Parathormone and 1,25(OH)2D3 but not 25(OH)D3 serum levels, in an inverse correlation, reveal an association with advanced stages of colorectal cancer

Experimental, epidemiologic, and clinical trial data indicate the antineoplastic effects of calcium and vitamin D in large-bowel neoplasia. The aim of this study was to determine serum levels of vitamin D metabolites and parathormone (PTH) in patients with colorectal cancer (CRC) and to extract conclusions comparing their different levels in serum with healthy individuals. Group 1 (cancer patients) was consisted of 140 patients with CRC with clinical stages Duke’s A: 12, B: 52, C: 62, and D: 14. Serum levels of 25(OH)D₃, 1,25(OH)₂D₃, and PTH were determined in all patients. The findings are: (a) No significant difference was found in the serum levels of 25(OH)D₃ in each Duke’s clinical stage in cancer patients, (b) serum 1,25(OH)₂D₃ levels decreased with advanced cancer stages, and (c) serum levels of PTH showed a corresponding increase. Low serum levels of 1,25(OH)₂D₃ on one hand and increased levels of PTH in patients with CRC on the other might be strongly related to the carcinogenetic process.     

Phase II trial of thalidomide for advanced and recurrent gynecologic sarcoma: a brief communication from the New York Phase II consortium

OBJECTIVE: To define the efficacy of thalidomide on the overall survival of patients with metastatic recurrent gynecologic sarcomas. PATIENTS AND METHODS: All patients with sarcoma or carcinosarcoma of gynecologic origin and documented recurrence or persistence of disease after appropriate surgery, radiation therapy and/or chemotherapy were recruited to the study. All patients were ambulatory and had measurable disease that could be documented on CT scan. Patients were started on 200 mg/day of thalidomide orally every night and escalated by 100-200 mg every 7 to 14 days. The length of the treatment was separated into 2 cycles with the first 84 days defined as the first cycle and the next 56 days as the second cycle. Common Toxicity Criteria were used to record toxicities. Because thalidomide was postulated to induce cytostasis, the end-points were progression-free and overall survival in this mixed group of patients. RESULTS: Seventeen patients were enrolled. The drug was not well tolerated because of constipation, fatigue, worsening performance status, drowsiness and sleepiness. The total dosage of medication given to each patient ranged from 3200 mg to 40,500 mg. The maximum dosage reached in each patient ranged from 300 mg to 750 mg, with the total time of treatment ranging from 13 to 99 days. All patients had progression of disease with a median progression-free survival time of 1.84 months (CI 1.54-2.79 months) and a median overall survival of 6.64 months. DISCUSSION: Thalidomide has no activity in patients with advanced or recurrent gynecologic sarcomas and was not well-tolerated. The overall survival was <7 months. The progression-free survival was <3 months, and, since the therapy was not tolerated well, we unanimously decided to close the study at this point. Despite the poor result, we still believe in the strategy of anti-angiogenesis and will continue to pursue other potential treatment options using the same concept.     

Role of the alpha-helical linker of the C-terminal translocator in the biogenesis of the serine protease subfamily of autotransporters

Autotransporters are secreted virulence factors that comprise three domains: an N-terminal signal peptide, an internal passenger domain, and a C-terminal beta-domain. The mechanism of passenger translocation across the outer membrane remains undefined, with four models having been proposed: the "hairpin," the "threading," the "multimeric," and the "Omp85 (YaeT)" models. In an attempt to understand autotransporter biogenesis, we screened the sequences of the serine protease subfamily of autotransporters (SPATEs) for conserved features indicative of a common secretion mechanism. Our analyses revealed a strictly conserved 14-amino-acid motif within the predicted alpha-helical linker region, upstream of the beta-domain of SPATEs. We investigated the function of this motif through a mutagenesis approach using Tsh as a model. Our studies demonstrate that mutations throughout the conserved motif do not block insertion of the beta-domain into the outer membrane. However, nonconservative mutations of four hydrophobic (V1099, L1102, G1107, and L1109) and three polar (N1100, K1104, and R1105) residues of the motif severely decrease or even abolish Tsh biogenesis. Further studies showed that these mutations interfere with passenger transport across the outer membrane. Bioinformatical analyses suggest that the critical polar and hydrophobic amino acids localize on opposite sides of the helix that runs through the beta-barrel pore. Our data indicate that the conserved motif is important for passenger secretion across the outer membrane and that mutations in certain residues severely affect the secretion process. We discuss how these results fit with the four proposed models for autotransporter secretion and potential applications in antimicrobial and vaccine development.     

Radiation therapy is well tolerated and produces excellent control rates in elderly patients with locally advanced head and neck cancers

PurposeManagement of locally advanced head and neck cancer (LAHNC) in the elderly is challenging due to multiple co-morbidities, poor organ function and performance status. The aim of this study was to evaluate efficacy of radiation therapy (RT) in elderly patients, defined as 65 years and older, with high-risk LAHNC.Materials and methodsAn IRB approved retrospective chart review of elderly patients was performed, of whom 73 patients were selected for analysis. The stages included were II–IV. Sites included were oropharynx, oral cavity, larynx, salivary gland, nasopharynx, nasal cavity, paranasal sinus, hypopharynx and unknown primary.ResultsMedian age was 74 years. Thirty-nine (53%) patients received concurrent chemotherapy. Median time to completion of RT was 53 days. Median external beam radiotherapy (EBRT) dose was 66 Gy. With a median follow-up of 24 months, overall local control (LC) was 80% and distant metastasis (DM) was 12%. Sixty patients (82%) were alive at the time of study. Two-year overall survival (OS) was 96% (95% CI = 87%, 99%). Chemotherapy did not improve LC [80% (chemo) vs. 79% (no chemo), p = 0.88] or DM [11% (chemo) vs. 14% (no chemo), p = 0.73]. Interestingly, patients receiving RT using intensity-modulated radiation therapy (IMRT) had a significantly higher rate of LC vs. three-dimensional conformal radiotherapy (3DCRT) (94% vs. 68%, respectively, p = 0.008). Grade 2/3 toxicity was seen in 70/73 (96%) patients while grade 4 toxicity was seen in three patients (4%).ConclusionElderly patients with LAHNC have high rates of LC and OS. Prospective studies can reveal more insight into this increasingly important clinical problem in elderly patients.