Case A was a 33-year-old man who lived alone. He had completed 13 years of education and had obtained a professional certificate in institutional plumbing. He was diagnosed with depression at age 28 and with schizophrenia (DSM-IV) at age 30. He had a past history of amphetamine dependence. His pharmacological treatment, which did not change throughout the intervention, included metformin (2 × 850 mg) for diabetes, modafinil (100 mg) to decrease sleepiness, atorvastatin (10 mg) for hypercholesterolemia, atenolol (12 mg) for recurrent migraines, clozapine (200 mg h.s.), desvenlafaxine (50 mg) for musical obsessions meeting criteria for obsessional compulsive disorder (in complete remission throughout the intervention), and two drops of atropine (1% h.s.) for hypersialorrhea. The patient met with his psychiatrist approximately once per month and with his psychologist and occupational therapist twice per month. Socially, Case A saw only members of his family once or twice a week; he has worked as a plumber until 2008 and has been unemployed since 2008.
At the first therapy session, Case A's therapist presented the cognitive remediation program and explained the study procedure in detail. Difficulties in daily life were also discussed. Case A reported the following cognitive complaints: difficulty retaining information, concentration and comprehension problems, and memory loss. The set of goals of cognitive remediation treatment was jointly agreed by both therapist and patient. Case A's objectives derived directly from his complaints and included the following: read a newspaper article and understand the text, read an entire book and retain the thread of the plot, and watch a movie without the use of the “pause” or “rewind” buttons.
Nine neuropsychological tests and two clinical tests were used to assess Case A before the cognitive remediation (). When a score below the 16th percentile was observed in at least one variable of a cognitive domain, then the cognitive domain was considered as impaired.
The experimental design included three steps: baseline assessment, a three-month cognitive remediation (CIRCuiTS), and posttest assessment. Baseline and posttest assessments both consisted of neuropsychological and clinical assessments; neuropsychological assessment was conducted by a research assistant, and clinical assessment was conducted by Case A's treating psychiatrist who had treated him since the beginning of treatment.
At baseline, Case A demonstrated pathological scores (<5th percentile) or impairments/difficulties (<16th percentile) in four of the nine cognitive domains assessed with neuropsychological tests (): visual episodic memory (immediate and delayed recalls), selective attention (inhibition variable), initiation/strategic search (phonemic and semantic categories), and problem solving (high trial number of first category in a card sorting test). Poor verbal fluency was also qualitatively observed during the baseline evaluation session (i.e., poverty of speech). Case A's scores were within the normal range (from 21st to 97th percentiles) for all of the remaining cognitive processes assessed (verbal episodic memory, working memory, sustained attention, and planning). Finally, Case A seemed to have good metacognitive skills because his cognitive deficits were congruent with his cognitive complaints (retaining information, concentration and comprehension problems, and memory loss).
The cognitive remediation program used is named CIRCuiTS []. Several cognitive remediation programs exist. The originality of CIRCuiTS can be summarized in key points. First, CIRCuiTS is theory-driven based on a metacognitive model of the relationship between cognitive and functional change. Using a strategy-based approach, CIRCuiTS has an integrated focus on the transfer of cognitive skills to daily activities. It aims to develop metacognitive regulation and metacognitive knowledge, which are hypothesized to be important for the appropriate generalization of cognitive skills to daily living []. The focus on transfer also comes from its use of real-world goals, homework to facilitate in vivo use of new strategies, and a formulation-based approach in which the impact of cognitive strengths and difficulties on daily living skills is considered. All of these factors are known to be associated with increased motivation [, ]. Second, CIRCuiTS has high feasibility and acceptability among both service users and therapists as seen in a series of quantitative and qualitative studies designed to inform and test the development of CIRCuiTS []. Third, CIRCuiTS has high adaptability to individual differences because it is based on a flexible modular system [].
CIRCuiTS is a computerized psychological therapy program; although patients can use the program independently, it is ideally administered by a therapist. Various cognitive training techniques and strategies are employed, including simplification and errorless learning. Those techniques have been proven to be effective in improving cognitive performance in empirical studies []. CIRCuiTS was designed to be completed in forty therapy sessions, at a minimum of three sessions per week. Therapy sessions last up to one hour, but therapists can adjust time according to the patient.
A therapy session consists of multiple (approximately 4–8) activities covering a wide range of cognitive functions: attention, memory, executive functions, visual-perceptual processing, and metacognitive skills. The activities are designed to target verbal skills, nonverbal skills, or both. Tasks are rotated to be diverse, interesting, and engaging for participants. The CIRCuiTS program includes two types of tasks: (1) abstract tasks, which are designed to improve cognitive functions in an abstract context (e.g., remembering a list of words), and (2) exercises, that is, complex tasks designed to reflect everyday activities (e.g., make a daily schedule and read a letter). Whereas abstract tasks are performed throughout the CIRCuiTS program, exercises are introduced gradually across sessions; the final sessions of the program consist primarily of exercises. The rationale is that patients learn new cognitive skills in an abstract context and subsequently gradually transfer the skills to everyday life. That overall objective of the program is for participants to eventually apply cognitive skills and new strategies developed in therapy in daily life.
Verbalization of cues, prompts, and strategies for completing a given task are key therapist strategies. During a task, the therapist verbalizes hints for the participant, in order to facilitate mentalization of relevant strategies. Verbalized prompts are often used repetitively; participants becomes increasingly independent as therapy progresses, with the therapist verbalising key instructions at first and the participant gradually taking over the verbalisation process which occurs first overtly (out loud) and, later, covertly (mentally). For example, in the “learning a list” task, the therapist may encourage the participant to repeat the list of words to him or herself.
Given a program that specifically addressed and targeted many of Case A's particular deficits, we expected improvement in each of his impaired scores. Improvements were expected in visual episodic memory (as measured by the RCFT), selective attention/inhibition (as measured by the Stroop inhibition test), and problem solving (as measured by the WCST). The underlying skills of verbal fluency were not directly practiced in CIRCuiTS. However, verbalization is one of the primary strategies used by the therapist and the patient during the therapy. Improvement in verbal fluency was therefore expected. No baseline deficits were observed in verbal episodic memory, working memory, or sustained attention and planning, and therefore no significant improvements were expected.
Two approaches were adopted to estimate changes on main outcomes after cognitive remediation. First, the Reliable Change Index (RCI) [] was calculated to determine whether posttherapy change observed for each variable for each participant reaches significance level. RCI, similar to a Z-change score, (a) allows estimating the extent by which a patient distance themselves from a distribution of similar symptomatic patients who were not exposed to the intervention, while (b) controlling for the instrument reliability and (c) allowing a conclusion about the “statistical significance” of the change. RCI larger than 1.96 are seen as statistically significant at a two-tailed 5% alpha level. It can be noted that this statistical approach is quite conservative []; a minimum change of two standard deviations is required to be considered significant. The conservative threshold means that an observed change is unlikely to be attributable to simple measurement unreliability or practice effect within pre- and posttests [].
The RCI were computed with these variables. The standard deviations for the neuropsychological variables were gathered from our laboratory (M. Maziade). The results have been published previously in Schizophrenia Bulletin. However, to have a greater sample size, we used unpublished standard deviations collected from our laboratory since the publication of the paper in Schizophrenia Bulletin. Only one neuropsychological variable, the Stroop from the D-KEFS battery, was gathered from a paper in the literature []. The standard deviations for the clinical variables were obtained from published research: Positive and Negative Syndrome Scale (PANSS) [] and global assessment of functioning (GAF) []. We fixed the same test-retest to 0.80 as a standard for each test. The reliability of 0.80 to 0.90 is considered as the minimum acceptable for internal consistency and 0.70 is the minimum for the test-retest reliability [].
The second approach (less conservative) was to consider the movement of scores from below to above the 16th percentile on instruments with available clinical normative data. In clinical practice, a score above the 16th percentile is considered as normal performance. As a consequence, changes in status from “deficit” to “normal” performance were considered to be a clinical improvement.
Difference between baseline and posttest assessment scores was calculated, and RCI are reported in .
The conservative method revealed that Case A significantly improved on RCFT immediate recall (RCI = 2.68) and RCFT delayed recall (RCI = 1.86). The expected improvement in verbal fluency was observed for both categories (phonemic fluency, RCI = 2.20; categorical fluency, RCI = 2.51). However, the expected improvement in selective attention between baseline and posttest assessments was not observed. Case A's score on the Stroop inhibition test remained unchanged, at the threshold of deficit (percentile = 16).
Finally, the less conservative method revealed that difficulties observed at baseline in problem solving (percentile = 11–16) disappeared at posttest assessment (percentile > 16); however, RCI was not significant.
No significant change was observed in clinical symptoms (as assessed with the PANSS) or in social functioning (assessed with the GAF) ().
The clinical case formulation (see Table 1 in the supplemental material; see Supplementary Material available online at ) pointed out severe difficulties in verbal fluency but important strengths with good comprehension and high motivation. Verbal fluency was not practiced with specific exercise during cognitive remediation with CIRCuiTS. At the beginning of therapy, Case A was unable to identify examples where the strategies learned in CIRCuiTS might be useful in his daily life. By midtreatment, it was expected that Case A would be able to identify applications in his daily life independently, but this was not the case. Case A's deficit in verbal fluency could prevent him from verbally generating a list of applications during the therapy session. His therapist therefore asked him to make a list of the areas of his life in which he experienced cognitive difficulties (e.g., work, friends, or medication) as homework for the following session. The task was very difficult for him, but, after several drafts, the final version was exhaustive, with concrete examples that reflected his daily life. In the following session, Case A's therapist asked him to use a CIRCuiTS strategy to organize his list. Case A successfully categorized each of the identified situations (e.g., food, interests, and social situations) and the list was used for the remainder of therapy. By asking participants to verbalize strategies during and after training exercises, the CIRCuiTS program helps participants gain awareness of strategies and generate new strategies if application efforts are not successful. The list was an interactive document open to modification and enhancement; it served to keep track of the objectives set at the beginning of therapy. As mentioned in the clinical case formulation (see Table 1 in the supplemental material), Case A's goals were very concrete and directly linked to his daily life (e.g., read a book). The “list” strategy was used because Case A demonstrated deficits in verbal fluency. This deficit made him a unique and interesting case study; however, the strategy is likely to be applicable and useful for other participants, even in the absence of verbal fluency problems.


A 65-year-old man presented with perineal pain, pollakiuria, and a serum carbohydrate antigen 19–9 level of 564.3 IU/mL (normal, <39.9 IU/mL). He had undergone a resection without preoperative chemoradiotherapy for a 4 × 4.5-cm rectal adenocarcinoma lesion 14 months previously, which was graded as IIA (T3N0M0) according to the AJCC TNM classification []. According to the surgical report, abdominoperineal resection with lateral lymph nodes resection and inferior mesenteric artery lymph node resection had done. Computed tomography (CT) and positron emission tomography (PET)/CT revealed a 3.5 × 3.0 × 2.7-cm perineal metastatic lesion obstructing the right ureter. Metastases were observed in the right obturator lymph node, and the largest lesion measured 4.0 × 3.3 × 3.0 cm. The metastatic lymph node had infiltrated the right internal iliac artery (Figure ).
After stent placement in the ureter, four cycles of a modified FOLFOX6 regimen (mFOLFOX6) comprising 85 mg/m2 oxaliplatin, 200 mg/m2 leucovorin, 400 mg/m2 5-fluorouracil (5FU) bolus on day 1 and 2400 mg/m2 5FU as a 46-h continuous infusion were administered at 2-week intervals. Subsequently, the patient experienced lower back pain, and a second PET/CT examination indicated tumor recurrence and lymph node metastases on one side of the pelvis. Chemotherapy was terminated and radiotherapy (30 fractions at 2 Gy per day; total, 60 Gy) was initiated. Upon pain relief, mFOLFOX6 therapy was reinitiated according to the previous regimen, and no signs of disease progression were observed until 10 months later. At this point PET/CT scans revealed that the perineal metastatic tumor had enlarged to approximately 9 cm (Figure ), and the patient was hospitalized and treated with a FOLFIRI regimen comprising 150 mg/m2 irinotecan, 200 mg/m2 leucovorin, 400 mg/m2 5FU bolus on day 1 and 2400 mg/m2 5FU as a 46-h continuous infusion. One week later, the patient developed grade 4 neutropenia (<500/mm3; Common Terminology Criteria for Adverse Events ver. 4.0).
Between treatments, DNA was extracted from sections of the primary tumor tissue and analyzed for KRAS and BRAF mutations and MSI []. No MSI or mutations at codons 12 or 13 of KRAS were identified. Direct sequencing for BRAF revealed a triplet nucleotide deletion (TGA) in coding nucleotides 1799–1801 (Figure ). This mutation resulted in the deletion of amino acid 601 (lysine) and a valine–glutamate substitution at position 600 (VK600–601E).
After recovery from severe neutropenia, the perineal metastatic tumor had grown rapidly and had invaded the bladder (Figure ), and consequent severe hematuria and nephropyelitis resulted in renal failure. Despite therapy for renal failure, the patient died 15 months after initiation of first-line therapy for tumor recurrence.


A 69-year-old Japanese woman with unremarkable personal and family medical histories presented to the general surgery department of our hospital with constipation for approximately one month. Her rectal examination revealed rectal stenosis and possible rectal cancer. Her subsequent barium enema examination showed rectosigmoid stenosis (Figure ), but no irregularities in her mucosa. Accordingly, a biopsy specimen was taken from her mucosa by lower abdominal gastrointestinal endoscopy, and showed no evidence of cancer cells in the area of the stenosis. Her blood tests revealed slightly elevated levels of the cancer antigens carbohydrate antigen 15-3 (CA15-3) and cancer antigen 125 (CA12-5), but all other values were within normal ranges.
Apart from thickening of her rectosigmoid wall in the stenotic region (Figure ), no other abnormalities were detectable in her abdominal and chest computed tomography (CT) scans. Full-length positron emission tomography (PET) was suggested as a non-invasive procedure for detecting the primary lesion, but she declined for financial reasons. Hence, an exploratory laparotomy was performed to identify the cause of her rectosigmoid stenosis.
Her surgical examinations revealed nodules dispersed throughout her abdominal cavity, and additional stenosis in her rectum and ileocecum, suggesting peritoneal metastasis. Histopathological findings from a biopsy specimen of the peritoneal material from around the rectosigmoid region were consistent with a diagnosis of peritoneal metastasis of an invasive lobular carcinoma, likely from the breast (Figure ). However, subsequent breast examinations by the breast oncology department revealed no visible or palpable abnormalities or secretions in either of her breasts.
Subsequent mammogram images showed a spiculated structure of lactiferous ducts in area C of her right breast (Figure ). Moreover, a ductal ultrasonography revealed a lesion of approximately 5 × 6mm in the same area (Figure ). A subsequent biopsy specimen of the duct showed cells with histopathological characteristics similar to those in her peritoneal nodules.
Therefore, the final diagnosis was of rectal stenosis caused by carcinomatous peritonitis arising from a metastatic invasive lobular breast cancer.
After her diagnosis, courses of hormone therapy and taxane- and anthracycline-based drugs were administered. Her rectal stenosis symptoms improved immediately after completion of two courses of weekly paclitaxel, and she was able to start ingestion. After discharge, a sequential regimen of paclitaxel, docetaxel, and anthracycline was administered in the out-patient department of our institution for one year, followed by hormone therapy for three years. However, the disease gradually progressed and she died four years after the initial diagnosis.


A 44-year-old Caucasian man presented to our Urgent Care clinic with a complaint of swelling in his right posterior mandibular molar teeth area that started about three months previously. There was no associated pain except for occasional interference of the swelling with occlusion and mastication. His vital signs were within normal ranges; his medical history included a family history of diabetes, cardiovascular disease, and cancers. His previous dental treatment included two right posterior quadrant dental implants, proximate to the lesion area, placed three months prior to presentation.
On clinical examination, he had slight extraoral facial swelling of his right posterior mandible, but his regional lymph nodes were not palpable. An intraoral examination showed a 45×25×15mm sessile, lobular soft tissue mass of his right posterior mandibular gingiva related to his first and second premolars (Figure ). The mucosal covering of the lesion exhibited surface tan, red, and bluish areas with a focal area of ulceration. A panoramic radiograph of his jaws revealed two implants at his right posterior mandible in the vicinity of the lesion (Figure ) with no other significant findings. These clinical and radiographic findings indicated a benign lesion, and the following differential diagnoses were generated: pyogenic granuloma, POsF, peripheral odontogenic fibroma, focal fibroepithelial hyperplasia, and PGCG. Malignant entities such as squamous cell carcinoma, other primary malignant lesions, and metastatic lesions, although thought to be unlikely, were also considered. Complete excision of the lesion was performed, and the entire specimen submitted for histopathologic examination.
Microscopic examination of the hematoxylin and eosin-stained sections of the specimen revealed a nodular soft tissue specimen consisting of an ulcerated benign cellular mesenchymal tissue proliferation supporting elaborate trabecular bone formation, and occasional cementum-like calcified deposits (Figure A,B,D). This interfaced with stroma supporting aggregates of benign multinucleated giant cells with hemorrhagic and hemosiderin deposits (Figure A-C). This framework was covered by discontinuous parakeratinized surface stratified squamous epithelium maintaining the usual pattern of cellular maturation, which rested on an intact basal cell layer with elongated rete ridges. Where the surface epithelium was discontinuous it was covered by a fibrinous layer supporting neutrophils and extravasated erythrocytes.


The patient was a 76-year-old man with abdominal pain who was transferred to our hospital in August, 2013 from another institution. He had experienced 48 hours of obstipation, and computed tomography of the abdomen was concerning for an incarcerated Morgagni’s hernia. He had a 10-month history of intermittent abdominal discomfort after eating large meals. Evaluation at another institution in 2012 had revealed a right Morgagni’s hernia that was managed non-operatively. He also had a longstanding history of gastroesophageal reflux disease and a known moderate-sized paraesophageal hernia.
A physical examination revealed decreased breath sounds in the base of the right lung and diffuse abdominal tenderness with guarding. There was focal tenderness at the right lateral chest wall. Computed tomography (CT) scans of the chest, abdomen and pelvis obtained for operative planning showed a large right Morgagni hernia containing small bowel, large bowel, and appendix with interval development of acute appendicitis when compared to CT scans obtained at the referring facility (Figures and ). A moderate paraesophageal hernia was stable in size compared to its appearance in prior studies. These physical and imaging findings indicated the need for surgical intervention.
We chose an upper midline laparotomy over a laparoscopic approach, given the possibility of ischemic or necrotic bowel. There was a 4 cm by 6 cm anterior defect 5 cm right of midline, anterior to the liver (Figure ), containing approximately 100 cm of distal ileum, cecum, appendix, and a portion of the ascending and transverse colon. The cecum was dilated but viable and the appendix had a dilated tip without evidence of perforation.
The Morgagni hernia contents were reduced and an appendectomy was performed. The paraesophageal hernia was reduced, the hiatal defect was repaired and a Nissen fundoplication was performed. The Morgagni defect was repaired primarily with interrupted prolene sutures without removal of the hernia sac (Figure ).
Postoperatively, the patient’s course was complicated by a pulmonary embolism that required anticoagulation with a direct thrombin inhibitor because of heparin resistance, new onset atrial fibrillation secondary to volume overload that improved with aggressive diuresis, Clostridium difficile colitis treated with oral vancomycin, and ileus that resolved with nasogastric decompression and bowel rest. He was discharged home on postoperative day 14. The final pathology report confirmed acute appendicitis and periappendiceal inflammation. At his follow-up visit, the patient was doing well and eating a normal diet without dysphagia or persistent gastroesophageal reflux.


A 14-year-old Japanese girl received a diagnosis of CPAM when she presented with pneumonia. Volumetric thin-section high-resolution computed tomography (CT) revealed almost complete absence of the left interlobar fissure (Figure ). A lesion was detected in the basal segment of her left lower lobe, consisting of multiple cysts but no abnormal vessels. The preoperative diagnosis was CCAM.
CT pulmonary angiography with three-dimensional reconstructions of her pulmonary vessels was performed. Images were acquired using a 16-slice scanner (LightSpeed Ultra; GE Healthcare, Milwaukee WI, USA). Iohexol (400mg I/kg of contrast medium, to a maximum of 100mL) was injected intravenously at a rate of 2mL/second. Images revealed her left lingual artery to be the first branch of her left main pulmonary artery, which is the so-called mediastinal lingual artery (Figure ).
Hybrid VATS lobectomy using differential lung ventilation was performed in the right lateral decubitus position. We used a small thoracotomy incision (5.5cm) along the fifth intercostal space centered on the midaxillary line, and two ports in the sixth intercostal space along the postaxillary line and in the seventh intercostal space along the midaxillary line. As seen on CT, her left lung had almost no fissure. Her left inferior pulmonary vein was first divided using a stapler (Endo-GIA™ white, Covidien, Mansfield MA, USA). It was difficult to free the affected arteries and bronchi from extensive adhesions. After we located the left upper and lower bronchi using a bronchoscope, we confirmed the CT finding of the mediastinal lingual artery arising medial to A6. Before the fissures were separated, the left lower bronchus was divided using a stapler (Endo-GIA purple) and her left pulmonary artery was divided, also with a stapler (Endo-GIA white), just proximal to the origin of A6. After her left lung was inflated by an anesthesiologist, the border line between the deflated and the inflated area clearly appeared (Figure ). Her left lower lung was divided with staplers (Endo-GIA purple one time and black four times). The procedure lasted 5 hours 22 minutes with a small amount of blood loss. There were no complications.


A 42-year-old Chinese male was admitted for a 6-year history of dysphagia lusoria. His past medical history was unremarkable. At admission, general conditions were satisfactory, and a physical examination of the thorax was normal. Routine laboratory tests were within normal values, but a chest radiograph revealed a large mass with calcification in the mediastinum. Esophagus barium opacification showed that the middle and inferior segment of the esophagus was compressed by the mass (Figure ). A computed tomography (CT) scan of the chest revealed the presence of an ovoid mass about 4.8 × 7.6 × 10.0 cm in the right posterior mediastinal region. The mass showed a heterogeneous density accompanied with pronounced calcification. Administration of contrast medium gave only a mild strengthening of mass (Figure ). A magnetic resonance (MR) imaging showed a well-circumscribed mass which was isointense-hypointense on T1-weighted imaging and hypointense on T2-weighted imaging (Figure ). An enhanced MR imaging of the head and spine revealed no abnormal findings. A diagnosis of teratoma was first suggested. The tumor was then surgically removed through a right thorax incision.
The patient underwent surgical resection of the mediastinal tumor through the right thorax incision. During the operation, the tumor was located in the posterior mediastinum. It was found to have extended under the bronchial bifurcation. Based on this surgical finding, the mass was in close relationship with the esophagus and pericardium; the esophagus was obviously compressed and displaced. The tumor was a clearly demarcated encapsulated solid mass with brown-gray color and off-white cut surface. After being routinely fixed with 10% formaldehyde and embedded in paraffin, the tumor sample was processed, and 4-μm-thick tissue sections were obtained. The hematoxylin and eosin (H-E) staining (Figure ) showed that the tumor was composed predominantly of bundles of elongated spindle-shaped cells with little oval nuclei. There was heavy deposition of collagen fibers between the tumor cells. In some areas, typical whorl structure of mengingioma was observed. In addition, multiple psammoma bodies were seen. There were no mitotic figures and necrosis. Immunohistochemical staining revealed that the tumor cells were positive for epithelial membrane antigen (EMA) and vimentin, and negative for CD34, bcl-2, SMA, and S-100 protein. The Ki-67-labelling index was <5%. According to the histological and immunohistochemical features, the tumor was diagnosed as a benign mediastinal psammomatous meningioma (World Health Organization (WHO) grade I, based on the 2007 WHO classification []). At follow-up 24 months after surgery, there was no evidence of local recurrence or distal metastasis.


A 38-year-old female nursing home resident with a body mass index (BMI) of 44 kg/m2 and bilateral sequential lower extremity amputations was found unresponsive and pulseless for an unknown period of time and was immediately intubated at the scene. Cardiopulmonary resuscitation was initiated with restoration of circulation. Following transfer to a nearby acute care hospital, neurological examination revealed apnea and a computerized tomographic (CT) scan of the head revealed diffuse cerebral edema. She was pronounced dead by brain death criteria and the family consented to organ donation.
Past medical history provided by the family and skilled nursing facility revealed that the patient had been hypertensive for 3 years and had a history of diabetes mellitus for 20 years. She also smoked tobacco and had resultant chronic obstructive pulmonary disease. However, she did not have any history of cancer or chronic weight loss. On the day of admission, the white blood cell count was 4800 cells/microL (differential 83% neutrophils, 4% monocytes, and 13% lymphocytes), hemoglobin was 10.3 grams/dL, and platelet count was 125,000/microL. Peripheral blasts were not detected on a blood smear. Both kidneys were recovered for transplantation. No other organs were used (the liver was not recovered because of steatosis). Although an autopsy was not performed, a preimplantation kidney biopsy revealed changes that were consistent with long-standing diabetes mellitus.


A 47-year-old female was admitted to our hospital with an enormous polypoid mass on her right labia majora initially noticed three years ago. The mass has gradually increased in size. On clinical examination a well-circumscribed polypoidal mass measuring approximately 25 × 20 × 6 cm was revealed. The lesion was soft and gelatinous in consistency, covered by normal appearing skin. The tumour was painless with no associated lymphadenopathy. On gynaecological examination the cervix and vagina were unremarkable. Her laboratory investigations were within normal limits and ultrasonography of the abdomen had nothing to add. Moreover, ultrasonography of the perineum showed a large mass with peripheral vascularity, heterogenous hyperechoic areas, measuring approximately 26 × 21 × 6 cm, and magnetic resonance (MRI) of the pelvis confirmed these features (Figures , , and ). The initial differential diagnosis included the fibroepithelial polyp, the vulval fibroma, or the giant acrochordon, and the patient underwent a wide local excision of the tumour. The procedure was complicated with profuse bleeding, but the postoperative course was uneventful.
Histopathological examination revealed an encapsulated neoplasm composed of stellate and spindled cells, embedded in a loose matrix with wavy collagen. The lesion contained thin-walled capillaries and thick-walled vascular channels. Neoplastic cells had relatively scant eosinophilic cytoplasm and their nuclei were ovoid, containing finely dispersed chromatin with one or two small eosinophilic nucleoli (). There was no significant nuclear pleomorphism nor mitoses observed. Immunohistochemically, the tumour cells were positive for vimentin, actin, desmin, and progesterone but negative for S100 protein, CEA, CKAE1/AE3, factor VIII (Figures and ). The background stroma stained positive with alcian blue (pH 2.5). Combining all the above the diagnosis of AA is set.
The patient developed local recurrent disease 18 months later, which was revealed on her follow-up visits.


A 32 years old couple attended for fertility consultation reporting a history of 5 years trying for pregnancy with no success. On investigation of the female the fertility workup included: check ovarian reserve by anti-mullerian hormone 3.72 ng/mL and antral follicle count 18 follicles on both ovaries, ultrasound examination of uterus and office diagnostic hysteroscopy. All showed no abnormalities. Semen analysis on the male showed a volume of 5.6 mL, concentration of 23 million/mL, 44% motile of which only 5% were progressively motile. Sperm morphology was reported as 2% normal with evidence of acrosome abnormalities (strict criteria, Figure ). DNA fragmentation index was 10.6% and high DNA stainability was 14.9%. Both were found by flow-cytometry method.
Male factor infertility was diagnosed and the couple counseled for IMSI. Informed consent was obtained. No history was known regarding other male family members fertility.
The female patient was treated with antagonist protocol using ganirelix (Orgalutran – MSD) and the administration of 150 IU rFSH (Puregon - MSD) daily for 9 days. Oocyte retrieval was undertaken 36 hours post hCG priming 10,000 IU (Pregnyl - MSD). A total of 7 oocytes were collected of which 5 were mature and suitable for injection. Semen analysis on the day of oocyte retrieval on high magnification using an inverted microscope equipped with Nomarski differential interference contrast optics (Leica AM 6000) showed no normal morphology only total round heads (globozoospermia). Due to the concern of a total failure to fertilize the couple were informed that IMSI would be the method of choice to continue to observe the sperm sample, trying to identify any sperm with a partial or small acrosome to avoid the use of oocyte activation media. However none were observed and post IMSI the use of oocyte activation media was undertaken. The couple were fully informed of the limited data available on the use of calcium ionophore with regard to the long-term health of resultant offspring. Written consent was obtained to carry out this procedure. The characteristics of the sperm used for insemination showed total round head nucleus with no acrosome present, however all were motile.
Following IMSI the 5 oocytes were placed into oocyte activation media (GM508, Cult Active, GYNEMED) for 15 minutes at 37 degrees 5% 02 and 6% CO2. The oocytes were then washed free of calcium ionophore through 8 drops of culture media. The oocytes were cultured over night in CSCM media (Irvine Scientific, Santa Ana, CA) in the embryoscope time lapse incubator (Fertilitech-Unisence Denmark). Sixteen hours post injection only one oocyte showed signs of fertilization and developed normally (Figure ; an additional movie file shows this in details, see Additional file ).
The embryo was cultured to day 5 uninterrupted in the embryoscope (Unisense FertiliTech, Aarhus, Danemarca) and a blastocyst grade 6AA [] was transferred under ultrasound guidance. BhCG level on day 12 post embryo transfer was 468.9 mUI/mL, 2 days later BhCG level was 916.1 mUI/mL. Ultrasound evaluation at 12 weeks and 5 days of gestation (Figure ) showed Fetal Heart Beat 149 bpm, CRL (crown–rump length 63 mm, nuchal transluency – 1.6 mm and intracranianal transluency 2.1 mm, ductus venosus dopller without notch, nasal bone present and tricuspid doppler in normal range. First trimester biochemical and ultrasound screening reveal low risk for trisomy.
As yet, it is unclear whether patients whose ejaculate contains both 100% globozoospermicornormal and globozoospermic cells (partial globozoospermia) suffer from a variation of the same syndrome [] and still remains to be elucidated. Yoon et al. [] reported absence of PLCz in both the normal and round-headed sperm of a partial globozoospermic patient, in line with the inability of partial globozoospermic sperm cell types to activate mouse oocytes as reported by Heindryckx et al. []. Numerous reports studying familial cases have suggested that globozoospermia is a genetic syndrome [-]. However, the specific mode of inheritance remains unclear, although recently it was reported that a mutation in the SPATA16 gene appears to be associated with certain types of globozoospermia in men [].


A 71-year-old Caucasian woman presented to our clinic with obscurations in the left eye (OS). On examination, her best-corrected visual acuity was 20/25 in both eyes (OU). Intraocular pressure was 11 mmHg in the right eye (OD) and 15 mmHg OS. Anterior segment was unremarkable except for moderate nuclear sclerosis OU. Pupils were round and equally reactive to light without an afferent pupillary defect. Dilated fundus examination revealed a highly pigmented, brown, papillary lesion with overlying small drusen OS (). The mass measured 3 mm × 2 mm. Ultrasonographic examination revealed an apical height of 1.2 mm with medium to high internal reflectivity. There were no marked signs of malignant transformation or vascular activity. As cataract progressed, pars plana vitrectomy (PPV), phacoemulsification with posterior chamber intraocular lens (IOL) implantation, membrane peel (MP), intravitreal triamcinolone acetonide (IVT), and laser ablation (LA) of the tumor with fine-needle aspiration biopsy (FNB) of the optic disk melanocytoma were performed. Gene expression profile assessment was undertaken at Castle Biosciences Inc. Postoperative follow-up included multicolor fundus photography and SD-OCT (Heidelberg) of the tumor and biopsy incision site (). Genetic expression profiling revealed a class 1A genetic signature.


A 45-year-old Hispanic woman was referred to the clinic for evaluation of an atypical optic nerve head melanocytoma OD. On examination, her best-corrected visual acuity was 20/50 OD and 20/20 OS. Intraocular pressure was 14 mmHg in both eyes. Visual acuity progressively decreased over the next year to the level of 20/200 secondary to cataract and optic nerve head compression. A relative afferent papillary defect developed OD. Visual field constriction OD was present. Dilated fundus examination OD revealed a deeply pigmented lesion in the optic nerve head with adjacent choroid and retinal involvement (). The tumor measured 5 mm × 5 mm in diameter. Echographic examination revealed tumor thickness of 2.1 mm. A-scan showed medium reflectivity. As cataract progressed and visual acuity decreased to 20/200, pars plana vitrectomy, phacoemulsification with posterior chamber intraocular lens implantation, membrane peel, intravitreal triamcinolone acetonide, and laser ablation of the tumor with fine-needle aspiration biopsy of the optic disk melanocytoma were performed. Genetic expression profiling was a class 1A. Best-corrected visual acuity was 20/100 at 1 month after surgery. SD-OCT thickness maps () show mild reduction of tumor volume after treatment.


A 74-year-old Caucasian male presented to our clinic with an atypical optic disk melanocytoma with associated subretinal fluid and neovascular activity OD. At examination, his best-corrected visual acuity was 20/200 OD and 20/20 OS. Fundus dilation revealed a choroidal papillary and peripapillary pigmented mass with associated subretinal fluid (). The lesion base measured 9.5 mm × 7.5 mm. Apical height was 1.7 mm by ultrasonographic testing. Close follow-up revealed enlargement over a 6-month period. Enucleation was performed due to growth and malignant transformation (). Histopathology report showed melanocytic malignant melanoma and a genetic expression profile of class 1A. No evidence of metastasis has been present after 2 years of follow-up.


In November 2011, a 53-year-old male patient presented to our clinics for chemoradiotherapy after resection of a cerebral lesion that was diagnosed as GBM WHO IV° by histopathology. An epigenetic silencing of O6-methylguanine-DNA methyltransferase (MGMT) by promoter methylation was not detected by real-time PCR of tumor DNA. Approximately six weeks after resection, the patient was started on standard combined chemotherapy and radiation (temozolomide 75 mg/m2/day and involved-field radiation at a total dose of 60 Gy in 2.0 Gy fractions over a 6-week period). The radiotherapy was well tolerated and the treatment with temozolomide was continued with 150 mg/m2 d1-5 in the first cycle followed by 200 mg/m2 d1-5 every 4 weeks. In April 2012, after three courses of temozolomide, the patient presented with intermittent disorientation and a worsened general condition. The native and Gadolinium-enhanced T1-weighted cerebral magnetic resonance imaging (cMRI) showed a tumor involving the right basal ganglia with strong peripheral and irregular contrast enhancement (Figure A and B). In the T2-weighted FLAIR a pronounced surrounding edema and mass effect was seen in the area of the basal ganglia (Figure C). Because of the clinical symptoms, the deteriorated general condition, and the unmethylated MGMT promoter status [] these radiographic findings were interpreted as GBM relapse. A radiotherapy-induced pseudoprogression is not considered to cause the radiographic findings. To confirm this we performed 18 F-fluoroethyltyrosine-positron emission tomography/computer tomography (FET-PET/CT) scan (Figure D and E). The PET/CT (Figure D) showed a focally increased 18 F-FET uptake corresponding to the contrast enhancement described in cMRI, which was emphasized in the fusion of PET and MRI (Figure E). The mean tumoral uptake (Tu) was evaluated and the ratio to background (Bg) was calculated with Tu/Bg ratio of 2.4. This value exceeds the threshold of 1.6 thereby indicating an active malignancy []. Because of the localization of the relapsed GBM and the reduced general performance status, resection was deemed impossible. It was decided to treat the patient with anti-VEGF antibody (bevacizumab) monotherapy (Avastin®) in an off-label setting. Bevacizumab was given at a dose of 10 mg/kg body weight on d1 and d15 every four weeks. Concurrently, the palliative care team was involved in patient’s care because of the poor general performance status. After three courses, a reduction in tumor size from 51 × 21 × 25 mm to 39 × 17 × 17 mm was observed at Gadolinium-enhanced T1-weighted cMRI, and the degree of contrast enhancement within the tumor had decreased (Figure ). On day one of the forth course of bevacizumab, our patient presented with dyspnoe at the emergency room and the suspected diagnosis of pulmonary embolism was confirmed by CT scan. Therapeutic anticoagulation was started using low molecular weight heparin. Bevacizumab was continued one week later at the initially used dosing regimen. Under low molecular weight heparin, there were no further thromboembolic events or other bevacizumab-related serious adverse reactions until to date. During ongoing therapy with bevacizumab, the patient’s Karnofsky performance status improved steadily from 50% at the beginning of treatment with bevacizumab to 80% after 6 months and the palliative care team stopped patient’s care. Concomitant corticosteroid therapy was reduced continuously and finally stopped. The last cMRI performed after 17 courses of bevacizumab showed a very good partial response to bevacizumab therapy with a tumor size of 35 × 15 × 15 mm in the unenhanced T1-weighted sequences (Figure A) and a lack of contrast enhancement in the lateral portions of the tumor in the Gadolinium-enhanced T1-weighted sequences (Figure B). T2-weighted FLAIR demonstrated a significant decrease of peritumoral edema (Figure C). A very low level of 18 F-FET tracer uptake was noted (Figure ), which was substantially lower than the tracer uptake observed before treatment (Figure D and E). Moreover, Tu/Bg ratio in the post treatment PET/CT scan was 1.3 consistent with reactive changes after treatment (Figure ). After the excellent treatment response observed under bevacizumab treatment, we evaluated to stop monotherapy with bevacizumab. However, since remaining active tumor cannot be fully excluded by the imaging modalities used, we decided together with the interdisciplinary tumor board to further extend the treatment.
26 months after the diagnosis of relapsed GBM, our patient remains in an excellent general condition with a Karnofsky performance status of 100% without further adverse side effects to the current therapy. Under ongoing treatment with bevacizumab the patient is able to live a self-reliant, socially active life.


A 61-year-old female presented to the emergency department complaining of constipation and vaginal bulge with valsalva 89 days after a robotic-assisted hysterectomy. The patient had intercourse three days prior to presentation and experienced postcoital abdominal discomfort with vaginal bleeding. She denied any other trauma. She had no other complaints and denies fevers, chills, nausea, vomiting, abdominal distension, or constipation. Physical exam revealed exposed bowel protruding through the vaginal cavity.


A 68-year-old man with history of coronary artery disease, ischemic cardiomyopathy, diabetes mellitus, primary prevention automated implantable cardioverter defibrillator (AICD), polio, obesity and systolic heart failure presented to our institution with increasing ischemic chest pain for three days. He was found to have a non-ST segment elevation myocardial infarction with decompensated heart failure with ejection fraction of 24%, as well as acute kidney injury secondary to cardiorenal syndrome. This was also complicated by sustained slow ventricular tachycardia (VT), which caused further decompensation.
A decision was made to perform emergency cardiac catheterization with possible PCI. No good radial pulses were palpable. Secondary to his underdeveloped lower extremities from polio, obesity and faint femoral pulses, micropuncture technique under fluoroscopic guidance was used to obtain retrograde right common femoral arterial access, with placement of a 6-French sheath. Selective left coronary angiography was performed with a JL4 catheter, revealing a distal left main into ostial left anterior descending artery (LAD) 70% in-stent restenosis (ISR) lesion which gave rise to a small diagonal after which the LAD was chronically occluded, and a chronically occluded circumflex (Figure ). This resulted in significant hypotension from severe ischemia and the development of cardiogenic shock. Distal abdominal aortography was performed using a 6-French JR4 catheter with bilateral iliofemoral runoff to determine if he was a candidate for Impella (Abiomed, Danvers, Massachusetts) percutaneous left ventricular assist device or IABP support and to outline the course of his femoral artery for contralateral groin access (Figure ). Utilizing micropuncture technique, left common femoral arterial access was gained with placement of an 8-French sheath. A 40cc Datascope IABP was advanced via the left common femoral access into the appropriate position, with difficulty during initial wiring with the 0.028” wire secondary to a distal abdominal aortic lesion (Figure ). IABP support was commenced at 1:1 ratio with vasopressor and inotropic support. From the right common femoral access site, a 0.035” J-wire or angled Glide wire (Terumo Interventional Systems, Somerset, New Jersey) could not get pass the abdominal aortic lesion with the IABP in situ. Thus, the distal abdominal aortic lesion was crossed with a 0.014” Runthrough coronary guidewire (Terumo Interventional Systems, Somerset, New Jersey) and the lesion was dilated with a Viatrec (Abbott, Abbott Park, Illinois) 7.0 × 40 mm balloon to 7 atm for 30 seconds serially (Figure ). A 5-French Glidecath was then used to exchange the Runthrough for an exchange length 0.035” J-wire in the ascending aorta. A 6-French JR4 was used to perform the selective right coronary angiography. Intravenous heparin was used as the procedural anticoagulant. The left main was engaged with a 6-French EBU 3.5 side hole guide, providing good support. The diagonal was wired with 0.014” Runthrough guidewire and the left main into ostial LAD ISR was directly stented with a Xience Xpedition 2.5 × 15 mm drug eluting stent (DES) (Abbott, Abbott Park, Illinois) to 20 atm for 10 seconds (Figure ). Subsequently a NC Trek (Abbott, Abbott Park, Illinois) 3.0 × 12 mm balloon was used to post-dilate to 24 atm for 10 seconds.
Post PCI, he developed recurrent slow VT and this was cardioverted with anti-tachycardia pacing via his implantable cardiac defibrillator (ICD). His right coronary artery (RCA) was then engaged with a 6-French AR1 guide with side holes and the posterolateral branch (PLB) was wired with the Runthrough guidewire. Overlapping Xience Xpedition 2.25 × 18 mm and 2.5 × 12 mm DES were deployed into the distal right, followed by proximally overlapping Xience Xpedition 3.0 × 38 mm and 3.0 × 15 mm DES for his mid to ostial ISR (Figure ). Final coronary angiographic images were obtained.
Distal abdominal aortography digital subtraction angiography (DSA) was then performed with the AR1 guide and repeat dilatation was then performed with an Armada 9.0 × 80 mm balloon (Abbott, Abbott Park, Illinois) to 12 atm for 30 seconds. Secondary to concerns about limb ischemia, the IABP and 8-French sheath were both removed and manual pressure was held for 30 minutes for hemostasis. He made a good initial clinical recovery without any acute post-procedural complications such as bleeding requiring blood transfusion or pseudo-aneurysm. However, he had continued deterioration of his renal function due to acute tubular injury from his previous episodes of hypotension and cardiorenal syndrome, to the point where dialysis was required. The patient and family decided against dialysis after several days, and the patient subsequently succumbed to his renal failure.


A 74-year-old male patient who was a passenger in Sydney to Istanbul commercial flight presented to our hospital with a history of sudden onset of painful swelling in the right eye which occurred 8 hours ago, while the aircraft was descending for landing. The patient had subconjunctival haemorrhage, upper eyelid swelling and proptosis in the right eye. We performed a complete ophthalmic examination. Best corrected visual acuity was 20/20 in both eyes. Direct and indirect pupillary light reflexes were normal. We didn’t observe relative afferent pupillary defect. There wasn’t any colour vision deficiency. The Hertel exophthalmometry measurements were 19 mm and 17 mm in the right and left eye respectively. There was lateral gaze restriction in the right eye which was causing diplopia (Figure ). Intraocular pressure (IOP) was 21 mmHg in right eye and 16 mmHg in left eye which was measured with Goldmann applanation tonometry. Dilated fundus examination was normal.
There weren’t any systemic disease, medication, bleeding disorder, surgery or general anaesthesia, sinus infection or mucocele and previous trauma in the medical history of the patient. Laboratory examinations were within normal limits. Computed tomography (CT) revealed a subperisotal haematoma at the retrobulbar-extraconal region of the right orbit (Figure ). We did an orbital magnetic resonance imaging (MRI) to support our diagnosis and the results confirmed haematoma in the right orbit (Figure ).
We adopted a conservative approach with close observation. Systemic corticosteroid and topical dorzolamide/timolol combination were administered to the right eye of the patient. We followed up visual acuity, pupillary reflexes, IOP, Hertel exophthalmometry and fundus examinations every 4 hours for the first two days and then daily for two weeks. After 24 hours, IOP decreased to 18 mmHg; visual acuity, pupillary reflexes and fundus examination were normal. The patient was stable for the following 10 days. At the 19th day, patient had minimal subconjonctival haemorrhage and slight proptosis whereas upper eyelid swelling, lateral gaze restriction and diplopia resolved. We stopped topical dorzolamide/timolol combination and reduced systemic corticosteroid dosage. Intraorbital haematoma resolved without sequelae on the control CT at the first month follow-up (Figure ) so that we stopped all medication. At the third month follow-up, patient didn’t have any sequelae and complete ophthalmic examination was normal.


A 41-year-old Caucasian woman was referred with a left-sided thyroid nodule. Fine-needle aspiration revealed a diagnosis of papillary thyroid carcinoma; the patient thus underwent a total thyroidectomy and left central nodal dissection. Pathology showed multifocal papillary thyroid carcinoma and one positive lymph node (AJCC Stage T1bN1aMx). In addition, epithelioid granulomas were identified within this node. This was reported as suggesting a concurrent infectious process, though the possibility of sarcoidosis was not ruled out.
In preparation for postoperative radioiodine remnant ablation, pre-ablation imaging was performed with Tc-99 m pertechnetate thyroid scanning. The patient was injected with 370 MBq (10 mCi) of Tc-99 m pertechnetate IV. Imaging began 15 minutes post-injection. Static images were acquired using a Siemens Symbia T1 gamma camera with a pinhole collimator of 4 mm aperture (matrix 128x128, zoom factor 2). A first static image was acquired over 108 seconds at 14.9 cm from the neck, with the patient supine and markers at the sternal notch and thyroid cartilage. A second static image was acquired from the same distance over 300 seconds. A third, magnified, image was obtained at a distance of 3 cm from the patient's neck.
SPECT/CT of the same area was performed over a 180° arc (clockwise rotation), using 128 projections (64 views x dual heads) at 12 s per view. Images were acquired into a 128x128 matrix at a zoom factor of 1, using a step-and-shoot rotation with an auto-continuing non-circular orbit. Scout CT was obtained (30 mA, 130 kV, scan time 0.8 s), followed by routine CT at a slice thickness of 5 mm, effective current of 17 mA, and voltage of 130 kV.
The radionuclide imaging showed uptake-positive lesions along the left internal jugular chain, highly suggestive of metastases (Figure ). At that time, total body 131I uptake was elevated at 7.4% (expected normal < 5%), and un-stimulated (TSH 10.28 mU/L) serum thyroglobulin was 5.5 pmol/L. Plain CT of the neck showed extensive nodal disease in the neck, as well as in the mediastinum. Notably, unlike the cervical nodes, these mediastinal nodes had not shown appreciable uptake on the pertechnetate thyroid scan. CT of the thorax showed mediastinal and bilateral pulmonary hilar lymphadenopathy. Percutaneous biopsies of the mediastinal and pulmonary nodes demonstrated findings consistent with a diagnosis of sarcoidosis and no coinciding malignancy.
The patient was presented with the option of fine-needle aspiration biopsy of the scan-positive cervical nodes as a means of confirming or discounting their metastatic etiology (versus being purely additional foci of sarcoidosis) before deciding whether to proceed with selective neck dissection. It was agreed that a negative FNAB would not be sufficiently reassuring to justify no further surgery, given the suspicious location, the absence of previous reports of convincing pertechnetate or radioiodine uptake by sarcoid tissue, and, moreover, the selective uptake of pertechnetate by the cervical nodes alone.
Left lateral neck dissection was therefore performed without complication. Final surgical pathology showed all level II, III, IV nodes negative for malignancy, and level IV nodes positive for granulomatous lymphadenitis compatible with sarcoidosis. The patient underwent radioiodine ablation in October 2009. Follow-up imaging (131I whole body scanning) to date has been normal, and there has been no clinical evidence of malignancy relapse in the primary site or the neck.


A 70-year-old Caucasian male presented to the Mersin State Hospital, Department of Gastroenterology, Mersin, Turkey, with vomiting and abdominal pain. Medical history showed weight loss up to 10 kg during the previous 3 months due to frequent bilious vomiting and colic abdominal pain, which restricted oral intake. The patient had undergone gastric surgery (distal gastrectomy and Billroth II reconstruction) 47 years earlier (1967) because of a peptic ulcer. The patient had a negative history of constipation and diarrhea. The patient had previously presented to numerous other medical centers with the same symptoms and had been unsuccessfully treated with proton pump inhibitors (PPIs) and antiacid agents. Physical examination showed a pale tongue and epigastric tenderness. He also had a cachectic body composition. Laboratory findings showed moderate anemia (hemoglobin: 9.89 g dL−1) and low serum albumin (3.31 g dL−1) and sodium (133 g dL−1), indicative of poor nutrition. Other biochemical parameters were in the normal range.
Abdominal and thoracic CT findings were normal liver and spleen parenchyma without any intra-abdominal fluid collection and an emphysematous lung disorder. Upper endoscopy showed an approximately 5 cm diameter ulcerovegetant mass with irregular borders on the gastrojejunostomy anastomosis, which was obstructing a major portion of the intestinal lumen, not allowing passage of the afferent loop. Biopsy of the mass showed a poorly differentiated adenocarcinoma (). The fundic and esophageal junctions were normal ().
Following preoperative preparation, the patient was scheduled for open surgery. A midline incision was performed and the explorative finding was an approximately 5 cm palpable, irregular severe obstruction and a dilated preobstructive afferent loop; however, there were no signs of locoregional or distal metastasis (). The neoplastic mass began on the gastrojejunal anastomosis and extended through the afferent loop. The total remnant stomach and affected intestines were resected with safe clear margins and omentectomy was also performed. Reconstruction was accomplished using Roux-en-Y esophagojejunostomy. Splenectomy was performed at the end of the surgery because of splenic injury caused by severe bleeding.
Histopathologic examination of the specimen showed serous adenocarcinoma with perineural infiltration. All surgical margins were intact and immunohistochemical examination was cerbB2 negative (). An anastomotic leak developed on postsurgical d 3. Fortunately, the leak was successfully managed with supportive therapy and enteral feeding via nasojejunal tube. The leak stopped on postsurgical d 20 and regular oral intake commenced. The patient was discharged on postsurgical d 30, at which time his final stage was T3 NO MO, requiring subsequent adjuvant chemotherapy; therefore, he was referred to the oncology department.


A 79-year-old man was referred to our hospital in November 2011 with a complaint of inability to move. His body temperature was 37.7°C, blood pressure was 103/58 mm Hg, peripheral oxygen hemoglobin saturation was 95%, and respiration rate was 25 breaths/min. Physical examination revealed an abnormally large left scrotum and cold extremities. He reported a history of gastric cancer, for which he had undergone surgery more than 30 years ago. His white blood cell count was 9600/μL (92.0% polymorphonuclear neutrophils), and his C-reactive protein level was 34.5 mg/dL.
Abdominal and inguinal computed tomography (CT) revealed an inguinal hernia that had perforated into the left scrotum and exhibited an air-fluid level (). These CT findings were compatible with those for direct hernia.
The patient did not have a wife or children, and he and his younger sister refused surgical intervention because he did not wish to live longer, although he had no other health problems. He was treated with sultamicillin tosilate hydrate and cefotiam hydrochloride. However, abdominal CT performed on the 5th day revealed progression to panperitonitis, and he succumbed to this condition 19 days after admission.


A twelve year old girl presented acutely to the emergency department, with a two day history of right iliac fossa pain associated with nausea and vomiting. No fevers or rigors were reported. The patient denied urinary symptoms and was pre-menstrual. She had a background of recurrent presentations to the emergency department with non specific abdominal pain in the preceding months. This girl had also been investigated by the paediatric service regarding episodes of dizziness, headaches and recurrent epistaxis. All previous investigations were normal. On this occasion, she had tenderness, localised guarding and rebound in the right iliac fossa. Her inflammatory markers were elevated, white cell count (WCC) 14.2 and a C reactive protein (CRP) of 23.4. Intravenous antibiotics were commenced and a plan for surgical intervention was made.
The patient underwent an emergency uncomplicated laparoscopic appendicectomy. At the time of surgery, it was noted that the apex of the appendix was distended. (Figure ) There were no signs of acute inflammation or purulent fluid. The base of the appendix was ligated using endoloops and the specimen was submitted for histology. The patient made an uncomplicated recovery and was discharged forty eight hours later.
Pathological examination of the appendix (measuring 60 mm in length) demonstrated a rare case of infiltrating neuroendocrine tumour of the appendix. The tumour penetrated the mucosa, submucosa and muscularis propria with extraluminal extenstion into the mesoappendix. This tumour was well differentiated measuring 25 mm in maximal diameter. The tumour stained positive for chromogranin, CD 56 and synaptophysin. The Ki67 proliferative index measured 15%, therefore consistent with a Grade 2 (G2) neuroendocrine tumour. A microscopic lymph node of the mesoappendix was also analysed which stained positive for chromogranin A, confirming a small metastatic deposit in the centre of the lymph node. (Figure ) The provisional staging of pT3, N1 Mx was assigned and the patient proceeded to staging investigations. A computerised tomography (CT) scan of the thorax, abdomen and pelvis was performed demonstrating a cluster of sub-centimetre lymph nodes in the right paracolic gutter of indeterminate significance. (Figure ) Urinary 5 HIAA testing was also completed and a normal level reported.
After discussion at the gastrointestinal multidisciplinary meeting, the decision to perform a laparoscopic right hemicolectomy was made. The pathological examination of the subsequent right hemicolectomy specimen showed no evidence of residual tumour grossly or microscopically. Forty seven loco-regional lymph nodes were retrieved. Two of these lymph nodes were positive for metastatic neuroendocrine tumour. These were located at 1 cm and 5 cm from the appendicectomy site. All peri-ileal lymph nodes were free of disease. The immunohistochemistry profile again was positive for chromogranin, synaptophysin and CD 56. (Figure ).
The patient is currently doing well and has been enrolled on a clinical and magnetic resonance imaging (MRI) surveillance programme.


A 5-year-old girl presented with a painless lump in abdomen for 3 weeks. On examination, a 10cm x 8cm, smooth and firm mass occupying the lower abdomen was found. Ultrasound showed a large predominantly solid mass of size 8cm x 7.3cm x 7cm in the pelvis on the right side, separate from the bladder, suspected of ovarian origin. Contrast enhanced CT scan showed the tumor in retroperitoneum with no obvious invasion of surrounding structures. Right kidney was mildly hydronephrotic and separate from the mass (Fig. 1). Levels of α-fetoprotein and HCG were normal. Trucut biopsy showed round to oval cells with eosinophilic cytoplasm with evenly distributed nuclear chromatin, arranged in tubular and acinar pattern with infrequent mitosis and no necrosis, suggesting possibility of ovarian tumor (Fig.2).
Intraoperatively, a 10cm x 10cm tumor in the retroperitoneum, adherent to the right ureter and well demarcated from the ovaries, kidneys and other surrounding structures was found (Fig. 3). Only near total excision of the tumor could be done because it was adherent to the ureter. Histopathology was reported as Wilms’ tumor – favorable histology (Fig 4). There was no evidence of vascular invasion. It was covered by a thin fibrous capsule that was focally infiltrated by the tumor. The fibrovascular and adipose tissue surrounding the ureter also showed focal deposits of malignancy. The patient was thus diagnosed to have extra-renal Wilms’ tumor (ERWT), Stage III – favorable histology. She has completed post-operative radiotherapy and chemotherapy as per NWTS protocol. She is now disease free and on regular follow-up.


A 34-year-old woman with severe Crohn’s disease, grade IV endometriosis, and bilateral tubal obstruction, booked for antenatal care at 13 weeks gestation. This was her first pregnancy following four attempts of in vitro fertilization and embryo transfer (IVF). Routine antenatal blood investigations were unremarkable. Her blood group was A-negative. Pregnancy was uncomplicated until 17 weeks gestation when she presented with spontaneous PPROM. This was confirmed by the presence of a pool of clear liquor in the vagina and a positive nitrazine test. High vaginal swab cultures for bacteria were negative. Ultrasound scans confirmed a singleton pregnancy with oligohydramnios. There was complete anhydramnion at 19 weeks gestation, and this rendered assessment of foetal anatomy difficult.
The couple was counselled on the poor outcome and risks of infection to the mother and foetus but expressed the wish to continue with the pregnancy. The risks of significant perinatal mortality and neonatal morbidity associated with chronic anhydramnios and the poor outcome associated with extreme prematurity was fully discussed by the neonatal team. The risks were based on the risk of infection to both mother and the foetus, up to date evidence and the ultrasound findings.
She was commenced on erythromycin 250 mg eight hourly, and managed expectantly as an outpatient with twice daily temperature checks at home, as well as serial full blood counts (FBC), serum C-reactive protein (CRP) and weekly low vaginal swabs. Two weekly growth scan showed a normally growing foetus, with visible breathing movements, and chest circumference growing along the 50th centile. Abdominal circumference (AC) measurement in foetuses with oligohydramnios may be technically difficult and less reproducible as the abdominal profile may be significantly deformed due to compression, thus, it is probably more reproducible to use ratios based upon head circumference rather than AC as the fetal head is more rigid, even in such conditions []. Liquor volume was never measurable due to continuous amniotic fluid leak and anhydramnios.
She remained well until 24 weeks gestation when she was admitted into hospital following a painful antepartum bleed. There was no clinical or laboratory evidence of chorioamnionitis. She was managed conservatively, with bed rest in hospital, and prophylactic antibiotics. Two doses of 12 mg intra-muscular. Betamethasone were given at 24 weeks, 24 h apart, in order to facilitate foetal lung maturity, and minimise neonatal respiratory distress syndrome (NRDS). Anti D immunoglobulin was also administered to prevent rhesus isoimmunization. She remained in hospital and pregnancy continued largely uneventful until 28 weeks gestation when she had a major placenta abruption; associated with foetal heart decelerations on the cardiotocogram. A live male infant weighing 1100 g was delivered by emergency caesarean section, with an Apgar score of 4 at 1 min. He was electively intubated immediately and given a dose of surfactant. A diagnosis of pulmonary hypoplasia was made on the basis of immediate onset of severe respiratory distress syndrome (RDS) requiring high ventilator pressures (MAP = 18) and no improvement in oxygenation or lung compliance after two doses of surfactant. Plain chest X-ray showed small lung fields with elevated diaphragms and a bell shaped thorax; highly suggestive of the diagnosis of pulmonary hypoplasia.
Apart from his compressed ears and mildly depressed tip of the nose, (mild degree of Potter’s features), there were no other gross skeletal deformities. The second day of life was complicated by pneumothorax probably secondary to the high-pressure ventilation. This resolved with no sequelae following chest tube drainage. He was extubated after 14 days of ventilation but required nasal continuous positive airway pressure ventilation for another 80 days. He tolerated bilateral inguinal herniotomy at the age of 130 days and was discharged home, self-ventilating in air and in good health; with a follow-up appointment for developmental assessment.


A 33-year-old woman para 4 (two term and two preterm at 34 and 28 weeks) all normal deliveries, one miscarriage, and one termination booked for antenatal care at eight weeks and five days gestation. Routine antenatal blood investigations were unremarkable. Her blood group was A Rhesus positive. The patient developed a urinary tract infection at 15 weeks and three days and was treated with antibiotics. At 22 weeks of gestation she presented with a history suggestive of spontaneous PPROM. This was confirmed by the presence of trickling of clear liquor through the cervix on speculum examination. High vaginal swab cultures taking at the time for infection were negative. Ultrasound scans confirmed a singleton pregnancy with complete oligohydramnios which made assessment of foetal anatomy difficult.
The couple was counselled on the outcome and risks of infection to the mother and foetus but expressed the wish to continue with the pregnancy. The risks of significant perinatal mortality and neonatal morbidity associated with chronic oligohydramnios and the outcome associated with extreme prematurity was also fully discussed with the couple.
She was commenced on erythromycin 250 mg, six hourly, and managed expectantly as inpatient with twice daily temperature checks, twice weekly FBC and serum CRP. Two weekly growth scan showed a normal growing foetus, oligohydramnios with visible breathing movements, and chest and abdominal circumference growing along the 50th centile. Abdominal circumference (AC) measurement in foetuses with oligohydramnios may be technically difficult and less reproducible as the abdominal profile may be significantly deformed due to compression so it is probably more reproducible to use ratios based upon head circumference rather than AC as the fetal head is more rigid, even in such conditions [].
Two doses of 12 mg intra-muscular betamethasone were given 24 h apart at 23 weeks in order to facilitate foetal lung maturity, and minimise NRDS. Liquor volume was never measurable due to continuous amniotic fluid leak and anhydramnios. While in hospital at 25 weeks and six days gestation she developed mild lower abdominal pain with minimal vaginal bleeding with no clinical or laboratory evidence of chorioamnionitis. At 27 weeks and 6 days, the bleeding was severe with moderate to severe intermittent lower abdominal pain. On bimanual vaginal examination the presentation was breech and cervix was 9 cm dilated with adequate contraction.
Cardiotocogram was normal and patient was delivered by breech extraction of a male infant weighing 1126 g with Apgar of 4, 7, and 10 at 1, 5, and 10 min respectively. He was electively intubated at 10 min of life and given a dose of surfactant and then transferred to the special baby care unit (SCBU).
In SCBU he was treated for presumed sepsis and briefly ventilated for 10 h for RDS and required nasal continuous positive airway pressure (CPAP) for 29 days, and oxygen until day 41. Echocardiography revealed a small patent ductus arteriosus (PDA) and ultrasound of the liver showed an abnormality, which was presumed to be a haemangioma. The patient was treated with diuretics and for gastro-oesophageal reflux disease and was discharged home, self-ventilating on air after 69 days in SCBU weighing 2250 g; with a follow-up appointment for developmental assessment in six weeks.


A 42-year-old A rhesus negative woman with minimal endometriosis, multiple uterine surgeries for removal of uterine fibroids, MTHFR—(methylene-tetra-hydro-folate-reductase) homozygous mutation with factor V Leiden deficiency booked for antenatal care at six weeks gestation following three embryo transfers. She was a para (Never carried a pregnancy beyond the viability stage is the 0 and the 3 is the three miscarriages as indicated) 0 + 3, three miscarriages with the fourth attempt of IVF. This was a triplet pregnancy with a monochorionic diamniotic (MCDA) twins’ and a singleton. The patient was placed on daily 60 mg of subcutaneous clexane and 75 mg of oral aspirin until 24 weeks gestation when her aspirin was stopped. Routine antenatal blood investigations were unremarkable.
On routine scan at 15 weeks, the MCDA twins’ were found to have developed severe Twin-to-Twin Transfusion (TTTs) with a 17.3% growth discrepancy and a velamentous cord insertion of the recipient twin. The couple was counselled on the condition, as well as the chances of survival of the MCDA twins’ either by expectant management or surgery. The later was agreed and performed at 16 weeks gestation with laser ablation of the communicating vessels.
At 18 weeks of gestation the patient presented into gynecology emergency clinic (GEAC) with history suggestive of PPROM, which was later confirmed by the presence of clear liquor in the vagina. High vaginal swab for cultures were negative for infection. Ultrasound scans confirmed a reduced liquor of maximum amniotic fluid index (AFI) of 3 cm in the MCDA donor twin, 11 cm of the recipient twin, and normal liquor volume in the singleton, with the later lying at the basal end of the uterus. Baseline FBC and CRP were taken and their results showed no sign of infection.
The couple was counselled on the poor outcome and risks of infection to the mother and foetus but expressed their desire to continue with the pregnancy. The risks of significant perinatal mortality and neonatal morbidity associated with persistent reduced liquor and extreme prematurity were also discussed by the neonatal team.
She was commenced on clindamycin 150 mg, six hourly throughout her stay in hospital, as she was allergy to penicillin, erythromycin, and metronidazole, and managed expectantly while in hospital as inpatient with routine daily vital signs, twice weekly FBC and serum CRP, as well as weekly low vaginal swabs. A weekly growth, liquor, and viability scan showed normal growing foetuses and maximum AFI depth of 3 cm in the MCDA twins with normal liquor in the singleton, with visible breathing movements and chest circumference of all three foetuses growing along the 50th centile.
At 23 weeks and four days gestation, two doses of 12 mg intra-muscular betamethasone were given, 24 h apart, to facilitate foetal lung maturity and minimise NRDS. She also had anti D immunoglobulin administered to prevent rhesus isoimmunization. At 27 weeks and three days the vagina liquor was blood stained with intermittent abdominal pain and ultrasound scan revealed a minor placenta abruption. She remained in hospital and pregnancy continued until 28 weeks and five days gestation when she had an elective caesarean section for worsening vaginal bleeding and lower abdominal pain with the delivery of three live female infants weighing 1350 g, 1165 g, and 1038 g, respectively, with cord blood and base excess (). Her estimated blood loss (EBL) during the procedure was 2 L. They were electively intubated immediately and each given a dose of surfactant and transferred to SCBU.


In March 2012, a caucasian 63-year-old man was seen in our institution for a painful swelling of the right knee joint present since 2 years. Pain was exacerbated by digital pressure. This patient resulted affected by D-TGCT that had been surgically treated with multiple synovectomies in 1987, 1990 and 1996, respectively. Histologic review of the original specimens of the primary tumor and of all recurrences was performed. All the specimens exhibited overlapping morphology by showing a combination of hyperplastic synovia, a mononuclear cell proliferation organized in a nodular pattern of growth, scattered hemosiderin-laden macrophages, xanthoma cells and multinucleated giant cells. These findings met the diagnostic criteria for D-TGCT and we therefore confirmed the primary diagnosis. Because of pain and persistent joint effusion, the patient underwent another synovectomy at our institution, and the histologic evaluation of the specimen confirmed the diagnosis of D-TGCT without atypical features. In contrast with previous samples a greater amount of fibrosis was seen.
Two years later the patient presented again with painful swelling of the right knee associated with pain localized in the right hip. Loss of weight and functional limitation of the right leg was observed. Magnetic nuclear resonance imaging demonstrated extra-articular soft tissue multilobular masses around the posterior part of the knee joint, with erosion of the lateral femoral condyle. Extension into the patello-femoral joint and the proximal tibia with a low signal intensity on T2-weighted image was present. In T1-weighted images, dark signal nodules, compatible with hemosiderin deposition, were readily identified (Figure a). Clinical examination showed recurrent tumour in the knee whereas computed tomography imaging revealed pelvic lymph nodes enlargement. In consideration of the extensive destruction with consequent functional compromise of the knee joint the patient underwent an “above the knee” amputation. During surgical procedure frozen examination of one inguinal lymph node was performed that showed a sub-capsular proliferation of mononucleated cells, associated with multinucleated giant cells and siderophages consistent with lymph node seeding of D-TGCT (Figure a, b).
Macroscopically, the evaluation of the knee disarticulation revealed a multinodular lesion of 30 cm × 25 cm × 21 cm, that was extensively infiltrating both the leg and the thigh with massive destruction of the knee joint. Alternation of white, yellowish and brownish areas with hematic-cystic lesions was seen (Figure b). Histological analysis of the lesion showed the same morphological features as the previous samples and confirmed the diagnosis of D-TGCT. In particular, the lesion showed synovial-like mononuclear cells lacking significant cytologic atypia, admixed with multinucleated giant cells (Figure c, d). Foci of ischemic necrosis were also evident. The mitotic rate was lower than two figures per 10 high power field. Ki67 proliferative index did not exceed 5% of neoplastic cells.
No areas of malignant transformation were identified in the specimen. Four months later a CT scan of the pelvis revealed a mass located in the soft tissue of the contralateral buttock, associated with inguinal lymph nodes swelling without evidence of lung metastases. In January 2015, the patient started systemic treatment with imatinib.


A 28-year-old female patient was admitted to the Emergency Department of Santa Casa Hospital in Porto Alegre, Brazil. She was referring epigastric pain for 14 days, with partial relief due to the use of weak analgesics. The pain was associated with diffuse cutaneous pruritus, jaundice, choluria, and acholia.
On physical examination, the patient was in a good general condition, jaundiced, with a hardened palpable mass in the epigastric and right hypochondrium regions. Laboratory tests showed a cholestatic pattern (). Tumoral markers (CEA and CA19-9) were normal.
Initially, an abdominal ultrasonography was performed, revealing a voluminous heterogeneous hypoechoic mass measuring about 13 cm width, 9 cm length, and 13 cm height. It presented cystic areas inside, between left hepatic lobe and pancreas. It was not possible to determine the origin of the mass. Dilatation of intrahepatic bile ducts and proximal common bile duct was also referred to ().
Computerized tomography with intravenous contrast unfolds a voluminous expansive lesion in pancreatic head and body, with well delimited borders, measuring about 12.8 × 12.1 × 10.9 cm. A heterogeneous density due to the presence of both liquid and solid areas is also shown in the CT. The image showed intense enhancement of an intravenous contrast agent. The lesion displaced adjacent structures, although no infiltration was detected. A significant ectasia of the intrahepatic and extrahepatic bile ducts could also be seen ().
The patient was evaluated by the hepatopancreatobiliary team and underwent a gastroduodenopancreatectomy, performed uneventfully. The gross appearance of the lesion was a solid cystic mass, was encapsulated and multiloculated, and was with necrotic aspect areas, measuring a total of 11.5 cm along its longest axis ().
The pathological study revealed a neoplasm of small round blue cells with scant cytoplasm arranged in nests with fibrovascular stroma. Few mitosis pictures and several areas of necrosis were also found. Immunohistochemistry was strongly positive for CD99 (), vimentin, automated CKM (creatine kinase, muscle), and CD56. Furthermore, it was negative for antibodies present in neuroendocrine tumors (chromogranins, synaptophysin, and neuroblastoma), myogenin, automated CD10, β-catenin, automated RP (ribosomal protein), and LCA (leucocyte common antigen).
The patient recovered well postoperatively, presenting normalized levels of bilirubin, alkaline phosphatase, γ-glutamyl transpeptidase, aspartate aminotransferase, and alanine aminotransferase. She was discharged on the 13th day after surgery and remains well, without signs of recurrence after 3 years. Considering R0 resection and controversies in the literature, adjuvant treatment with chemotherapy and/or radiotherapy was not performed.


We report a case of a 45-year-old female who presented to us with a swelling in her left wrist of about one-year duration. The plain radiograph showed a subarticular expansile lytic lesion with “soap-bubble” appearance involving distal radius epiphysis with metaphyseal extension and with well-defined margins, suggestive of GCT (Figures and ). Further on the skeletal survey an osteolytic lesion was noted in her right sacral ala. Biopsy of both lesions was performed, and it revealed both lesions as GCT (). Only lesion in her wrist was operated on initially, and the sacral lesion was left untreated as the patient was unwilling to undergo major surgery on her back.
“Resection-reconstruction arthroplasty” of distal radius was done using autogenous nonvascularized proximal fibula (Figures and ). The graft was fixed to radius proximally with narrow dynamic compression plate and distally to the ulna with K-wires. In the follow-up, K-wires were removed and the patient was doing well for six months after which she was lost to follow-up.
Twelve months later, she came back to us with complaints of low back pain for three months. Pain was disabling at the time of presentation. There was no history of motor weakness or paraesthesias in her lower limbs, bladder bowel disturbances, or any fever. She could sit and walk with the help of support with difficulty.
On physical examination, no swelling or local signs of inflammation were noted in her low back. Tenderness was noted in the sacrum and right sacroiliac joint. We ordered for a radiograph of pelvis in which we found a large expansile lytic lesion involving body of sacrum and right sacral ala and breach of sacroiliac joint was noted (). Further CT with three-dimensional reconstruction was done to delineate the lesion ().
The review radiographs of her left forearm showed wrist subluxation (Figures and ), though the patient had no complaints in her wrist. Skeletal survey and screening radiographs showed suspicious lesions in her lung fields which turned out to be pulmonary metastases on Contrast Enhanced CT (CECT) of chest (). CECT of brain and abdomen were normal. Technetium99 whole body bone scan showed hotspots in the sacrum and both lungs; there was no evidence of recurrence at distal radius.
After optimizing the patient, sacral lesion was treated by thorough intralesional curettage and bone grafting (). The procedure relieved patient of severe episodic pain. The patient developed superficial surgical site infection which later went on to heal with regular dressings and antibiotics. Patient is clinically asymptomatic at one-year follow-up. Pulmonary metastases could not be evaluated further or treated as the patient was unwilling for any intervention.


This 14-year-old female was relatively healthy before this presentation without systemic diseases. She was first admitted to our hospital due to fever, hemoptysis, anemia with a hemoglobin level of 4.2 g/dL and hyperpigmented macula on her legs. High resolution computed tomography revealed PH, as shown in Fig. . Her clinical symptoms were response well to initial management including empiric antibiotics and blood transfusion, and no hemoptysis, anemia and fever were noted after the third hospital day. Serial examinations to survey the etiology of PH, including ruling out infections such as tuberculosis and viruses, vasculitis and other autoimmune diseases, coagulopathy and cardiac-related conditions were performed. On the sixth hospital day, serum anti-myeloperoxidase antibody (MPO-ANCA) results were found to be positive. The diagnosis of ANCA-associated vasculitis was established by the findings of a skin biopsy which showed leukocytoclastic vasculitis with negative immunofluorescence staining (Fig. ). Renal biopsy was not performed because of normal serum creatinine level and mild proteinuria. Due to her family’s concerns of the side effects of cyclophosphamide such as gonadal suppression and infertility, we administered oral prednisolone (1 mg/kg/day) and oral mycophenolate mofetil (250 mg twice daily) to induce remission. At the end of the first hospitalization, chest radiograph revealed bilateral clear lung fields without patchy infiltration. She was discharged after 12 days of hospitalization.
Five days after discharge, she was admitted to our hospital again due to 2-day-history of swollen right lower limb. There were no fever, hemoptysis, cough, pleuritic chest pain, cyanosis or dyspnea, however skin rash was noted on her right leg. Her blood pressure was 112/85 mmHg with a heart rate of 79/min with a regular rhythm and her respiratory rate was 18 per minute with a body temperature of 37.1 °C on admission. On physical examination, swelling with different calf diameters, warmth, erythema, and positive Homan’s sign of right lower extremity, as well as multiple purpura over her right leg with local tenderness were noted. Chest, abdominal, and neurological examinations revealed no abnormal findings. The initial chest radiograph was normal without patch infiltrates, effusion, hemidiaphragm, Hampton hump or Westermark sign. The laboratory findings showed hemoglobin level of 9.1 g/dL, platelet count of 390,000/uL, white blood cell count of 12,800/mm3, international normalized ratio of 0.9, and D-dimer level of 2048 FEU ng/mL, blood urea nitrogen 30.6 mg/dL, creatinine 0.76 mg/dL, C-reactive protein 2.41 mg/L, albumin 3.33 g/dL and mild to moderate proteinuria. A Doppler ultrasound scan of her lower limbs showed a thrombus at the right common femoral vein. There were no other classic risk factors for DVT, and investigations of hypercoagulable status including anti-cardiolipin antibody, anti-β-glycoprotein antibody, lupus anti-coagulant, anti-thrombin III, protein C, and protein S were all within normal ranges. Under the diagnosis of DVT, subcutaneous low molecular weight heparin (enoxaparin; 30 mg twice daily), in addition to intravenous methylprednisolone and mycophenolate mofetil were delivered. Due to lack of associated clinical symptoms, PE was not considered. Her palpable purpura and leg swelling improved 2 days after admission.
However, she suddenly experienced hemoptysis and a decreased hemoglobin level on the third hospital day. Laboratory studies did not show coagulopathy or thrombocytopenia, and chest radiograph demonstrated diffuse ground glass appearance mixed with multiple patch consolidation on both lung fields. Due to concerns of PH, enoxaparin was discontinued to prevent further exacerbation of bleeding. Methylprednisolone pulse therapy (30 mg/kg/day) was given immediately to control the active AAV. However, the diffuse alveolar hemorrhage exacerbated with the consequent development of hypoxemia, hemoptysis, and dyspnea. She was intubated with ventilator support due to progression of PH on the sixth hospital day. Aggressive plasmapheresis was administered to remove excessive auto-antibodies. Supportive care with frequent blood transfusions and bronchoscope to remove clots were also given. An inferior vena cava filter was not considered due to resolving DVT and the concerns of a high risk with anesthesia in her critical condition. The PH resolved within 1 week after the initiation of these interventions, and she was extubated successfully on the 13th hospital day. No further hemoptysis or cough was noted during the rest of the hospitalization.
Neither DVT nor PE recurred after withdrawing the anticoagulants. To prevent further VTE, we added warfarin on the 20th hospital day. Intravenous cyclophosphamide (500 mg/m2) was administered thereafter. She was discharged with oral cyclophosphamide (1.5 mg/kg/day) and oral prednisolone (1 mg/kg/day). We planned to prescribe wafarin for at least 6 months if without recurrence of VTE.
She was symptom-free after discharge without hemoptysis, cough, chest pain or swollen leg. Her consciousness was clear without any abnormal neurological signs. Warfarin was prescribed and target level of international normalized ratio between 2 to 2.5 was maintained. However, she developed a sudden coma 3 weeks after the second discharge, and brain MRI revealed diffuse subarachnoid hemorrhage which favored cerebral vasculitis. After methylprednisolone pulse therapy and rituximab, she survived but in a vegetative state after that episode. We have followed this patient for 2 more years, and no PE, VTE or other relapse has occurred.
We searched PubMed, Medline, and Cochrane databases for literature published between 1980 and December 2014 in English, using the keywords “ANCA-associated vasculitis”, “thromboembolism”, and “pulmonary hemorrhage”. We also scanned the references of all included article for additional studies.
Only 5 cases of coexisting PH and VTE in patients with AAV were found. Table shows the general characteristics, clinical presentations, and therapeutic interventions of these 5 patients and our patient [, ]. Three of these cases (50 %) were female and the mean age at diagnosis of AAV with coexisting PH and VTE was 36.3 years (range, 14–61 years). Beside renal manifestations, ears, nose, and throat (67 %), central nervous system (33 %), and skin (33 %) were the most commonly involved organs. One case presented with dermatomyositis, and our case presented with palpable purpura. Among these patients, 67 % had positive PR3-ANCA autoantibody, while only 33 % had positive MP3-ANCA autoantibody.
Most patients with VTE had both PE and DVT (3 of 6, 50 %). Two patients had only PE, and our case had only DVT. With regards to the time sequence, 3 of these 6 patients had VTE prior to the episode of PH with an interval of 5 to 14 days. Simultaneous episodes of PH and VTE were noted in 2 patients. Only 1 patient had PH before VTE.
With regards to the therapeutic management of AAV, all patients received glucocorticoids, and 4 patients (67 %) received additional cyclophosphamide. Other immunosuppressant agents were prescribed instead of cyclophosphamide in 2 cases; 1 received mycophenolate mofetil, and the other who had the involvement of 5 organs received rituximab plus IVIG. Plasmapheresis was performed in 4 patients (67 %) after diagnosis of PH. When facing VTE with concurrent PH, the therapeutic management and considerations in these patients were all different. There were 2 cases with simultaneous PH and VTE, of whom 1 received only an inferior vena cava filter instead of anticoagulant, and the other took unfractionated heparin without an inferior vena cava filter. Three patients had VTE prior to PH, and they all received anticoagulants after a diagnosis of VTE. When PH was noted, 1 case received low-molecular weight heparin continuously, and also insertion of an inferior vena cava filter. Another case received an inferior vena cava filter first, followed by anticoagulant. In our case, we discontinued the anticoagulants when PH was noted with no implantation of an inferior vena cava filter, and began prophylactic anticoagulant treatment thereafter.
Even though three of these patients were admitted to intensive care unit for mechanical ventilation and other supportive care, all of the 6 patients survived after treatment. Four of the 6 patients received short-term anticoagulation treatment to prevent further VTE, and the other 2 patients received long-term anticoagulant treatment.