Clinico‐pathological spectrum of gallbladder disease in children

Aim: Because of wide variation in clinico‐pathological spectrum of gallbladder disease in children the world over, the data of gallbladder disease from this stone belt of India were analysed. Methods: Children who underwent cholecystectomy over a period of 8 years January 2002–December 2009 were reviewed. Results: Out of 7076 cholecystectomies, 56 (0.79%) were in children. Thirty‐nine (69.6%) children were 11–16 years of age. Thirty‐seven (66.07%) children were girls and nineteen (33.9%) were boys. In 12 (21.4%) children, cholecystitis was acalculus. Five (8.9%) children had associated haemolytic disease and 4 (7.1%) children had congenital anomaly in the form of choledochal cyst. Ultrasound findings were available in 44 cases and showed cholelithiasis in 36 cases. Twenty‐two (39.3%) children had mixed cholelithiasis, 8 (14.2%) pigment cholelithiasis, 10 (17.8%) combined cholelithiasis and 4 (7.1%) patients had small concretions. Microscopically, changes of chronic cholecystitis were seen in 98.2% while 1.7% showed acute on chronic cholecystitis. There was single unusual case of cysticercus in the wall of the gallbladder. Conclusions: The frequency of gallstone disease is 0.79%. Nonhaemolytic type of cholelithiasis is more common than haemolytic type in this region. Presence of cysticercus in the gallbladder wall in one case was an unexpected finding.     

Quantitation of primitive and lineage-committed progenitors in mobilized peripheral blood for prediction of platelet recovery post autologous transplant

Leukapheresis collections obtained following one of four mobilization regimens from 90 cancer patients were analyzed for their content of various progenitor cell types including erythroid and granulopoietic colony-forming cells in methylcellulose (total CFC), CFC-megakaryocyte (CFC-Mk), CFC detected after 10, 35 and 56 days in long-term culture (LTC), and total CD34+ cells. The number of each of these progenitor cell types collected from individual patients varied over 1000-fold. Nevertheless, within an individual leukapheresis, there was a significant correlation between the number of CD34+ cells and each progenitor type (except day 56 LTC CFC) suggesting that all of them are mobilized by a common mechanism. Patients who had previously received extensive chemotherapy and/or radiotherapy mobilized fewer of all these cell types than those who had not. For the 65 patients who proceeded to autologous transplantation, the median times to an absolute neutrophil count (ANC) of > or =0.5 x 109/l and the last platelet transfusion post transplant were 13 and 11 days, respectively, with 14 (22%) of patients having platelet recovery delayed beyond day 21. There was no significant difference between patients who had or had not received extensive chemo/radiotherapy or among the different mobilization regimens for time to neutrophil or platelet recovery or the number of platelet or red blood cell transfusions received post transplant. Threshold doses of the different cell types transplanted (per kg of patient weight) which predicted rapid platelet recovery were 2 x 106 CD34+ cells, 5 x 105 total CFC and 2.5 x 104CFC-Mk. Corresponding thresholds for progenitor activity measured in LTC could not be established. These results further support the view that standard mobilization regimens yield progenitor numbers that are, in most cases, nonlimiting for generating neutrophil and platelet recoveries within 2 to 3 weeks after myeloablative therapy. Assessment of the CD34+ cell and/or CFC content of leukapheresis collections may identify patients in whom platelet recovery is likely to be significantly delayed although CFC-Mk enumeration does not appear to offer any unique predictive advantage.     

A phase I pharmacokinetic and pharmacodynamic study of TKI258, an oral, multitargeted receptor tyrosine kinase inhibitor in patients with advanced solid tumors.

PURPOSE: To determine the maximum tolerated dose (MTD) dose-limiting toxicity, and pharmacokinetic and pharmacodynamic profile of TKI258 (formerly CHIR-258). EXPERIMENTAL DESIGN: A phase I dose escalating trial in patients with advanced solid tumors was performed. Treatment was initially as single daily doses on an intermittent 7-day on/7-day off schedule. Following a protocol amendment, a second schedule comprised, during cycle 1, 7-day on/7-day off treatment followed by 14 days of continuous daily dosing; subsequent cycles comprised 28 days of daily dosing. Pharmacokinetics and evaluation of phosphorylated extracellular signal-regulated kinase (ERK) in peripheral blood mononuclear cells were done during the first 28 days of each schedule. RESULTS: Thirty-five patients were treated in four intermittent (25-100 mg/d) and three continuous (100-175 mg/d) dosing cohorts. Observed drug-related toxicities were nausea and vomiting, fatigue, headache, anorexia, and diarrhea. Dose-limiting toxicities were grade 3 hypertension in one patient at 100 mg continuous dosing, grade 3 anorexia in a second patient at 175 mg, and grade 3 alkaline phosphatase elevation in a third patient at 175 mg. One patient had a partial response (melanoma) and two patients had stable disease >6 months. TKI258 pharmacokinetics were linear over the dose range of 25 to 175 mg. Five of 14 evaluable patients had modulation of phosphorylated ERK levels. CONCLUSIONS: The MTD was defined as 125 mg/d. Evidence of antitumor activity in melanoma and gastrointestinal stromal tumors warrants further investigation, and other phase I studies are ongoing. Further pharmacodynamic evaluation is required in these studies to evaluate the biological effects of TKI258.     

Partial cystectomy for invasive bladder cancer

Thirty two patients—23 males and 9 females with a mean age of 52.5 years—underwent planned partial cystectomy for histologically proved muscle invasive bladder cancer. Twenty patients had transitional cell carcinoma and 12 had adenocarcinoma of the bladder. One patient had well-differentiated, 18 had moderately differentiated, and 13 had poorly differentiated tumours. The tumour size was <2 cm in 7 patients, 2–4 cm in 19 patients, and >4 cm in 6 patients. Patients with single primary muscle invasive tumours situated in the upper half of the bladder were considered eligible for partial cystectomy. The presence of multicentric urothelial disease, of dysplasia, or carcinoma-in-situ in bladder mucosa away from the tumour on multiple random punch biopsies was considered contraindications to partial cystectomy. All patients underwent partial cystectomy with bilateral pelvic lymphadenectomy. The tumour-free margins of resection were confirmed by intraoperative frozen section examination. The bladder was closed primarily in all patients, although three patients required re-implantation of the ureter. No patient received adjuvant radiation or chemotherapy. Five patients had pathological stage Bl (T2), 18 had B2 (T3A), and 9 had C (T3B) disease. No patient had metastatic pelvic lymph nodes. There was one postoperative death due to unrelated medical cause. Five patients had minor complications that resolved with conservative measures. All patients had adequate bladder capacity of >250 cc at 6 months after surgery, and none had symptoms attributable to reduced bladder capacity. The overall actuarial survival was 80.1% at 5 years. The 5-year survival for patients with stage T2 tumours was 100%, for stage T3A 88.5%, and for stage T3B 45.7% (P = 0.028). The 5-year survival for patients with tumour size < 2 cm was 100% compared to 83. 1% for 2-4 cm and 50% for size more than 4 cm (P = 0.078). There was no significant difference in survival for patients with transitional cell carcinoma (83.8%) and adenocarcinoma (74.1%) (P = 0.511). Patients with well-differentiated tumours had a 5-year survival of 100% as compared to 94.4% for moderately and 53.5% for poorly differentiated tumours (P < 0.001). Fourteen patients relapsed—12 in the bladder and 2 in the lungs without relapse in the bladder. Of the 12 patients who relapsed in the bladder, 5 had noninvasive (stage Ta/Tl) relapses and were salvaged with transurethral resection of the tumours. Seven patients had invasive tumours at relapse that were related to tumour stage and grade. Four of these could be salvaged with radical total cystectomy, where as the remaining three and the two patients with distant relapses died due to disseminated disease. © 1995 Wiley-Liss, Inc.     

Blood pressure lowering effect of an olive leaf extract (Olea europaea) in L-NAME induced hypertension in rats

A specially prepared olive leaf extract (EFLA 943) has been tested for its blood pressure lowering activity in rats rendered hypertensive by daily oral doses of L-NAME (NG-nitro-L-arginine methyl ester, 50 mg/kg) for at least 4 weeks. Oral administration of the extract at different dose levels at the same time as L-NAME for a period of 8 weeks showed a dose dependent prophylactic effect against the rise in blood pressure induced by L-NAME, best effects being induced by a dose of 100 mg/kg of the extract. In rats previously rendered hypertensive by L-NAME for 6 weeks and then treated with that dose of the extract for a further 6 weeks without discontinuation of L-NAME, normalisation of the blood pressure was observed. The findings confirm previous reports on the hypotensive effects of olive leaf. The special extract, EFLA 943, was shown to give consistent results with little individual variability. The antihypertensive effect of the extract may be related to a variety of factors involving reversal of vascular changes involved in the L-NAME induced hypertension.     

Intra-cerebral relapse following prolonged remission after autologous stem cell transplantation for multiple myeloma

Central nervous system (CNS) myeloma is a rare phenomenon, especially so after high-dose therapy (HDT) and stem cell transplantation. We describe a case of isolated CNS relapse of myeloma post autologous transplantation that followed a prolonged progression-free interval. Issues regarding the pathophysiology and management of this unusual complication are discussed.