Noncanonical effector functions of the T-memory-like T-PLL cell are shaped by cooperative TCL1A and TCR signaling.

T-cell prolymphocytic leukemia (T-PLL) is a poor-prognostic neoplasm. Differentiation stage and immune-effector functions of the underlying tumor cell are insufficiently characterized. Constitutive activation of the T-cell leukemia 1A (TCL1A) oncogene distinguishes the (pre)leukemic cell from regular postthymic T cells. We assessed activation-response patterns of the T-PLL lymphocyte and interrogated the modulatory impact by TCL1A. Immunophenotypic and gene expression profiles revealed a unique spectrum of memory-type differentiation of T-PLL with predominant central-memory stages and frequent noncanonical patterns. Virtually all T-PLL expressed a T-cell receptor (TCR) and/or CD28-coreceptor without overrepresentation of specific TCR clonotypes. The highly activated leukemic cells also revealed losses of negative-regulatory TCR coreceptors (eg, CTLA4). TCR stimulation of T-PLL cells evoked higher-than-normal cell-cycle transition and profiles of cytokine release that resembled those of normal memory T cells. More activated phenotypes and higher TCL1A correlated with inferior clinical outcomes. TCL1A was linked to the marked resistance of T-PLL to activation- and FAS-induced cell death. Enforced TCL1A enhanced phospho-activation of TCR kinases, second-messenger generation, and JAK/STAT or NFAT transcriptional responses. This reduced the input thresholds for IL-2 secretion in a sensitizer-like fashion. Mice of TCL1A-initiated protracted T-PLL development resembled such features. When equipped with epitope-defined TCRs or chimeric antigen receptors, these Lckpr-hTCL1Atg T cells gained a leukemogenic growth advantage in scenarios of receptor stimulation. Overall, we propose a model of T-PLL pathogenesis in which TCL1A enhances TCR signals and drives the accumulation of death-resistant memory-type cells that use amplified low-level stimulatory input, and whose loss of negative coregulators additionally maintains their activated state. Treatment rationales are provided by combined interception in TCR and survival signaling.

Partnership for rehabilitation: looking beyond impairments.

Rehabilitation of leprosy-affected persons extends beyond the physical domain of prevention and treatment of impairments. A holistic rehabilitative approach should include addressing those problems that people may have in activities and difficulties that may prevent people from fully participating in social functions, i.e. being fully accepted as integrated members of the societies and communities to which they belong. This article highlights the activities of the Partnership for the Rehabilitation Program (PFR) of the International Nepal Fellowship (INF), Pokhara, Nepal. These activities aim to prevent, reduce or alleviate problems and difficulties that leprosy-affected persons may face in being respected and being contributing members of the communities of which they are a part.

A comparative analysis of immunohistochemistry and fluorescent in situ hybridization assay to detect anaplastic lymphoma kinase status in lung adenocarcinoma cases: A search for a testing algorithm.

INTRODUCTION: Testing for echinoderm microtubule-associated protein-like 4 (EML4) anaplastic lymphoma kinase (ALK) translocation by fluorescence in situ hybridization (FISH) is well established whereas the Food and Drug Administration (FDA) ALK immunohistochemical (IHC) test is relatively new. AIMS AND OBJECTIVE: The aim of this study is to compare FDA-approved ALK IHC test (D5F3 clone) with the standard ALK FISH test. MATERIALS AND METHODS: A validation and a test arm with 100 and 200 cases of Formalin-Fixed, Paraffin-embedded blocks of lung adenocarcinoma, respectively, comprised the material. All cases had ALK IHC test on automated Ventana Benchmark XT IHC slide stainer using anti-ALK D5F3 rabbit monoclonal primary antibody; when positive tumor cells (any percentage) showed strong granular cytoplasmic staining. For the FISH test, Vysis ALK Dual Color Break Apart Rearrangement Probe (Abbott Molecular Inc.,) was used to detect ALK gene 2p23 rearrangements; when positive the red and green signals were split two signal diameter apart and/or isolated 3'red signal were detected in more than 15% tumor cells. The ALK FISH results were available in all 100 validation cases and 64-test arm cases which formed the basis of this analysis. RESULTS: The ALK IHC test was positive in 16% cases; four discordant cases were ALK IHC positive but ALK FISH negative, but no case was ALK IHC negative and ALK FISH positive. There was 100% sensitivity, 90.5% specificity, and 93.75% accuracy. CONCLUSION: A negative ALK IHC result obviates the need for a FISH test barring those with a strong clinical profile, and a positive ALK IHC result is sufficient basis for the initiation of treatment.

Pancreaticoduodenectomy for periampullary carcinoma.

OBJECTIVES: To assess the morbidity, mortality and 1- and 2-year survival rates, and safety of pancreaticoduodenectomy for periampullary (including pancreatic head) carcinomas in a non-oncology surgical set-up. METHODS: Records of 45 patients undergoing pancreaticoduodenectomies for periampullary cancers between July 1996 and April 2000 were reviewed. These included ampullary (n=23), pancreatic (14) and duodenal (2) adenocarcinomas, lower-end cholangiocarcinoma (5), and ampullary carcinoid (1). Thirty-seven patients underwent the Whipple procedure and 8 underwent the pylorus-preserving modification. RESULTS: The overall mortality rate was 11% and morbidity rate was 46%. Wound infection was the most common postoperative complication. The 1- and 2-year survival rates for periampullary cancers were 61% and 39% and those for pancreatic cancers were 57% and 36%, respectively. CONCLUSION: Pancreaticoduodenectomy for periampullary tumors remains a formidable procedure in our set-up. However, it can be performed safely with low mortality and morbidity rates.

Pancreaticoduodenectomy for metastatic colonic cancer--report of two cases.

Benefit of resection of metastatic lesions to the liver and lung from colonic cancer is well established. Resection of solitary metastasis or of locally recurrent malignancies in the periampullary region has now become the norm, as it increases survival. We present our experience with two patients with metastases in the periampullary region from previously treated colonic carcinoma who were treated with pancreaticoduodenectomy.

Hepatic resection for benign liver pathology--report of two cases.

Hepatic resection for benign pathology is rare. We report our experience in two patients with hepaticolithiasis. One patient underwent left hemihepatectomy with removal of segments II, III and IV for localized Caroli's disease with multiple intrahepatic calculi. The second patient underwent resection of segment II and III with Roux-en-Y hepaticojejunostomy for right and left intrahepatic calculi with an abscess in the left lobe of the liver and a choledochal cyst.

Palliative surgery in malignant obstructive jaundice: prognostic indicators of early mortality.

A prospective analysis of 50 patients undergoing palliative bypass surgery for incurable malignant obstructive jaundice was carried out in an attempt to identify factors predicting post-operative mortality. Five clinical and nine laboratory parameters were studied. Fourteen patients died within 30 days of surgery. It was seen that levels of haemoglobin, hematocrit and serum albumin levels were significantly lower while serum bilirubin was significantly higher in patients who died compared with the survivors. Patients having Hb < 10 Gm/dL, serum bilirubin > 350 micromol/dL, serum albumin < 2.5 g/dL and prothrombin index < 60% exhibited a higher percentage of mortality. On multivariate analysis, levels of haemoglobin, serum albumin and serum bilirubin could be used to independently predict the outcome with an accuracy of 86%. This was validated by prospectively applying the regression equation derived from the first 30 patients to the next 20 patients. It was seen that the predicted outcome correlated with the actual outcome with a correlation coefficient of 0.5098 (P = 0.01). It is concluded that in patients with high bilirubin, low haemoglobin and low albumin levels palliative surgical procedures carry a high risk of post-operative mortality and non-surgical methods may be more suitable.