Increased cancericidal activity of PTT.119; a new synthetic bis-(2-chloroethyl)amino-l-phenylalanine derivative with carrier amino acids

Summary A new synthetic tripeptide (p-F-Phe-m-bis-(2-chloroethyl)amino-Phe-Met ethoxy HCl), PTT.119, was demonstrated to have significant cancericidal activity against seven in vitro tumor cell lines of different origins and etiologies and against primary human AMML, ALL, and hairy cell leukemias. Viabilities of each murine tumor and rabbit, marmoset, and human leukemia and lymphoma line were significantly reduced by treatment with 1–50 g PTT.119 in media containing serum. Continuous 24-h exposure or pulse treatment as short as 15 and 30 min with the tripeptide resulted in irreversible damage to the tumor cells. Under identical treatment conditions, freshly isolated human leukemic cells, particularly ALL lymphoblasts, were even more susceptible to PTT.119 than any of the tested tumor cell models.Examination of the parameters of PTT.119 activity revealed that reductions of tumor cell survival were dependent on the concentration of the tripeptide. Prolongation of PTT.119 exposure from 15 min to 24 h increased the rates of tumor cell death but did not proportionally reduce the numbers of surviving cells. Assessment of tumor cell viabilities for 5 consecutive days following pulse exposure to PTT.119 demonstrated increasing reductions in tumor cell survival, which were greatest 5 days after treatment with the tripeptide.The cancericidal activity of PTT.119 was compared with its three parental components either as individual agents or as a mixture. Both the alkylator moiety, m-sarcolysin (m.L.SL) alone or together with p-fluoro-phenylalanine and l-methionine ethoxy HCl, and l-PAM (l-phenylalanine mustard), the p-isomer of m.L.SL, were 1.5- to 3-fold less cytotoxic to L1210 leukemia and MJY-alpha mammary tumor cells than PTT.119. Covalent linkage of the amino acid residues to m.L.SL yielded a molecule with greatly augmented cancericidal activity capable of acting against a broad spectrum of tumor cells.     

Does center or surgeon volume influence adoption of minimally invasive versus open pancreatoduodenectomy? A systematic review and meta-regression

BackgroundThere has been increasing uptake of minimally invasive pancreatoduodenectomy during the past decade, but it remains a highly specialized procedure as benefits over open pancreatoduodenectomy remain contentious. This study aimed to evaluate current evidence on minimally invasive pancreatoduodenectomy versus open pancreatoduodenectomy in terms of impact of center volume on outcomes.MethodsA systematic review of articles on comparative cohort and registry studies on minimally invasive pancreatoduodenectomy versus open pancreatoduodenectomy published until 31st December 2019 were identified, and meta-analyses were performed. Primary endpoints were International Study Group on Pancreatic Fistula grade B/C postoperative pancreatic fistula and 30-day mortality.ResultsAfter screening 7,390 studies, 43 comparative cohort studies (8,755 patients) with moderate methodological quality and 3 original registry studies (43,735 patients) were included. For the cohort studies, the median annual hospital minimally invasive pancreatoduodenectomy volume was 10. No significant differences were found in grade B/C postoperative pancreatic fistula (odds ratio: 0.98, 95% confidence interval: 0.78–1.23) or 30-day mortality (odds ratio: 1.14, 95% confidence interval: 0.65–2.01) between minimally invasive pancreatoduodenectomy when compared with open. No publication biases were present and meta-regression identified no confounding for grade B/C postoperative pancreatic fistula, center volume or 30-day mortality. Minimally invasive pancreatoduodenectomy was only strongly associated with significantly lower rates of postoperative pulmonary complications and surgical site infection, shorter length of stay, and significantly higher rates of R0 margin resections.ConclusionMinimally invasive pancreatoduodenectomy remains noninferior to open pancreatoduodenectomy for grade B/C postoperative pancreatic fistula but is strongly associated with significantly lower rates of postoperative pulmonary complications and surgical site infection. Minimally invasive pancreatoduodenectomy can be adopted safely with good outcomes irrespective of annual center resection volume.     

A Case of Large Calcifying Fibroma of Tendo-achilles Managed by En-block Resection and Tendon Reconstruction

Calcifying aponeurotic fibroma is a rare benign fibrous tumor with typical radiological and histopathological features seen in young children and adolescents. It commonly involves the extremities and is characterized by a very high chance of local recurrence. A complete excision of the tumor is considered to be the treatment of choice. We report a case of the tumor involving the substance of achilles tendon and extending up till its insertion in the calcaneum. To the best of our knowledge, this is the largest reported case of calcifying fibroma, with the tumor measuring 10 cm in its largest diameter. The tumor was excised in toto followed by reconstruction of the tendon defect with V-Y plasty of the native tendon and supplemented with semitendinosus and gracilis graft. There was no evidence of recurrence during the follow up period of 1 year.     

Dyslipidemia and its associated factors in patients with type 2 diabetes mellitus

Journal of Public Health - Dyslipidemia is a major risk factor known to be associated with diabetes and cardiovascular diseases. This study determined the frequency of lipid abnormalities among...     

Endothelial lipopigment as an indicator of α-tocopherol deficiency in two equine neurodegenerative diseases

Two spontaneous neurodegenerative diseases of the horse, equine motor neuron disease (EMND) and equine degenerative myeloencephalopathy (EDM), have been associated with -tocopherol deficiency, and both were characterized by prominent accumulations of endothelial lipopigment in the small vessels of the spinal cord. These endothelial pigment deposits appear to be reversible. In EMND horses pasture-supplemented for 9 months or more after the progression of weakness and wasting had arrested, there was very little endothelial lipopigment. The origin and the potential effects of these endothelial lipopigment accumulations are discussed.     

Paediatric Nosocomial Urinary Tract Infection at a Regional Hospital

From a total of 26,603 admissions to the paediatric wards, 1360 paediatric nosocomial urinary tract infections (PNUTI) were identified during a 5-year retrospective chart review at the SFGH. The ages ranged from 3 days to 13 years, with 46% boys and 54% girls. The highest rates of PNUTI per service per 100 admissions were seen in the nursery (11.28) followed by paediatric surgery (2.89) and paediatric medicine (2.86). Although the greatest number of PNUTI occurred in the nursery, comparison between the years was not statistically significant. About 90% (1218 of 1360) of PNUTI occurred in catheterized patients. No documentation was found specifying the type of catheterization (intermittent or continuous). About 90% (1210 of 1360) of isolates were single organisms with Escherichia coli, Proteus mirabilis, Klebsiella spp. and Group B streptococci accounting for a total of 70% of all pathogens. However, the composition of the most common isolate in each service differed. The most common isolate in the nursery was E. coli, in the paediatric medical and surgical services the most common isolates were Klebsiella spp. and Proteus mirabilis, respectively. Proteus mirabilis was isolated predominantly from boys with structural abnormality of the urethral tract. No PNUTIs were complicated by bacteraemia. The antibiotics with least effectiveness (in increasing order) for UTIs were cephalexin, ampicillin, trimethoprim, co-trimoxazole and tetracycline. The most effective antibiotics were nalidixic acid, gentamicin and amoxicillin-clavulanic acid.     

T-maze learning, spontaneous activity and food intake recovery following systemic administration of the noradrenaline neurotoxin, DSP4

Following systemic administration of the noradrenaline (NA) neurotoxin, DSP4 (50 mg/kg), rats were found to be retarded in the rate at which they acquired the "right-turn" running response in a modified T-maze choice situation, as measured by the total number of errors per session and median latency to reach the goal box. Desipramine (DMI, 20 mg/kg), injected 30 min before DSP4 blocked the acquisition retardation. DSP4 was found to have a short-lasting effect upon spontaneous motor activity, while food and water intake recovery was complete within 7 days of the injection. Both the NA-accumulation data and endogenous NA concentrations indicated profound NA, but not 5-hydroxytryptamine (5-HT) and dopamine (DA), depletions in the cortex, hippocampus and cerebellum. These data seem to confirm the role of the locus coeruleus-noradrenaline (LC-NA) system in an instrumental learning situation.     

A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778,123 and radiotherapy for locally advanced pancreatic cancer.

PURPOSE: Preclinical and clinical studies have demonstrated that inhibition of prenylation can radiosensitize cell lines with activation of Ras and produce clinical response in patients with cancer. The aim of this study was to determine the maximally tolerated dose of the dual farnesyltransferase and geranylgeranyltransferase I inhibitor L-778,123 in combination with radiotherapy for patients with locally advanced pancreatic cancer. EXPERIMENTAL DESIGN: L-778,123 was given by continuous intravenous infusion with concomitant radiotherapy to 59.4 Gy in standard fractions. Two L-778,123 dose levels were tested: 280 mg/m2/day over weeks 1, 2, 4, and 5 for dose level 1; and 560 mg/m2/day over weeks 1, 2, 4, 5, and 7 for dose level 2. RESULTS: There were no dose-limiting toxicities observed in the eight patients treated on dose level 1. Two of the four patients on dose level 2 experienced dose-limiting toxicities consisting of grade 3 diarrhea in one case and grade 3 gastrointestinal hemorrhage associated with grade 3 thrombocytopenia and neutropenia in the other case. Other common toxicities were mild neutropenia, dehydration, hyperglycemia, and nausea/vomiting. One patient on dose level 1 showed a partial response of 6 months in duration. Both reversible inhibition of HDJ2 farnesylation and radiosensitization of a study patient-derived cell line were demonstrated in the presence of L-778,123. K-RAS mutations were found in three of the four patients evaluated. CONCLUSIONS: The combination of L-778,123 and radiotherapy at dose level 1 showed acceptable toxicity in patients with locally advanced pancreatic cancer. Radiosensitization of a patient-derived pancreatic cancer cell line was observed.