 50–120 umol/L), and estimated glomerular filtration rate at 41 mL/min/1.73 m2 (normal >80 ml/min/1.73 m2). Two days after dronedarone administration a marked decline in kidney and liver function was observed with a serum alanine transaminase level increase to 1045 U/L, serum creatinine level of 231 umol/L, and estimate glomerular filtration rate of 21 ml/min/1.73 m2. Dronedarone therapy was subsequently discontinued. Unfortunately the patient’s liver and renal failure continued to worsen despite drug discontinuation. He died eight days later from multi-organ system failure and metabolic shock.


A 37-year-old woman went to the clinic of a local hospital because of abdominal pain and hematochezia for one week. Colonoscopy examination showed a polypoid mass protruding into the rectum cavity, measuring approximately 5 cm in maximum diameter, with a rough and uneven surface (Fig. ). Then the patient underwent a partial rectectomy. The lesion was considered as a myogenic sarcoma, preferring pleomorphic leimyosarcoma by the referring pathologists. The postoperativ adjunctive therapy was not administrated . There was no evidence of recurrence or metastasis 8 months after surgery.


The patient was a 55-year-old man who complained of abdominal pain and distension lasting for two days. Physical examination showed abdominal mass with tenderness. No obvious mass was found by colonoscopy. X-ray displayed intestinal obstruction. Computed tomography (CT) scan demonstrated a solid mass in the pelvic cavity (Fig. ). Clinically, the lesion was suspicious of gastrointestinal stromal tumor (GIST). Intraoperatively, the mass was found on the terminal ileum nearing the ileocecal junction. Partial ileal resection and appendectomy with intestinal anastomosis were performed shortly after. The lesion was originally diagnosed as malignant mesothelioma by the referring pathologist. After reevaluation of the H&E slides with application of immunohistochemistry and FISH analysis, the diagnosis of EIMS was finally rendered. The patient developed local recurrence 2 months after surgery. A re-excision of the recurrent tumor with adjuvant chemotherapy was performed. He was free of disease at 10-month follow up.


A 22-year-old young man presented with abdominal mass with intermittent abdominal pain for eight days and fever for five days. Subsequent CT scan revealed a solid heterogeneous mass of the right abdominal cavity, suspicious of GIST. After the admission, the patient underwent a complete excision of the abdomen mass and partial transverse colectomy soon. Intraoperatively, an enormous mass measuring approximately 20 × 15 cm was identified, with multiple small omental or mesenteric nodules. Pathological examination of the submitted specimen showed that malignant tumor was suspected as GIST. To confirm the diagnosis, the pathological materials were sent to our department for further consideration. With the adjunctive study of immunohistochemistry and FISH, the lesion was re-diagnosed as EIMS. The patient developed local recurrence 2 months after surgery. The targeted therapy of ALK inhibitor (crizotinib) was administrated later. He achieved a partial response to the treatment. He was alive with disease at 14-month follow up.


The patient was a 58-year-old woman who complained of a slowly enlarging and painless mass on the abdomen for two months. Physical examination showed an ill-defined solid mass of the right lower abdominal wall with no tenderness. Then she received a local resection. Intraoperative examination revealed that the mass was firm in consistency and infiltrated into the skeletal muscle of the abdomen wall. Pathologically, the tumor was considered as pleomorphic sarcoma by the referring pathologist. After surgery, the patient was treated with the additional chemotherapy. She developed local recurrence 2 months later and died of disease at 8-month follow-up.


A 15-year-old young woman complained of recurrent abdominal pain for four months and abdominal mass for four days. Physical examination revealed a well-defined solid mass of the right abdomen with mild tenderness. Ultrasonography displayed an abdominal tumor with heterogeneous internal echoes, measuring about 10.2 × 7.5 cm. Subsequently, the patient received a complete excision of the abdomen mass and partial transverse colectomy. During the operation, the tumor was identified on the transverse colon and measured approximately 12 × 8 cm, with multiple enlarged omental or mesenteric lymph nodes. The lesion was considered as fibrosarcoma with inflammatory cell infiltrates by the referring pathologist. After surgery, the patient did not receive the adjunctive therapy. She was free of disease at 7-month follow up.


The first patient is a 43-year-old male, who consulted our center for night sweats and weight loss in the last 3 weeks. He had no previous history or records in our center. The physical examination was normal except for a slight splenomegaly and the blood test was compatible with hyperleukocytosis, anemia and thrombocytopenia, (leukocytes 136.00 · 109/L, hemoglobin 11.70 g/dl, platelet count 39.70 · 109/L) and 93 % of small-medium sized lymphoblast in the Grunwald-Giemsa blood smear. The bone marrow aspirate examination had an hypercellular infiltration of 90 % which was confirmed by immunophenotype (CD19+, CD10+, CD34+, TdT+, DR+, CD79 alfa+, CD20−, cytoplasm IgM negative). 80 % of the blast cells also expressed CD33+. A fresh sample from the bone marrow aspirate was collected for molecular and cytogenetic analysis. The assay revealed the presence of the following karyotype:46,XY,t(9;22)(q34;q11) [2] /46,XY,del(9)(p22)t(9;22)(q34;q11) [4] /46,XY,del(9)(p22)t(9;22)(q34;q11),del(20)(q13) [5] /46,XY [9]. FISH analysis confirmed the presence of BCR-ABL1 fusion gene (Fig. ). The patient’s RNA was isolated from the peripheral blood and subjected to a two round multiplex reverse transcription and polymerase chain reaction (RT-PCR). In order to avoid RNA quality and/or handling errors, we included an internal positive control in where a 690-bp segment of the ubiquitously expressed transcription factor E2A mRNA was amplified. The primers and PCR conditions used in the first and second round of the nested PCR reaction are described by Pallisgaard et al. []. We identified an atypical amplification band of approximately 100 bp, much smaller than the p190 (e1a2) fragment. In order to confirm the presence of a BCR-ABL transcript this band was extracted from the agarose gel, purified and then analyzed by DNA sequencing. cDNA sequence revealed the presence of the e1a3 variant (Fig. ).
The patient started induction treatment with ALL-type polychemotherapy and Imatinib, achieving complete response by morphology and immunophenotype. However, the BCR/ABL was still detected by RT-PCR at the end of the induction phase. He is ongoing consolidation with allogenic stem cell transplantation (SCT) from an HLA-identical sibling donor, 7 months after diagnosis.


The second patient is a 65-year-old male who consulted for pain in the right leg and a history of recurrent periodontal infections in the last month. An eco-doppler confirmed a thrombophlebitis and the blood test found hyperleukocytosis and anemia (leukocytes 223.00 · 109/L, Hemoglobin 11.60 g/dl, platelet count 118 · 109/L) and the presence of 80 % lymphoblasts in the Grunwald-Giemsa blood smear. The bone marrow aspirate found an infiltration of 25 % lymphoblast which was confirmed by immunophenotype (CD19+, CD34+, DR+, CD10+, CD22+, low intensity CD20−, TdT+, cytoplasmatic IgM negative, CD33+). The karyotype was 46,XY,t(9;22)(q34;q11) [20]. FISH analysis confirmed the presence of BCR-ABL1 fusion gene (Fig. ). The patient’s RNA was isolated from the peripheral blood. We identified an atypical e1a3 variant after a two round PCR amplification by DNA sequencing (Fig. ).
The patient started induction treatment and Imatinib. The bone marrow aspirate on day 34 confirmed progressive disease with 30 % blast and persistence of BCR/ABL. After a second line of intensive ALL-type induction therapy the patient finally died due to toxicity (gastrointestinal bleeding). No SCT had been planned due to age and unfit status. It is noteworthy that the blood counts in a regular check-up 4 months before the diagnosis had a slight leukocytosis that was not studied.


A 13-year-old boy attended pediatric neurology clinic with a 2-year history of repeated paroxysmal muscle tone loss, in order to be assessed for possible atonic seizures. Having been previously neurologically intact, symptoms started with an episode in a restaurant where he abruptly lost axial tone and his head hit the table. He subsequently experienced frequent similar episodes, especially when experiencing positive emotions, during laughter or while playing games with excitement. Episodes were varied as follows: they ranged from subtle involuntary head nods, which he could conceal and were not always noticed by others, to complete postural collapse. They were consistently symmetrical, involving both the left and right side of his body. All instances were described as short-lived, lasting no longer than a few seconds.
During the same period, he would drift off to sleep several times a day without warning, and not wake up until roused. At night, his sleep was interrupted, waking up frightened while feeling unable to move. In addition, his mother also noticed a marked weight gain associated with a significant increase in his appetite. He was previously well, with an unremarkable birth and family history. He never received the Pandemrix influenza vaccine, but ~2 weeks prior to symptom onset had been vaccinated with the Stamaril live, attenuated yellow fever vaccine for a family trip to Africa.
Neurological clinical examination was unremarkable and initial investigations, including electrocardiography (ECG), brain magnetic resonance imaging (MRI), and routine blood tests were within normal limits. Polysomnography (PSG) showed rapid sleep onset with rapid eye movement (REM) latency of 47 min (normal 70–110, full results given in Table , hypnogram of overnight sleep and multiple sleep latency is shown in Figure ). He had significant sleep fragmentation, with frequent REM intrusions interrupting the usual consolidation of non-REM periods but no evidence of sleep disordered breathing. Multiple sleep latency test (MSLT) performed the following day was significantly abnormal with a mean sleep latency of 1.6 min (normal >8 min) and sleep onset REM evident in four out of four nap periods.
The clinical history of weight gain, hypnagogic hallucinations, sleep paralysis, and clear episodes of loss of muscle tone (cataplexy) is strongly suggestive of narcolepsy. With that clinical context, the fragmented sleep without sleep disordered breathing on PSG together with significantly shortened sleep latency and sleep onset REM on MSLT confirmed the diagnosis of narcolepsy. Periods of non-REM sleep were interrupted by REM intrusions, resulting in a proportional increase in REM sleep compared to non-REM sleep phases (as indicated in Table ). While sleep fragmentation does occur for other reasons, this pattern shown on PSG is typical of young patients with untreated narcolepsy. These findings taken together meet level 2 evidence for narcolepsy according to the criteria laid out by the Brighton Collaboration Narcolepsy Working Group (), as well as fulfilling the diagnostic criteria for narcolepsy type 1 defined in the International Classification of Sleep Disorders, third edition ().
He was found to have the strongly associated HLA-type DQB1*0602. MRI brain, including T1 and T2 weighted scan and FLAIR imaging was normal, with normal hypothalamic appearances. Because of the clear clinical history of cataplexy and the invasiveness of the procedure in a pediatric patient, CSF levels of hypocretin (orexin) were not measured. Treatment was mainly directed at managing daytime sleepiness through improved sleep hygiene and daytime naps, in addition to stimulant medication (slow release methylphenidate, 18 mg once a day increased in two steps to 45 mg once a day) and anti-cataplectic medication (venlafaxine, 37.5 mg once a day).


A 49-year-old immune-competent male was admitted to the Neurosurgical Intensive Care for fever (up to 38°C) associated with ideomotor slowdown, severe confusional state, and meningism. Two months prior hospitalization, the patient underwent surgical removal of a pontocerebellar acoustic neuroma with placement of a ventriculo-peritoneal (VP) shunt and received an successful 10-day Fluconazole (FLU) treatment course for a catheter-related C tropicalis urinary tract infection. CSF analysis, performed at the admission, revealed glucose concentration of 34.2 mg/dL, protein level of 332 mg/dL, and leukocytes cell count of 471 cells/μL (75% polymorphonucleocytes). No signs of persistent Candida urinary tract infection were found in serial urine analysis and cultures performed during this second hospitalization. Fungal meningitis was diagnosed on the basis of C tropicalis isolation from the CSF culture. The same pathogen was also cultured from the removed VP shunt, while blood cultures were negative. Intravenous voriconazole (VOR) was started (loading dose 6 mg/Kg/q12 for 2 doses, then 4 mg/Kg/q12) and an external ventricular drainage (EVD) was inserted. The clinical course and the main laboratory findings, expressed in function of time, are shown in Fig. .
On day 13, 22, and 29 of VOR treatment, C tropicalis was still cultured from CSF and consequently EVD was changed. On the day 31 of VOR treatment, CSF cell count and glucose concentration achieved normal values and CSF culture yielded no microbial growth. With apparent C tropicalis microbial eradication from CSF, a clinical improvement of patient's condition in terms of Glascow Coma Score (Fig. ) has been observed with initial impressive reduction of CSF BDG.
C tropicalis was isolated again from the CSF culture on the day 48 of therapy concurrently with new clinical-neurological deterioration. Increased CSF BDG levels proceeded new isolation of the offending pathogen from CSF. No increase in serum BDG has been detected in day 16, 34, 45 of VOR treatment (Fig. ).
VOR was replaced by liposomal Amphotericin B (LAMB) (3 mg/kg/daily) along with FLU (loading dose 800 mg, then 400 mg/daily) and EVD was changed again. On the day 66 of antifungal therapy, the patient died for a concurrent bacterial sepsis, showing no further significant clinical improvement of his meningitis after the replacement of VOR by LAMB along with FLU. CSF cultures remained positive for C tropicalis. Given that interventions and all investigations described in this case report were performed as part of the standard health care whose informed consent was obtained, no ethical approval was either sought or obliged.


A 61-year-old white female was brought to our hospital by family for 8 hours of lethargy and confusion. Medical history was significant for COPD on home oxygen, stage 1A adenocarcinoma of the lung (status post-RLL lobectomy), prior opiate abuse (in stable remission on oral buprenorphine-naloxone), prior alcohol abuse (in stable remission per family), and anxiety treated with lorazepam (2 mg daily). One week prior to presentation, she developed increased dyspnea, cough, subjective fevers, and fatigue. The patient's family administered her usual medications during her acute illness but had omitted her lorazepam for the past 3 days. She became increasingly somnolent and was found on the morning of presentation with a “blank stare” and slurred speech.
On arrival at the hospital, vitals were as follows: temperature 36.8°C, HR 104 beats/min, BP 177/110 mmHg, RR 16, and SpO2 96% on 2 L nasal cannula oxygen. She was moderately somnolent but interacted normally and was oriented to person, place, and time. Within hours, she became persistently disoriented with impaired short-term memory and difficulty following commands. All psychoactive medications were held. After 12 hours, symptoms had progressed to near-complete unresponsiveness, immobility, and periodic agitation. Extensive workup showed no abnormalities to explain symptoms. Blood counts, chemistries, liver enzymes, arterial blood gas, TSH, B12, chest X-ray, and brain MRI were unremarkable. Blood cultures, urine cultures, sputum cultures, and Lyme serology were negative. Urine toxic screen was negative for drugs of abuse, including benzodiazepines. Neurology examined the patient and found no focal neurologic deficits. Based on their exam, they also endorsed low clinical suspicion for nonconvulsive status epilepticus.
Despite absence of chest pain or acute coronary syndrome (ACS) equivalents, admission ECG showed deep anterior T-wave inversions. Troponin I was 0.16 ng/L (normal < 0.013) and rose to 1.37 ng/L over 18 hours. However, ACS treatment was not pursued as the patient was known to have a coronary calcium score of zero and her exercise ECG stress test ten months priorly had shown no inducible ischemia. Urgent TTE was obtained, which revealed hypokinesis and dilation of the left ventricle consistent with takotsubo cardiomyopathy. Left ventricular ejection fraction (LVEF) was 35%, down from 60% ten months priorly.
Twenty-four hours after initial presentation, the patient became too restless to allow completion of a routine ECG, so 1 mg of midazolam was given. Within minutes of receiving this medication, she began to talk again and became aware of her surroundings. She was able to recognize her daughter, follow commands, and walk. Scheduled lorazepam was initiated. Within 48 hours, the patient was back to her baseline mental status except for feeling fatigued. She denied chest pain and had no symptoms of congestive heart failure. The patient was discharged on hospital day 3 with a lorazepam taper and metoprolol succinate; TTE 10 weeks later showed reversal of apical remodeling and improvement in LVEF back to 60% ().


The importance of monitoring calcium levels in patients with renal impairment is highlighted by an individual case of a 68-year-old woman with renal impairment who developed severe hypocalcemia after receiving a single 60-mg dose of denosumab. Patient comorbidities included chronic obstructive pulmonary disease, hypertension, osteoporosis, depression, rheumatoid arthritis, polycystic kidney disease, and chronic renal insufficiency. The patient was not able to tolerate alendronate, an oral bisphosphonate prescribed by her private medical doctor, which was discontinued on April 19, 2010, by Dr T. If an oral agent is not well-tolerated, both intravenous and subcutaneous routes of administration for bone supportive care agents are feasible options. Denosumab (60 mg every 6 months) was chosen over the intravenous bisphosphonate zoledronic acid because of the patient’s poor renal function. On October 13, 2010, denosumab was given per label to this patient with chronic renal insufficiency and no symptoms of hypocalcemia. Calcium (8.9 mg/dL) and serum creatinine (2.7 mg/dL) levels were last checked on June 2, 2010, 4 months prior to receiving denosumab. Other relevant laboratory values from this date included albumin (3.8 g/dL), alkaline phosphatase (47 U/L), total bilirubin (0.3 mg/dL), BUN (48 mg/dL), glucose (105 mg/dL), sodium (140 µg/L), potassium (4.7 µg/L), and chloride (109 µg/L).
Eleven days after denosumab administration (October 24, 2010), the patient presented at the hospital with fever and chills for 1–2 days, productive yellow cough with clear lungs and no shortness of breath, swelling, generalized pain and tenderness, mild confusion, and dyskinesia (i.e., twitching throughout the body). The patient was admitted to the hospital and was diagnosed with severe hypocalcemia (blood calcium 6.7 mg/dL). Thyroid hormone T4 (4.2 µg/dL), thyroid stimulating hormone (TSH, 0.726 µIU/mL), and vitamin D 1,25-dihydroxy (48 ng/mL) levels were normal, but parathyroid hormone (PTH) was high (409 pg/mL). Other relevant laboratory values included serum creatinine (2.23 mg/dL), albumin (2.1 g/dL), alkaline phosphatase (41 U/L), BUN (27 mg/dL), glucose (94 mg/dL), sodium (141 µg/L), potassium (4.5 µg/L), and chloride (116 µg/L). Blood calcium levels remained low (7.2 mg/dL) through October 28, 2010. With treatment (intravenous calcium gluconate, increased oral calcium, and continued vitamin D supplementation), the patient’s blood calcium returned to near normal (8.3 mg/dL) 3 weeks later (November 16, 2010).


An 11-year-old Indian girl presented with a history of recurrent non-healing left leg venous ulcers associated with swelling of the involved limb. There was no associated erythema and her leg was non-tender. There was no history of trauma. There was no significant antenatal history in her mother and our patient was delivered normally at a local hospital with an uneventful postnatal period. There was no history of umbilical cannulation, cardiac catheterization, or any other femoral intervention. She had reported these symptoms since early childhood but no medical evaluation was done in the past. There were no other complaints.
Her physical examination was remarkable for large venous collaterals on her anterior abdominal wall with flow from below upwards (Fig. ). She was also noted to have swelling and multiple venous ulcers on her left lower limb (Fig. ). Both lower limbs had varicose veins. There was no calf tenderness. There was pedal edema on her left lower limb. The rest of her examination was normal.
On color Doppler examination, her infrarenal IVC as well as her bilateral internal and external iliac veins were not visualized. A short segment of her proximal right common femoral vein and proximal superficial femoral vein were faintly visualized. Her left-sided common femoral, superficial femoral, and popliteal veins were not visualized.
A computed tomography (CT) venogram done to define her venous anatomy showed absence of infrarenal IVC as well as absence of bilateral common iliac and left common femoral veins (Fig. ). A short segment of her right common femoral vein was seen with collaterals draining into her anterior abdominal wall. Her venous system at the level of the renal vein and above was normally developed (Fig. ). There were well-developed collaterals over her anterior abdominal wall and in her bilateral lower limbs. The superficial venous system of her bilateral lower limbs was well developed and draining from collaterals.
Echocardiography showed normal cardiac anatomy and function.
With symptomatic treatment, her venous ulcers improved. There were no surgical or interventional therapies possible in this case. She was not started on anticoagulation therapy.


The patient is a 65-year-old man referred to the senior author's clinic with persistent right shoulder pain and severely restricted range of motion approximately 10 months after a primary anatomic TSA. The indication for the primary procedure was longstanding severe osteoarthritis with an intact cuff. The Exactech Equinoxe (Exactech Inc., Gainesville, FL) shoulder system was used for the index procedure, with a pegged, caged glenoid (model number 314-02-04). Utilizing a standard deltopectoral approach, a 15 mm press fit humeral stem with a 47 × 18 humeral head, offset with a 4.5 mm replicator plate and a large beta curvature, pegged glenoid with cage was implanted. No complications had been noted at the time of the primary procedure. The patient had an uneventful, atraumatic postoperative course, but he failed to progress. His range of motion was severely restricted to about 15 degrees in all planes 8 months after surgery. A CT arthrogram was ordered to evaluate if there was a rotator cuff tear but instead found that the glenoid component had dissociated and was sitting posterior to the humeral head (). The polyethylene glenoid component had disengaged from its metallic cage and one of the three metallic peg caps, which remained seated in the glenoid. Close inspection of the postoperative films, as early as those immediately following surgery in the postanesthesia care unit, confirmed that the glenoid had in fact failed acutely ().
The patient was subsequently referred to the senior author and underwent revision TSA. The glenoid component was retrieved from the posterior capsule. The component failure occurred at the interface between one of the pegs and its metallic cap as well as at the cage component, which had disengaged from the polyethylene (). Inspection of the native glenoid revealed a region of proud bone, consistent with inadequate reaming of the glenoid. The retained glenoid cage and peg were extracted and the glenoid was prepared for the new implant. A new pegged glenoid was cemented into place and the humeral head was downsized.
Six months later, the patient was progressing well. He regained 90 degrees of pain-free forward flexion (110 passive) with good rotation. He planned to continue to work on strength and range of motion with physical therapy. However, after the 6 month visit the patient was lost to follow-up. A good faith effort was made to contact the patient, but he could not be reached.


A 26-year-old previously healthy female presented to emergency department with complaints of headaches for two weeks associated with right sided numbness, weakness, diplopia, facial droop, dysarthria, and ataxia. The patient underwent work-up for a cerebral vascular accident. MRI confirmed the diagnosis of acute stroke involving the left posterior cerebral artery territory with smaller foci of ischemia in various cerebral territories, consistent with embolic phenomena. Transesophageal echocardiography revealed a large, papillary, solid, fixed mass, measuring 7 × 7 mm on the left coronary cusp () of the aortic valve that was suspected to be an aortic fibroelastoma due to its papillary structure and size. She underwent valve sparing excision of the fibroelastoma (). Pathology later returned consistent with thrombus. The patient was recommended to have a hypercoagulable work-up as an outpatient but was lost to follow-up.
Four months after the initial surgery she presented with complaints of left lower quadrant abdominal pain, described as sharp and stabbing in nature. CT scan of the abdomen and pelvis revealed massive ascites. Recommended correlation study with transvaginal ultrasound was conducted and revealed a complex mass of mixed echogenicity with mildly increased vascularity measuring 7.6 × 7.2 × 9.0 cm, located posterior to the uterus and extending to the right adnexa. Biopsy of the lesion revealed adenocarcinoma. She went on to undergo bilateral salpingooophorectomy, omentectomy, lysis of adhesions, and peritoneal biopsies confirming a final diagnosis of papillary serous ovarian carcinoma, Stage IIc.


A 37-year-old primigravid woman was referred to the emergency department due to premature ablation of a normally implanted placenta. After admission, an extremely low birth weight female infant (birth weight, 532 g; length, 27 cm) was delivered by Cesarean section at 24 + 0 weeks of gestation. Her Apgar scores at 1, 5, and 10 min were 1, 3, and 7, respectively. The umbilical artery pH was 6.91. She was intubated shortly after birth due to respiratory distress, and surfactant was administered. The surgical ligation of a patent ductus arteriosus was performed at 15 days of life. She began receiving hydrocortisone from 16 days of life because of respiratory deterioration. Enteral feeding with fresh breast milk was started on 2 days of life, and the infant was on full feeding by 28 days of life.
A cystic lesion had been identified below the liver during the fetal period, and we diagnosed biliary atresia after her birth. On 34 days of life, cholestatic jaundice developed (direct bilirubin 16.9 mg/dL), and a biliary drainage procedure was performed.
On 43 days of life, she developed progressive abdominal distension and a septic appearance. Laboratory values showed thrombocytopenia (41 × 103/μL) and elevation of C-reactive protein levels (16.2 mg/dL). Empiric antibiotic therapy, using vancomycin and meropenem, and intravenous immunoglobulin therapy were started for clinically suspected sepsis. Serial blood cultures were negative for both aerobic and anaerobic bacterial infections.
In view of thrombocytopenia and necrotizing enterocolitis-like ileus, we performed a CMV screening at the same time. Her urine was positive for CMV DNA, and real-time polymerase chain reaction (PCR) showed a VL of 5.0 × 106 copies/mL in the peripheral blood. The CMV DNA from the umbilical cord and Guthrie card, both of which were collected on 16 days of life, were below the limits of detection. Real-time PCR of her mother’s breast milk showed a CMV load of 3.9 × 104 copies/mL. Although she had received five red packed cell transfusions by 43 days of life, they were all irradiated and leucocyte-depleted. Those results suggested that the breast milk was the most likely source of virus transmission to the patient.
As the thrombocytopenia and necrotizing enterocolitis-like ileus further deteriorated, we decided to begin antiviral therapy with intravenous ganciclovir. Ganciclovir therapy (5 mg/kg per dose every 12 h) was initiated at 49 days of life (postmenstrual age of 31 weeks).
We performed the TDM for ganciclovir three times, using liquid chromatography-tandem mass spectrometry. The estimated 12-h area under the concentration–time curve (AUC0–12) was determined using the trapezoidal method. When the drug interval was 24 h, the estimated AUC0–12 was corrected for half of the calculated value using the trapezoidal method. Table shows the association between the CMV load and the ganciclovir TDM analysis. At 55 days of life (7th treatment day), we performed the first ganciclovir TDM analysis. The plasma ganciclovir levels at 30 min, 90 min, 6 h, and 11 h after ganciclovir infusion were 5.3 mg/L, 6.0 mg/L, 4.0 mg/L, and 3.5 mg/L, respectively; the estimated AUC0–12 was 53.9 mg · h/L. The CMV load decreased from 5.0 × 106 to 5.3 × 104 copies/mL in parallel with the increase of platelet counts. The ganciclovir trough level and the estimated AUC0–12 were too high, so we extended the dosing interval from 12 h to 24 h on 62 days of life (14th treatment day). On 70 days of life (22nd treatment day), we performed the second TDM analysis, demonstrating that the plasma peak and trough ganciclovir levels were 6.0 mg/L and 0.3 mg/L, respectively, and the estimated AUC0–12 was 19.2 mg · h/L. Concurrently, the CMV load modestly rebounded from 5.3 × 104 to 1.6 × 105 copies/mL, and the thrombocytopenia worsened (35 × 103/μL). Therefore, we shortened the dosing interval from 24 h to 12 h on 29th treatment day. On 84 days of life (36th treatment day), we performed the third TDM analysis, demonstrating that the plasma peak and trough ganciclovir levels were 4.2 mg/L and 1.1 mg/L, respectively, and the estimated AUC0–12 was 31.8 mg · h/L. Although the VL markedly decreased from 1.6 × 105 to 2.4 × 103 copies/m/L, her clinical condition deteriorated with thrombocytopenia, hepatitis (aspartate transaminase: 422 IU/L; alanine transaminase: 87 IU/L), and unconjugated hyperbilirubinemia (serum direct bilirubin: 10.3 mg/dL). Neither neutropenia nor renal impairment was observed during ganciclovir therapy. On 85 days of life (37th treatment day), the ganciclovir therapy was discontinued, because of the concern that the thrombocytopenia and hepatitis resulted from its adverse reactions. Her clinical condition further deteriorated with increase of VL to 1.0 × 106 copies/mL on 107 days of life. On 109 days of life, she died of hepatic failure. Extensive hepatocyte necrosis was noted at necropsy and on histopathological examination; however, the precise mechanism of liver injury was not revealed by the postmortem analyses. This infant’s clinical course is summarized in the accompanying supplemental time-line file (Additional file ).


A 42-year-old woman with anorexia since adolescence and a 5-year history of recurrent nephrolithiasis was presented because of accumulated renal colics, migraine, and nausea. Noncontrast CT imaging showed bilateral nephrolithiasis and hydronephrosis. The stones were homogeneous and had a Hounsfield unit around 1900 (). She was severely malnourished with a BMI of 12.0 (height: 162 cm, weight: 31.6 kg) when she was first presented. The patient initially refused abuse of laxantia, but later in the disease course she admitted to have had a long-standing intake of magnesium oxide. Blood samples at admission showed low albumin, low total plasma calcium, low magnesium, and normal potassium, sodium, phosphate, creatinine, and urea. Urine pH was 7.0. Urine dipstick was positive for blood, leucocytes, and protein. Urine culture was negative. A 24-hour urine analysis showed a volume of 1865 mL, low citrate (0.4 mmol/24 hour), normal oxalate (211 μmol/24 hour), moderately high calcium (5 mmol/24 hour), and low creatinine (5 mmol/24 hour). Renography showed a left/right ratio of 22%/78%.
The patient underwent bilateral percutaneous stone removal (PCNL). Stone analysis from both sides using IRS revealed pure calcite (CaCO3) (). The patient had several recurrences within the next 3 years, and underwent repeated flexible retrograde intrarenal surgery (RIRS) and extracorporeal shockwave lithotripsy (SWL) procedures with subsequent IRS stone analyses of the extracted and post-SWL-cleared stones, confirming pure calcite. Due to low urinary citrate excretion, moderately high calcium excretion, high urine pH, and normal systemic acid–base status, incomplete renal tubular acidosis was initially suspected. Oral potassium citrate therapy failed to prevent frequent recurrences, however. Because the patient had high urine pH (7.0), a new treatment strategy with oral ammonium chloride (800 mg three times a day, 1 day per week) was initiated, based on the assumption that calcite crystallization may be promoted at high urine pH, as indicated by a study of Gault and colleagues. On this treatment, the patient has not formed new stones during an observation period of 23 months.


A 10-month-old boy was referred to the urology clinic with an undescended right testis. A presurgical history of the patient revealed that the patient had agenesis of the right kidney and no other concomitant anomalies of the genitourinary system had been evaluated before surgery. The clinical examination presented orthotopically positioned left testis but right testis was palpable neither in the inguinal region nor in scrotum. Left hemiscrotum showed no redness or swelling and left epididymis was also verified by palpation. The inguinal area had no palpable mass referring to inguinal hernia. However, an absence of the vas deferens on the right hemiscrotum was found. Then a scrotal ultrasonography was undertaken and it confirmed cryptorchidism of right testis located at the level of right internal inguinal ring and the suspected diagnosis of agenesis of the right epididymis. Left epididymis and testis had no pathological signs seen (). Moreover, abdominal ultrasonography revealed that renal agenesis on the right side and left kidney accompanied no compensatory hypertrophy or hydronephrosis (). Laboratory test presented creatinine level of 0.75 mg/dL proving normal kidney function. After informed consent was obtained from the patient's parents, the patient underwent a laparoscopic surgery for right orchiopexy and absence of right vas deferens and epididymis was noted (). However, due to relatively short length of right spermatic cord structure, laparoscopic orchiectomy was performed instead of orchiopexy. The patient's postoperative histologic analysis of right testis confirmed a normal testicle with absent epididymis.


A 50-year-old Japanese man was referred to our hospital with fatigue and swelling of the parotid glands and inguinal nodes. His blood count was normal, and no major organ dysfunction was detected by biochemical tests. However, markedly elevated values of serum IgG (6188 mg/dL; normal range 870–1700 mg/dL) and IgG4 (2970 mg/dL; normal range 4.8–105 mg/dL) were noted. Soluble-IL2 receptor (sIL2-R) (2130 U/mL; normal range 124–466 U/mL) was also increased. A high level of EBV DNA was detected in the serum plasma (3.0 × 104 copies/mL), with elevated IgG antibodies to EBV viral capsid antigen (VCA) (detectable at a 1:1280 titer) and early antigen (EA) (detectable at a 1:160 titer). Anti-EB nuclear antigen (EBNA) antibody was also detected (detectable at a 1:80 titer), indicating a chronic active EBV infection. Antibodies to hepatitis B virus, hepatitis C virus, human immunodeficiency virus, and human T-cell lymphotrophic virus type I were negative. Systemic positron emission tomography-computed tomography (PET-CT) with fluorodeoxy glucose (FDG) revealed an uptake of FDG in our patient’s enlarged parotid glands and kidneys, as well as the cervical, mediastinal, and inguinal lymph nodes (Fig. ). An inguinal lymph node biopsy was performed. Histologically, the lymph node architecture was almost preserved except for an expanded interfollicular zone. Both small- or medium-sized plasmacytoid cells and large lymphoid cells proliferated in the interfollicular zone with formations of small vessels (Fig. ). Most plasmacytoid cells were positive for IgG/IgG4 and CD20 (Fig. ), fulfilling the histological criteria for IgG4-related disease []. In contrast, large lymphoid cells were positive for CD20 and CD30 (Fig. ). These large lymphoid cells were also positive for latent membrane protein (LMP)-1 and EBER (Fig. ), indicating latency III infection of EBV []. Since EBV+ LPDs consist of EBV-associated reactive lymphoid hyperplasia, EBV-associated polymorphic lymphoproliferative disease, and EBV+ DLBCL [], we evaluated the rearrangement of Ig heavy- and light-chains by polymerase chain reaction. This analysis did not show clonal rearrangement, suggesting that the B-cell proliferation of this patient belongs to a subtype such as EBV-associated polymorphic lymphoproliferative disease rather than EBV+ DLBCL. Thus, diagnoses of both IgG4-RD and polymorphous EBV-associated B-cell LPD were made. On the other hand, there was no evidence of EBV infection in the parotid gland specimen, although it was heavily infiltrated with IgG/IgG4-positive plasmacytoid cells, but not large lymphoid cells. Ig-kappa+ cells and Ig-lambda+ cells were similarly distributed, indicating polyclonal proliferation of these plasmacytoid cells. Thus, we worked up his baseline immunodeficiency, which can potentially contribute to the development of IgG4-RD or chronic EBV infection. However, the proportions of CD3+, CD4+, and CD8+ lymphocytes were normal, and a review of the patient’s medical records did not show any evidence of genetic or inherited immunodeficiency in his family.
Considering the massive proliferation of EBV-infected large B cells with the IgG4+ plasmacytoid cells, he was treated with rituximab (375 mg/m2), oral cyclophosphamide (100 mg/day for 5 days), and prednisolone (40 mg/day for 5 days) biweekly. After eight courses of therapy, FDG uptake disappeared and the size of the parotid gland, as well as the lymph nodes, was normalized in PET-CT (Fig. ). In addition, plasma EBV DNA became undetectable and sIL2-R (395 U/mL) and IgG4 (655 mg/dL) were reduced (Fig. ). Despite our recommendation, our patient did not receive maintenance therapy, because he was concerned about potential adverse reactions due to the consecutive administration of steroids.


A 30-year-old woman presented with a large dorso-lateral synovial cyst of the right wrist previously ultrasonographically checked (2 months before); at the first examination the wrist was painful and swollen without a specific localization and the overlying skin appeared without local erythema. There was no reported fever, palpitations, irritability, dysphagia, dyspnea, weight loss, or other significant family medical history. The patient did not have a history of smoking but reported a history of recent trauma. The patient was treated with a functional bandage, rest and anti-inflammatory drugs for a week. At the next examination, there was an appreciable reduction of reactive synovitis of the extensor compartment, with evidence of the synovial cyst previously described. Therefore, an excision of the entire cyst was proposed.
Under brachial plexus block an S italic skin incision was performed on the dorso-ulnar surface of the wrist; the deep dissection showed a circumscribed and well-cleavable lesion like a tenosynovitis of the extensor carpi ulnaris (ECU) without a pedicle joint that was removed en bloc. Surprisingly, the pathologist found a 20-mm diameter, well-circumscribed and multilobulated tumor: each lobule was composed of abundant myxoid stroma with cellular elements in part fusal, in part epithelial and in part giant; all lobules showed a tendency to confluence but there was no cellular polymorphism or nuclear hyperchromia. Margins were tumor free. With immunohistochemistry there was positivity to vimentin but S100-protein, epithelial membrane antigen (EMA), cytokeratin AE1-3, CD99 and CD34 were all negative. There was a mitotic activity of 7 % (Ki67). This pattern suggested a myxoid tumor form of neurothekeoma, mixed subtype.
A close follow-up was performed; at 3 months a new subcutaneous lesion in the dorsal compartment was detected (Fig. a, b) and scanned with ultrasonography. The patient underwent revision surgery with dorsal and proximal extension of the previous scar; the subcutaneous lesion appeared surrounded by scar tissue and adherent to the tendon sheath (Fig. c). Histologically, a recurrence of neurothekeoma, with discrete myxoid stroma and cellular elements in part epithelial and in part giant, was found (Fig. ). With immunohistochemistry there was positivity only to vimentin; S100-protein, EMA and CD10 while cytokeratin AE1-3, CD99, CD34, actina and NSE were all negative. There was a mitotic activity of 4 % (Ki67). All margins were negative.
There was no recurrence by the 12-month follow-up, according to magnetic resonance evaluation (Fig. d).


Patient 1 is a 51 year old man from Ecuador, with severe large plaque psoriasis for 15 years, and a strong family history of psoriasis. His medical background included recent-onset hypertension and diabetes, and renal calculi. He takes lisinopril and glyburide, as well as doxepin and atarax when required. His past psoriasis treatments include topical steroids, methotrexate (not tolerated due to nausea), and UVB with minimal effect.
He was first seen at The Rockefeller University, NY, USA, in December 2000 and received numerous courses of biological therapies in the context of our clinical trials program. He initially received efalizumab (100 mg [1 mg/kg] sc weekly for 12 weeks) with good effect. His re-treatment with efalizumab was required in May 2001 because of a sunburn-induced flare, and was permitted under our clinical trial protocol. Another psoaisis flare in Sept 2001 was treated with alefacept (7.5 mg IV for 12 weekly doses) with good effect. Subsequent disease exacerbations were managed well with a course of daclizumab (anti-CD25) therapy, NB-UVB, and cyclosporine.
Due to previous success with efalizumab and recent USA FDA approval, a disease flare in March 2004 was managed with efalizumab at the standard dose (1 mg/kg/wk sc) at a private clinic. However, he missed a dose in June 2004 and his skin flared again, so he re-attended our clinic (Fig ). Despite missing a dose, there was still leukocyte CD11a saturation by efalizumab (Fig. , solid line identical to isotype, shaded). At this time, his psoriasis was complicated by Staphlococcal skin infection. To gain control of his skin disease and while waiting for his skin infection to respond to antibiotic treatment (dicloxicillin), he was given low-dose NB-UVB. Efalizumab was re-commenced in September 2004 with good result (110 mg/wk, 1 mg/kg). This has been continued and the patient is currently in remission.
Immunohistochemistry during the flare reaction (Fig. ), shows there are relatively less lesional CD3+ cells compared to untreated psoriasis, and they are predominantly all CD8+. CD103 is also expressed on epidermal T cells. In addition, there are abundant CD11c+ and inducible nitric oxide synthase (iNOS)+ inflammatory cells infiltrating the dermis and epidermis. CD14+ cells are relatively rare (not shown).


Patient 2 is a 33 year-old Australian-born Caucasian female with a 14 year history of severe plaque psoriasis, and psoriatic arthritis for 12 years. Her first presentation of psoriasis was with erythroderma at 19 years old. Her past medical history included appendicectomy, infectious mononucleosis, and Chloroquine-resistant P. falciparum malaria at age 15 years following travel to Papua New Guinea. She was not taking any medications at the time of initial referral to Royal Prince Alfred Hospital Department of Dermatology, New South Wales, Australia, in 1994.
Past rotational treatments for her psoriasis and psoriatic arthritis included cyclosporine (1990 and 1995), methotrexate (1993 and 1996), acitretin (1994 and 1997), as well as periodic courses of NB-UVB. She was hospitalized in 1999 for erythrodermic psoriasis. In 2001 her psoriasis flared and other therapies tried without success were mycophenolate mofetil, hydroxyurea, tacrolimus, and thioguanine. From July 2001 to November 2002 she received periodic treatment with cyclosporine and acitretin therapy, with poor disease control.
Over the next 2.5 years, this patient was treated with a number of newer biological therapies with standard dosing, sometimes requiring cyclosporine cover and subsequent withdrawal as the patient responded. Etanercept (anti-TNF receptor) (Dec 2002–Feb 2003, 25 mg sc twice week) was initially successful, but was ceased on relapse to erythroderma. Alefacept (anti-CD2) (15 mg IM weekly for 3 months) had no beneficial effect.
Efalizumab (anti-CD11a) (80 mg [1 mg/kg] sc weekly, Dec 2003) induced a dramatic clinical response, and after 6 weeks, cyclosporine was ceased. The patient missed the 18th dose of efalizumab, but the regular dose was given at the subsequent visit. Two days after the "catchup" dose, the patient developed a psoriatic flare involving extensive plaques on all body surfaces. Immunohistochemistry at this time (Fig. ) shows similar results to patient 1: there are relatively reduced CD3+ and CD8+ cells, epidermal T cells are CD103+, and there are abundant CD11c+ and iNOS+ inflammatory cells infiltrating the dermis and epidermis.
During this flare, NB-UVB was administered concomitantly with efalizumab, however a UVB-induced burn was associated with recurrence of her psoriasis. However, by June 2004 there was almost confluent severe plaque psoriasis again with features of erythroderma. The efalizumab dose was increased to 125 mg (1.5 mg/kg) sc weekly, but was ceased in Sept 2004 as there was no further improvement.
Infliximab (anti-TNF-α) (400 mg [5 mg/kg] at 0 and 2 weeks, followed by 400 mg every 6 weeks) was commenced with excellent effect for 4 months, when the patient then experienced another flare of her psoriasis. It was decided to carefully combine infliximab and efalizumab therapy. In February 2005, 62.5 mg (0.7 mg/kg) efalizumab was given sc, and a second dose of 125 mg (1.4 mg/kg) a week later, and she started to respond clinically. She is currently well controlled on this therapy.


A 38-year-old female presented with a one day history of acute epigastric pain. There was no nausea or vomiting. She had developed non-Insulin dependant diabetes 18 months previously. On examination she was overweight and there was epigastric tenderness, but no mass was palpable. All haematological and biochemical parameters were within normal limits.
Abdominal ultrasonography demonstrated a 5 × 3 cm partially cystic mass in distal pancreas with a possibility of a cystic neoplasm. A contrast enhanced computed tomography (CT) scan confirmed a 2 cm mass in the body of pancreas (Figure ). Dynamic contrast enhanced magnetic resonance imaging (MRI) showed a 4 cm cystic lesion in the body of Pancreas suggestive of a mucinous cyst adenocarcinoma (Figure ). No liver or abdominal metastases were detected on either the ultrasound or CT examination.
The patient underwent staging laparoscopy which showed no metastases. Laparotomy was performed. An en-block distal pancreatectomy, including the pancreatic mass, and splenectomy was performed with full clearance of peri-pancreatic and coeliac nodes. The patient made an uneventful recovery.
On gross examination the pancreatic tumour was oval, 7.0 cm in diameter, and was surrounded by a fibrous pseudocapsule. Its cut surface showed solid and cystic spaces (Figure ). On microscopy, the solid portion of the tumour revealed sheets of uniform polygonal cells as well as dyscohesive papillae arranged around fine fibrovascular cores. The cyst wall was composed of dense acellular fibrous tissue within which the tumour cells were arranged as cords and trabeculae set within a mucinous background (Figure ).
No invasion of the tumour into surrounding normal tissue was present. The tumour cells were strongly positive for vimentin and alpha-1 antitrypsin and showed faint focal positivity with MNF116 and chromogranin.


We describe the case of a 54 year old, non-smoker, Caucasian woman, a computer programmer, who was admitted to the General Hospital in June 2003, following an episode of overdose with Citalopram and alcohol. At the time of her admission, she gave a history of depression and suicidal ideation for six months. She was not known to the local psychiatric service.
The patient was discovered by her twin sister soon after the overdose. Initially, she had disclosed to the medical doctor admitting her that she had taken approximately 14 tablets of 20 mgs of Citalopram along with 2 bottles of red wine. However, later on she informed us that she might have taken up to 30 tablets of 20 mgs Citalopram. The actual amount ingested remains unclear.
Soon after her admission, she complained of painful left eye with blurred vision, and was seen by the Ophthalmologist, who found that our patient had an intra-ocular pressure of 23 mmHg in the right eye and 60 mmHg of mercury in the left eye (Normal IOP-10–20 mm Hg), with left corneal edema, and fixed dilated pupils. She was not hypermetripic and had averaged sized eyes. She was noted to have shallow anterior chambers (central and peripheral depth not available) in both of her eyes. A diagnosis of left angle-closure glaucoma was made and medications were commenced to reduce the elevated IOP. Further investigations including routine blood investigations revealed no abnormalities. Her pulse rate and blood pressure were normal. She had a blood alcohol level of 85 mgs/dl (Less than 10 indicates safe levels and 50–100 indicates toxic levels). Her blood test did not reveal any detectable levels paracetamol or salicylates.
With regard to her background history, there was previous episode of overdose with paracetamol tablets in 1978. There was no history suggestive of physical illness, and specifically, no history of previous eye problems. There was no family history of eye related conditions. In December 2002, her general practitioner had diagnosed her to be suffering from depression with harmful misuse of alcohol, and commenced her on Citalopram 20 mgs daily. Later, she informed us that she had not taken any of this prescribed medication prior to her overdose and had only been taking Estrogens, given for hormone replacement (Prempak-C).
Approximately 48 hours after the overdose, on examination of her eyes, she was found to have left subhyaloid and retinal hemorrhages. After 72 hours, the visual acuity in the right eye was 6/9 and hand movements in the left eye. The intraocular pressures were reasonably controlled and she had bilateral Yag laser iridotomies. Subsequently, she was discharged to the local psychiatric unit as she continued to express suicidal thoughts and was low in mood. Apart from receiving treatment for her eye problems at the general hospital, she was commenced on a reducing regime of chlordiazepoxide for her alcohol dependence. On discharge from the general hospital, she was advised to continue on Timolol, pilocarpine and dexamethasone eye drops for further 14 days.
She remained free of anti-depressants and her mood improved gradually in the absence of alcohol. After 14 days, her visual acuity was noted to be 6/18 in the left eye, which improved to 6/12 on pinhole. Her ocular condition was noted to be stable. Her ocular pressures were 14 mmHg in the right eye and 15 mmHg in the left eye, but still had retinal hemorrhages on the left eye, with a clearing vitreous hemorrhage.
She was followed-up by the Ophthalmologists and discharged from the psychiatric hospital after 4 weeks with further community support.
In August 2004, her right eye visual acuity was noted to be 6/9, which improved to 6/6 with pinhole and her left eye vision was 6/24, which did not improve with pinhole. She had a left afferent papillary deficit. The pre-retinal and retinal hemorrhages had cleared, but she still had some residual vitreous hemorrhage. Her right eye Intra-ocular pressure was 18 mmHg and left was 19 mmHg without any treatment. She is reviewed by the local eye clinic every six months.


A 52 year old man presented for evaluation of left flank pain of 1 year duration. He was nonsmoker with a history of left nephrolithotomy for staghorn calculus 20 years back. He had hypertension and ischemic heart disease as co-morbid conditions. He also had history of pulmonary kochs in childhood. On clinical examination patient had a scar of left flank incision with a palpable hard kidney. His urine analysis showed microscopic hematuria and culture was sterile. His renal biochemistry was normal. On renal ultrasound a staghorn calculus was detected without associated hydronephrosis. The kidney was nonvisualised on intravenous urogram (figure ) &contributed 8% of total renal function on DTPA renal scan. Patient underwent transperitoneal laparoscopic nephrectomy. During surgery there were dense perirenal adhesions especially near the hilum. During attempted adhesiolysis there was a rent in renal pelvis with resultant spillage of putty material. The hilar lymph nodes were also enlarged and densely adherent to the renal vessels. In view of past history of pulmonary kochs we suspected associated renal kochs in the patient. The procedure was electively converted to open surgery via flank incision. The total operating time was 5 hours and 20 minutes with estimated blood loss of 200 ml. The patient had a smooth post-operative recovery. The histopathological examination of the specimen revealed presence of keratinizing type of squamous cell carcinoma of renal pelvis with metastasis to hilar lymph nodes. Patient was advised postoperative palliative chemo-radiotherapy. After six weeks of surgery patient developed fulminant herpes zoster and expired due to same.


A 54 year old female presented with complains of right flank pain and dysuria of 2 year duration. There was no significant past history & on clinical examination she had a palpable right kidney. She was anemic with preoperative hemoglobin of 9.2 gm%. Her renal biochemistry was normal. On sonography she had a large renal & upper ureteric calculus with mild hydronephrosis. On intravenous urography right kidney was not visualized while the left kidney showed normal function (figure ). The differential function on DTPA renal scan revealed that right kidney contributed 12 % to the total renal function. In view of patient's age, normal serum creatinine & normally functioning opposite kidney, option of renal conservation versus nephrectomy were discussed with patient. She opted for retroperitoneoscopic nephrectomy. Intraoperatively there were dense adhesions of kidney with duodenum & inferior venacava with loss of normal tissue planes. To continue laparoscopic dissection was considered hazardous & the procedure was electively converted to open surgery through flank approach. Nephrectomy with removal of ureter upto pelvic brim was done to remove the stone bearing part of ureter after extending the incision anteriorly in paramedian fashion. The total operating time was 4 hours and 45 minutes with estimated blood loss of 700 ml. Patient was transfused two units of blood postoperatively. The intraoperative findings raised a suspicion of xanthogranulomatous pyelonephritis. However the histopathological examination of specimen revealed high grade transitional cell carcinoma of renal pelvis with infiltration of renal parenchyma and ureteric adventitia. The renal hilar lymph nodes were not involved with disease. The cut margin of ureter revealed carcinoma insitu. Patient was informed about need for segmental ureterectomy and lymphadenectomy. However she was not willing for any surgical intervention. She was treated with combination chemotherapy. On follow-up at 6 months she had developed massive pulmonary metastasis.


A 28-year-old gravida 2, para 1, 30 weeks pregnant woman presented with sudden onset abdominal pain and distension for two days. There was previous history of right upper abdominal pain for six months, which got relieved on analgesics. The previous pregnancy had been uneventful. On physical examination, she was moderately dehydrated and her temperature was 39.6°C. Her pulse was 110/minute, blood pressure was 90/60 mmHg and there was no pallor or icterus. On abdominal examination, there was generalized tenderness, guarding, rigidity and rebound tenderness. Shifting dullness and fluid thrill was present. The uterine fundal height corresponded to 30 weeks gestation. Bowel sounds were absent. Routine laboratory tests revealed hemoglobin of 10.4 g/dL, total leukocyte count of 18850 cells per mL. The blood sugar, kidney and liver function tests were normal. The chest X ray was normal and there was no free air under the diaphragm. Abdominal sonography revealed bowel loops floating in large amount of free fluid. A Single live foetus of 30 weeks gestation was seen. Gall bladder with multiple calculi and wall thickness of 4 mm was also noted. Paracentesis yielded a free flow of purulent fluid admixed with bile.
A clinical diagnosis of peritonitis due to bowel perforation was made and the patient underwent an exploratory laparotomy, which revealed about 4 litres of purulent fluid inside the peritoneal cavity. A thorough exploration revealed normal bowel. A gall bladder with multiple stones and a perforation at the fundus was seen. A cholecystectomy with peritoneal lavage was performed. Postoperative course was uneventful and the patient was discharged one week later. Histopathology of the gall bladder was suggestive of acute cholecystitis. Her pregnancy continued and at 37 weeks' gestation she vaginally delivered a healthy baby. The patient is asymptomatic after a follow up of three years.


A 21-year-old primipara with 32 weeks pregnancy was referred to us from the gynecology department with upper abdominal pain and high-grade fever for 3 days associated with abdominal distension. On examination, the patient had a pulse of 124/minute and her blood pressure was 96/64 mmHg. Mild pallor was noted and there was no icterus, lymphadenopathy or pedal edema. On abdominal examination, the patient had generalized tenderness, guarding, rigidity and rebound tenderness. Bowel sounds were absent. The uterine fundal height corresponded to 32 weeks' gestation. Routine laboratory tests revealed hemoglobin of 12.1 g/dL, total leukocyte count of 14100 cells per mL. The blood sugar, kidney and liver function tests were normal. Abdominal sonography showed a viable fetus of 32 weeks gestation. There was a large collection of fluid in the right side of peritoneal cavity below the liver. Other viscera were normal. Ultrasound guided diagnostic aspiration of the collection revealed frank bile, the presence of which confirmed by biochemical analysis of the fluid. With the presumptive diagnosis of duodenal ulcer perforation peritonitis, the patient was taken up for an exploratory laparotomy. There was an 800 mL collection of bile in the subhepatic and right paracolic space. The stomach and intestines were normal. The gall bladder was distended and a 0.5 × 0.5 cm perforation in the lateral wall of the supraduodenal portion of the CBD was seen. There was no evidence of gall stones. The CBD perforation was closed over a T-tube. The midline incision was closed after inserting a drain in the subhepatic space. The patient went into spontaneous labor 48 hours later and a preterm baby was delivered. Subsequently, on 15th postoperative day, after a normal T-tube cholangiogram (figure ), the T-tube was removed and the patient was discharged the next day. The mother and child are doing well after a follow up period of one year.


A 12-year-old female patient presented with clinical signs and symptoms of acute appendicitis over a duration of one day. General examination revealed tenderness and rebound localised to the McBurney's point. Routine hematological and biochemical investigations were within normal limits except for raised total leucocyte count (16,000/ml). She was diagnosed as acute appendicitis and taken up for appendectomy in the emergency. Surgery was unremarkable, the appendix turgid, and showing signs of inflammation. She was discharged on the very next day.
On OPD follow up, she was detected to have wound infection that was managed conservatively. She subsequently developed an incisional hernia at the appendectomy site that was repaired electively later.
Histopathology analysis of the appendectomy specimen revealed the presence of caseating granulomas and Langhan's giant cells, suggesting tuberculosis of the appendix (Figure ).
She was started on Anti Tubercular Therapy on OPD follow up. Efforts to detect a primary focus of tuberculosis elsewhere in the body were unsuccessful. The patient is presently well on a follow up of two and a half years.


We report the case of a 9-year-old asymptomatic girl who presented a 3 on 6 holosystolic murmur, discovered during a cross sectional survey estimating rheumatic heart disease prevalence in schoolchildren of Maputo in Mozambique. The apical impulse was displaced to the left, and a third heart sound and a short diastolic rumble reflect the rapid and voluminous left ventricular filling. No hepatomegaly or other right ventricular failure was found. According to the physical examination, the severe mitral regurgitation was estimated on the trans-thoracic echocardiography, using the PISA method (effective regurgitant orifice of 26 mm2, body mass index of 0.80 m2). Though unfortunately frequent in sub-Saharan Africa, this case draws a particular attention. As seen on the figure, the giant left atrium (73 cm2, 2-D four cavities apical view) contrasted with a normal pulmonary artery pressure estimated on Doppler analysis of the minimal tricuspid regurgitation (Doppler velocity 2.45 m/s, giving a systolic pulmonary artery pressure about 29 mmHg), well correlated with normal convexity of the interventricular septum and low speed of the pulmonary diastolic flow. This profile illustrated the important role that left atrial compliance may have on pulmonary artery pressure.
Pressure decay across the mitral valve depends on mitral valve area, trans-mitral gradient, and atrio-ventricular compliance []. Atrio-ventricular compliance can be estimated by Doppler echocardiography from the ratio of mitral valve effective orifice area (calculated by the continuity equation, cm2) and E-wave downslope (cm/s2); according of Flachskampf et al. [] the net auriculo-ventricular compliance (Cn) can be calculated as follows: Cn = 1270 × (MVA/E dv/dt) (ml/mmHg) [MVA: mitral valve area in cm2. E dv/dt: E wave downslope of the mitral Doppler signal in cm/sec2]. Atrio-ventricular compliance implies compliance characteristics of the both chambers, atrium and ventricle, as a single unit. When the compliance of either of these chambers is normal, any abnormality of atrio-ventricular compliance reflects abnormal compliance of the other. In case of pure mitral stenosis in young people without additional cardiac pathology, the left ventricle compliance is expected to be normal, and atrio-ventricular compliance is also equivalent to the left atrial compliance, and is a major independent determinant of pulmonary artery pressure measured by catheterization []. This low atrial compliance may explain the overestimation of mitral valve area by pressure half-time, in comparison with continuity equation method or planimetry. Moreover, this limitation of the pressure half-time method is well recognized in the setting of percutaneous mitral valvotomy, which induces substantial changes in chamber compliance within a short period of time.
On the opposite, in case of mitral regurgitation, very few data are reported. Echocardiographic atrio-ventricular compliance evaluation may remain difficult because of difficulties to assess to the mitral valve area. In addition, on the contrary of mitral stenosis, in which auriculo-ventricular is essentially dictated by atrial compliance, auriculo-ventricular compliance in mitral regurgitation is more difficult to evaluate. However in mitral regurgitation, atrial size is known to be proportional to its compliance [], and may explain a normal pulmonary artery pressure in spite of a chronic severe mitral regurgitation.


The patient is a 70 year-old white female who has the previous history of a right breast cancer that was treated approximately twelve years ago by a lumpectomy to the upper central portion of her right breast, right axillary lymph node dissection, and postoperative radiation therapy for a pT1c, pN0, M0, estrogen receptor positive, and progesterone receptor positive invasive ductal carcinoma. She was maintained on tamoxifen for five years thereafter. In her routine annual follow-up at The JamesCare Breast Center of The Arthur G. James Cancer Hospital, she reported feeling a new pea-sized palpable event in the inferolateral aspect of her right breast for only one-week duration.
On clinical breast examination, the patient was noted to have a well-healed periareolar, curvilinear scar along the superior aspect of her right breast from approximately the 10 o'clock to 2 o'clock axis. There were no associated palpable events within this region of her right breast representing the area of her previously treated breast cancer. However, within the mid to peripheral portion of the lower outer quadrant of her right breast in the 7 o'clock axis, the patient had a less than one centimeter suspicious palpable nodule that appeared to be relatively superficially located within the breast tissue.
Mammography (Figure and ) showed stable, asymmetrical, increased density to the tissue within the upper retroareolar portion of her right breast, consistent with her prior lumpectomy site. However, a new 0.8 × 0.5 cm mammographic density was noted in the inferolateral portion of her right breast. Targeted right breast ultrasound (Figure ) showed a 0.78 × 0.63 × 0.49 cm hypoechoic lesion that was located in the 7 o'clock axis and approximately 4 cm from the nipple, which was associated with acoustic shadowing. This was thought to be suspicious for malignancy and was classified as BI-RADS 4, for which a biopsy was recommended.
A minimally invasive right breast ultrasound-guided 8 gauge Mammotome® vacuum-assisted biopsy was performed. Microscopic evaluation revealed fragments of breast parenchyma in which a bland spindle cell proliferation was present, forming long interlacing fascicles (Figure ). The cells showed cigar-shaped nuclei with vesicular chromatin and pinpoint nucleoli that were dispersed amidst varying degrees of collagen deposition, ranging from scant to thick bundles (Figure ). In some fragments, the proliferation could be seen entrapping lobular units. Immunohistochemical stains for cytokeratin were negative.
The patient was subsequently taken to the operating room at to The Arthur G. James Cancer Hospital and underwent an ultrasound directed wide local excision of the inferior portion of her right breast in the 7 o'clock axis within the mid to peripheral breast field.
Gross pathologic evaluation of the specimen, which overall measured 7.5 × 4.5 × 4.0 cm in size, revealed a 0.8 × 0.7 × 0.4 cm gray-white firm mass abutting a 2.5 × 2.0 × 1.2 cm biopsy cavity (Figure ). Microscopic evaluation revealed residual fibromatosis. All surgical margins were negative. The residual fibromatosis came to within 0.6 cm of the overlying skin margin and was 1.1 cm from the closest parenchymal margin. No evidence of carcinoma was seen.
The patient is currently nine months out from her wide local excision of fibromatosis of her right breast and she remains disease free.


In March 2004 a 51-year-old male patient was referred to our outpatient's department because of oropharyngeal pain of the right tonsillar region. The complaints had started one year before with a right sided feeling of pressure in the oral cavity and the neck. In 1966, 38 years before the patient presented to our department, he had been treated for a squamous cell carcinoma of the left tonsil in the territory of the former Soviet Union. At that time, the then 13-year-old boy underwent radical surgery followed by adjuvant radiotherapy with a cumulative radiation dose of 101 Gray. Although the patient was only 13 years old at the time when the diagnosis of a squamous cell carcinoma of the left tonsil was made, the presented documents left no doubt about the initial histological diagnosis. When the 51-year-old patient presented to our department in 2004, the otorhinolaryngological examination showed a smooth bounded neoformation in the region of the right-sided tonsillar fossa and soft palate with a diameter of about 2.5 cm (Fig. ). The tumor's palpation was dense. Computed tomography (CT) of the oropharynx confirmed the neoformation to be smooth bounded and well separated from the surrounding tissue (Fig. ). Computed tomography and ultrasonic examination of the neck did not reveal enlarged cervical lymph nodes that might have indicated lymphogenic metastatic spread. No indication for hematogenous metastatic spread was found on plain x-rays of the chest, ultrasonographic examination of the abdomen and positron emission tomography imaging studies.
An endoscopic examination of the larynx and hypopharynx was performed in general anesthesia and revealed these regions to be without pathological findings. Tumor-resection was then carried out by a transoral approach in combination with a mapping of the oropharyngeal mucous membrane. Histological examination of the tumor revealed spindle cells with marked polymorphism implicating a storiform growthpattern (Fig. ). Via immunohistochemistry focal expression of α-actin and S100 could be detected (Fig. ). The proliferation-index was high (70 %) (Fig. ). Upon these morphologic and immunohistochemical findings a leiomosacroma of the oropharynx was diagnosed. The tumor was completely removed by surgical resection and histological examination revealed the resection margins to be free of tumor cells. Two months postoperatively an endoscopic control-investigation with biopsy collection was carried out for evaluation of microscopic tumor relapse. Histological examination revealed marginal tumor-extension in the region of the left-sided soft palate. Re-operation was carried out by laser-surgery of the left-sided soft palate and histological examination revealed no tumor-remnants to be left in situ. The course of disease and treatment was then supervised by clinical and radiological follow-up control-investigations at regular 3 months intervals. Unfortunately, a biopsy taken from the middle of the soft palate in June 2005 again revealed microscopic signs of tumor-relapse. At that time the patient was free of symptoms and did not show a clinical correlate of tumor-recurrence. Surgical resection of these findings had to be performed two more times and histological investigations finally revealed an R0-resection status. Up to now, the patient did not undergo chemotherapy or radiotherapy of the radiogenic-induced leiomyosarcoma. Close clinical follow-up control-examinations with biopsies of the former tumor region will now be performed. In case of new tumor-relapse radical surgical resection and defect reconstruction by a free radial forearm flap will be the treatment of choice.


A Caucasian 33-year-old married woman had recurrent delusions of persecution for a period of four years. Diagnosis of schizophrenia was established according to DSM-IV-TR. The severity of her psychotic symptoms was assessed using the Brief Psychiatric Rating Scale (BPRS). Family history was negative for schizophrenia and affective disorder, as well as for obesity and diabetes mellitus. At the beginning of treatment (BPRS score = 62) 6 mg/day of risperidone and 15 mg/day of clorazepate were administered; her body mass index (BMI) at the time was 29.4 (height 165 cm, weight 80 kg, baseline prolactin level = 4.5 ng/ml). After five weeks of risperidone treatment prolactin level was 18.1 ng/ml.
At the end of the first year a significant improvement in her psychotic symptoms was observed (BPRS score = 29; prolactin level = 16.1 ng/ml), but also a modest weight gain (5 kg, BMI reached 31.2). During the second year, she was fired from her job, spent more time at home and developed depressive symptomatology; 40 mg/day of fluoxetine was gradually added to her treatment regimen for about 9 months. During this time, she gained another 3 kg (BMI = 32.3; prolactin level = 13.4 ng/ml). After the remission of depression, fluoxetine was discontinued and she experienced carbohydrate cravings and "binge eating" episodes, especially during the evening. In the middle of the third year of treatment, although risperidone was gradually reduced to 2 mg/day without signs of relapse (BPRS score = 27), a dramatic increase in body weight was observed (weight 140 kg, BMI = 51.5; prolactin level = 10.7 ng/ml). All the attempts she made to reduce her weight by consulting a dietician failed. Since it was after the remission of depressive symptomatology and the discontinuation of fluoxetine that she began gaining excessive weight, fluoxetine (20 mg/day) was re-administered for few weeks but without any reduction in weight gain. This suggests that fluoxetine is not related to the patient's weight gain.
Six months later, she developed polydipsia and polyuria. Diabetes was diagnosed (her fasting blood glucose level was 170 mg/dl); thus 1700 mg/day metformin hydrochloride (an oral hypoglycaemic agent []) was prescribed, and after one month fasting blood glucose level was stabilized within the normal range. At the same time, in collaboration with an endocrinologist, 360 mg/day orlistat- a lipase inhibitor [] – was administered. Her body weight was reduced to 120 kg (BMI = 44.1; prolactin level = 8.7 ng/ml) within a period of six months. During the fourth year of treatment, she was hospitalized for a six-week period in an attempt to promote further weight loss. On admission, it was decided to add 200 mg/day topiramate to her regimen, since it has been reported that topiramate is an anticonvulsant with mood stabilizing and weight loss properties []. This helped her to lose a further 10 kg in a six-month period (BMI = 40.4; prolactin levels = 7.2 ng/ml).
The patient never had any abnormalities regarding thyroid function or her menstrual cycle (the levels of reproductive hormones were within normal range) during the four years of treatment. Prolactin levels were not elevated throughout the treatment with risperidone (range of prolactin levels in our patient under risperidone treatment: 7.2–18.1 ng/ml, normal prolactin levels: 2.5–26.5 ng/ml). It is worth noting that the patient complied well with pharmacotherapy.