Whole Exome Sequencing reveals NOTCH1 mutations in anaplastic large cell lymphoma and points to Notch both as a key pathway and a potential therapeutic target.

Patients diagnosed with Anaplastic Large Cell Lymphoma (ALCL) are still treated with toxic multi-agent chemotherapy and as many as 25-50% of patients relapse. To understand disease pathology and to uncover novel targets for therapy, Whole-Exome Sequencing (WES) of Anaplastic Lymphoma Kinase (ALK)+ ALCL was performed as well as Gene-Set Enrichment Analysis. This revealed that the T-cell receptor (TCR) and Notch pathways were the most enriched in mutations. In particular, variant T349P of NOTCH1, which confers a growth advantage to cells in which it is expressed, was detected in 12% of ALK+ and ALK- ALCL patient samples. Furthermore, we demonstrate that NPM-ALK promotes NOTCH1 expression through binding of STAT3 upstream of NOTCH1. Moreover, inhibition of NOTCH1 with γ-secretase inhibitors (GSIs) or silencing by shRNA leads to apoptosis; co-treatment in vitro with the ALK inhibitor Crizotinib led to additive/synergistic anti-tumour activity suggesting this may be an appropriate combination therapy for future use in the circumvention of ALK inhibitor resistance. Indeed, Crizotinib-resistant and sensitive ALCL were equally sensitive to GSIs. In conclusion, we show a variant in the extracellular domain of NOTCH1 that provides a growth advantage to cells and confirm the suitability of the Notch pathway as a second-line druggable target in ALK+ ALCL.

Renal angiomyoadenomatous tumour.

Renal angiomyoadenomatous tumour is a newly described rare neoplasm. This tumour is characterised microscopically by admixture of three components- epithelial cells arranged in tubules and nests, angiomyomatous stroma and capillary sized interconnecting vascular channels in close association with the epithelial cell clusters. Microscopically it has wide range of differential diagnoses which include mixed epithelial and stromal tumour of kidney, angiomyolipoma and clear cell renal cell carcinoma with angiomyolipomatous/angiomyoadenomatous areas. Renal angiomyoadenomatous tumour should be differentiated from these tumours. Till now, only 10 cases have been reported in English medical literature. Here, we are reporting a case of renal angiomyoadenomatous tumour in a 29 year- old female patient who presented with hematuria and low backache and describing its main features so as to differentiate this entity from other renal tumours. To the best of our knowledge, this is the first case to be reported from India.

Bilineage T-lymphoblastic/myeloid extramedullary blast crisis in chronic myelogenous leukemia.

The blast crisis of chronic myelogenous leukemia (CML) can be hematological or extramedullary. About 25% of these cases fulfill the criteria for mixed phenotype acute leukemia. We here report a case of a second blast crisis of CML which was extramedullary and was immunophenotypically bilineage T/myeloid.

Rickettsial infection with hemophagocytosis.

A five-year-old girl admitted with scrub typhus developed multiple organ dysfunction associated with hyperferritinaemia, hypofibrinogenaemia and hyperlipidaemia. Bone marrow aspiration studies confirmed haemophagocytic lymphohistiocytosis (HLH). HLH is a syndrome characterized by the uncontrolled activation and proliferation of macrophages and T-cells and can occur together with infections, connective tissue disorders, malignancies and genetic disorders.

Plasma cell leukemia with pleomorphic plasma cells--a case report.

A case of plasma cell leukemia showing mostly pleomorphic plasma cells in the form of convoluted and multilobated nuclei with some having bilobed nuclei and internuclear bridges is being reported for its rarity of occurrence. Patient presented with congestive cardiac failure and features of nephropathy. There were no lytic lesions in the bone. Serum electrophoresis did not show any M-band while urine electrophoresis demonstrated Bence Jones protein confirming a light chain only type of myeloma. Patient is in remission 5 months after diagnosis. The significance of recognising such pleomorphic plasma cells is discussed.

Strongyloidiasis presenting as duodenal obstruction.

Small bowel obstruction due to Strongyloides stercoralis is rare especially in immunocompetent individuals. We report a case of a 45-year-old man who presented with a history of severe abdominal pain, intermittent low-grade fever and vomiting. An upper GI endoscopy revealed a diffusely edematous second portion of duodenum and narrowing in the third part of duodenum with food residue in the stomach. Barium contrast upper-GI radiography revealed partial small-bowel obstruction. Duodenal biopsy specimens revealed Strongyloides stercoralis in the submucosa with inflammatory infiltrate. The patient was treated with ivermectin and had complete resolution of symptoms.

OSPE in pathology.

Undergraduate medical education is currently undergoing extensive re-evaluation with new core educational objectives being defined. Consequently, new exam systems have also been designed to test the objectives. Objective structured practical examination (OSPE) is one of them. We conducted OSPE in a regular batch of 64 students. The batch was divided into 4 groups, one group taking the conventional practical exam and the other groups OSPE with minor variations. Different aspects were compared and analyzed and we found that OSPE was more objective, measured practical skills better, had a wide discrimination index and eliminated examiner bias. The questionnaire given to the students revealed a high acceptance rate among them.

Papillary cystic tumor of pancreas--report of two cases.

Two cases of Papillary cystic tumor of pancreas--one metastasizing to lymph node and the other non-metastasizing are reported for their rare occurrence. Both occurred in young females and presented with heaviness and pain in the left hypochondrium with palpable mass. On radiological examination, mass was arising from tail of pancreas and had typical gross features. The histological findings seen in metastasizing tumor were capsular invasion, infiltration to surrounding pancreatic tissue and vascular invasion with metastasis to lymph node. Difference in nuclear grade or mitosis was not observed. Adjuvant chemotherapy was given for metastasizing tumor and patient is symptom free after 56 month. Non-metastasizing case is well after 15 months.

Sickle cell disease in Wayanad, Kerala: gene frequencies and disease characteristics.

BACKGROUND: A large number of patients with sickle cell anaemia are seen at the Medical College, Calicut from among the tribals and Chetti communities of the adjacent Wayanad district. We carried out a population-based study of gene frequencies and disease characteristics to plan an appropriate intervention. METHODS: Clinical examination and haemoglobin electrophoresis were done in 1016 subjects belonging to the tribal and Chetti communities in Wayanad district, by visiting hamlets and schools and evaluating everyone present at the time of the visit. RESULTS: The gene frequency of haemoglobin S ranged from 0.019 in Kattunayakan to 0.196 in Wayanadan Chettis. Wayanadan Chettis, Kurumas and Adiyas showed a high number of homozygotes with the oldest being 48 years. The survival of homozygotes is longer than what is generally recorded in other states. The disease was mild in 52.2% of cases. Painful crises were found in 43.5% and splenomegaly and leg ulcers in 4.3% each. The mean haemoglobin F rate in homozygotes was 25.9%. It was higher in clinically mild cases and in those showing an absence of irreversible sickle cells in the peripheral smear. CONCLUSIONS: The survival of patients with sickle cell anaemia seems to be higher in Kerala as compared to other states. It appears that even small improvements in primary health care available to the population (as in Kerala) are sufficient to achieve this effect. Integration of disease diagnosis and management into the already existing health care delivery system may lead to even better survival and quality of life.

Apathetic thyrotoxicosis.

A previously fit 37-year-old woman was admitted with acute left ventricular failure, atrial fibrillation and a left-sided thromboembolic stroke. Her ventricular rate progressively increased despite full digitalisation. She had a cardiac arrest and was successfully resuscitated. Investigations revealed evidence of hyperthyroidism and she was treated for thyrotoxic crisis. She has made a complete recovery from the hemiparesis and is now in sinus rhythm. She denied any symptoms of hyperthyroidism. This patient had apathetic thyroid crisis, which is exceedingly rare in the young.

Mullerian adenosarcoma of the uterine cervix.

Two cases of mullerian adenosarcoma with heterologous elements which occurred in uterine cervix and had a gross appearance of sarcoma botyroides are reported. Histologically, the tumours were composed of an admixture of benign appearing glands and a sarcomatous stroma, with heterologous elements consisting of skeletal muscle, bone and cartilage. No malignant epithetial components were observed. Indications are that, the prognosis of these tumours are much better than the usual malignant mixed mullerian tumours.

Gaucher's disease among Mappila Muslims of Malabar.

Seven cases of Gaucher's disease admitted in Medical College, Calicut, Kerala State, were studied. All cases were classified as Type I (adult) Gaucher's disease. Splenomegaly was the consistent feature. Routine hemogram and liver function tests were within normal range. Bone marrow smears and liver biopsies were studied. Bone marrow smears showed typical Gaucher cells. In liver biopsy storage cells were seen as scattered foci in sinusoids. One case showed diffuse distribution affecting all zones. All cases belonged to distinct community called Mappila Muslims of Malabar which account for only 35 percent of the population in Malabar region, situated in the northern part of Kerala. Type I Gaucher's disease has a well known racial predilection reported in Askenazi Jews. Mappila Muslims of Malabar may be another such group. This is the largest series of cases to be published in India seen in one particular community.