The role of biological therapy in metastatic colorectal cancer after first-line treatment: a meta-analysis of randomised trials.

PURPOSE: Biologic agents have achieved variable results in relapsed metastatic colorectal cancer (mCRC). Systematic meta-analysis was undertaken to determine the efficacy of biological therapy. METHODS: Major databases were searched for randomised studies of mCRC after first-line treatment comparing (1) standard treatment plus biologic agent with standard treatment or (2) standard treatment with biologic agent with the same treatment with different biologic agent(s). Data were extracted on study design, participants, interventions and outcomes. Study quality was assessed using the MERGE criteria. Comparable data were pooled for meta-analysis. RESULTS: Twenty eligible studies with 8225 patients were identified. The use of any biologic therapy improved overall survival with hazard ratio (HR) 0.87 (95% confidence interval (CI) 0.82-0.91, P<0.00001), progression-free survival (PFS) with HR 0.71 (95% CI 0.67-0.74, P<0.0001) and overall response rate (ORR) with odds ratio (OR) 2.38 (95% CI 2.03-2.78, P<0.00001). Grade 3/4 toxicity was increased with OR 2.34. Considering by subgroups, EGFR inhibitors (EGFR-I) in the second-line setting and anti-angiogenic therapies (both in second-line and third-line and beyond settings) all improved overall survival, PFS and ORR. EGFR-I in third-line settings improved PFS and ORR but not OS. CONCLUSIONS: The use of biologic agents in mCRC after first-line treatment is associated with improved outcomes but increased toxicity.

Bisphosphonates as a supplement to exercise to protect bone during long-duration spaceflight.

UNLABELLED: We report the results of alendronate ingestion plus exercise in preventing the declines in bone mass and strength and elevated levels of urinary calcium and bone resorption in astronauts during 5.5 months of spaceflight. INTRODUCTION: This investigation was an international collaboration between NASA and the JAXA space agencies to investigate the potential value of antiresorptive agents to mitigate the well-established bone changes associated with long-duration spaceflight. METHODS: We report the results from seven International Space Station (ISS) astronauts who spent a mean of 5.5 months on the ISS and who took an oral dose of 70 mg of alendronate weekly starting 3 weeks before flight and continuing throughout the mission. All crewmembers had available for exercise a treadmill, cycle ergometer, and a resistance exercise device. Our assessment included densitometry of multiple bone regions using X-ray absorptiometry (DXA) and quantitative computed tomography (QCT) and assays of biomarkers of bone metabolism. RESULTS: In addition to pre- and post-flight measurements, we compared our results to 18 astronauts who flew ISS missions and who exercised using an early model resistance exercise device, called the interim resistance exercise device, and to 11 ISS astronauts who exercised using the newer advanced resistance exercise device (ARED). Our findings indicate that the ARED provided significant attenuation of bone loss compared with the older device although post-flight decreases in the femur neck and hip remained. The combination of the ARED and bisphosphonate attenuated the expected decline in essentially all indices of altered bone physiology during spaceflight including: DXA-determined losses in bone mineral density of the spine, hip, and pelvis, QCT-determined compartmental losses in trabecular and cortical bone mass in the hip, calculated measures of fall and stance computed bone strength of the hip, elevated levels of bone resorption markers, and urinary excretion of calcium. CONCLUSIONS: The combination of exercise plus an antiresoptive drug may be useful for protecting bone health during long-duration spaceflight.

The GOFURTGO Study: AGITG phase II study of fixed dose rate gemcitabine-oxaliplatin integrated with concomitant 5FU and 3-D conformal radiotherapy for the treatment of localised pancreatic cancer.

BACKGROUND: Locally advanced inoperable pancreatic cancer (LAPC) has a poor prognosis. By increasing intensity of systemic therapy combined with an established safe chemoradiation technique, our intention was to enhance the outcomes of LAPC. In preparation for phase III evaluation, the feasibility and efficacy of our candidate regimen gemcitabine-oxaliplatin chemotherapy with sandwich 5-fluorouracil (5FU) and three-dimensional conformal radiotherapy (3DCRT) needs to be established. METHODS: A total of 48 patients with inoperable LAPC without metastases were given gemcitabine (1000 mg m(-2) d1 + d15 q28) and oxaliplatin (100 mg m(-2) d2 + d16 q28) in induction (one cycle) and consolidation (three cycles), and 5FU 200 mg m(-2) per day over 6 weeks during 3DCRT 54 Gy. RESULTS: Median duration of sustained local control (LC) was 15.8 months, progression-free survival (PFS) was 11.0 months, and overall survival was 15.7 months. Survival rates for 1, 2, and 3 years were 70.2%, 21.3%, and 12.8%, respectively. Global quality of life did not significantly decline from baseline during treatment, which was associated with modest treatment-related toxicity. CONCLUSION: Fixed-dose gemcitabine and oxaliplatin, combined with an effective and safe regimen of 5FU and 3DCRT radiotherapy, was feasible and reasonably tolerated. The observed improved duration of LC and PFS with more intensive therapy over previous trials may be due to patient selection, but suggest that further evaluation in phase III trials is warranted.

Long-term outcomes of patients with localized rectal cancer treated with chemoradiation or radiotherapy alone because of medical inoperability or patient refusal.

PURPOSE: The standard management of rectal cancer continues to be defined by the results of randomized, clinical trials exploring the optimal timing and use of adjuvant chemotherapy and radiation therapy in relation to surgery. The patient with rectal cancer who is elderly and/or has significant comorbidities and the patient who refuses surgery are clinical contexts for which there is limited current data to guide decision making. METHODS: A retrospective analysis was performed at six Australian centers of patients with rectal cancer treated with radiation therapy or chemoradiation alone because of excessive operative risk or patient refusal of surgery. RESULTS: We identified 48 patients treated between August 1998 and June 2005 with a median age of 76 (range, 49-94) years. Twenty-four patients (50 percent) were considered medically inoperable and 24 patients refused surgery. Treatment was with chemoradiation (with 5-fluorouracil) in 36 patients and radiotherapy alone in 12 patients; 93 percent completed the planned therapy. A clinical complete response was seen in 56 percent and a partial response in 30 percent of patients. At a median follow-up of 49 months, 18 patients have disease progression, including 10 of 24 in the medically inoperable group and 8 of 24 in the refused surgery group. Of the 25 deceased patients, 16 died from progressive disease and 9 from noncancer causes. CONCLUSIONS: Chemoradiation or radiotherapy alone is a safe alternative that results in significant progression-free and overall survival times in patients who are considered medically inoperable or refuse to undergo surgery. Ultimately, however, many patients will progress.

Gemcitabine with a specific conformal 3D 5FU radiochemotherapy technique is safe and effective in the definitive management of locally advanced pancreatic cancer.

The aim of this phase II study was to assess the feasibility and efficacy of a specific three-dimensional conformal radiotherapy technique with concurrent continuous infusion of 5-fluorouracil (CI 5FU) sandwiched between gemcitabine chemotherapy in patients with locally advanced pancreatic cancer. Patients with inoperable cancer in the pancreatic head or body without metastases were given gemcitabine at 1000 mg m(-2) weekly for 3 weeks followed by a 1-week rest and a 6-week period of radiotherapy and concurrent CI 5FU (200 mg m(-2) day(-1)). The defined target volume was treated to 54 Gy in 30 daily fractions of 1.8 Gy. After 4 weeks' rest, gemcitabine treatment was re-initiated for three cycles (days 1, 8, 15, q28). Forty-one patients were enrolled. At the end of radiotherapy, one patient (2.4%) had a complete response and four patients (9.6%) had a partial response; at the end of treatment, three patients (7.3%) had a complete response and two patients (4.9%) had a partial response. Median survival time was 11.7 months, median time to progression was 7.1 months, and median time to failure of local control was 11.9 months. The 1- and 2-year survival rates were 46.3 and 9.8%, respectively. Treatment-related grade 3 and 4 toxicities were reported by 16 (39.0%) and four (9.8%) patients, respectively. Sixteen out of 41 patients did not complete the planned treatment and nine due to disease progression. This approach to treatment of locally advanced pancreatic cancer is safe and promising, with good local control for a substantial proportion of patients, and merits testing in a randomised trial.

Computerized morphometry and three-dimensional image reconstruction in the evaluation of scalp biopsy from patients with non-cicatricial alopecias.

BACKGROUND: A major challenge in the histopathological examination of scalp biopsies is to perform an adequate evaluation of all the hair follicles present in the tissue. Transverse sectioning is currently the preferred technique to demonstrate every follicular structure in a punch biopsy specimen, although diagnostic accuracy is dependent on subjective evaluation of follicular morphology and hair size. OBJECTIVES: To determine if computer-based morphometry and three-dimensional (3D) image reconstruction software can be used to evaluate scalp biopsies from patients with non-cicatricial alopecias. METHODS: Nine 4-mm scalp punches were taken from nine patients with noncicatricial alopecias and step-sectioned transversely at 0.1-mm intervals from the epidermal surface to the subcutaneous fat. Each tissue section was then digitized and analysed using morphometric and 3D image reconstruction software. Morphometric data and 3D images were collated with clinical and conventional light microscopic diagnoses, as well as follow-up information. RESULTS: In four of the nine patients, results of morphometric analysis concurred with conventional clinicopathological diagnoses. In the remaining five patients, morphometry revealed a lower telogen count in one patient and higher telogen count in four patients. One of the four patients with a higher telogen count also had a low mean hair diameter and miniaturized anagen follicles in the 3D image that were suggestive of early androgenetic alopecia (AGA). 3D virtual microscopic imagery allowed the direct visualization of colour-coded, scaled hair follicles which demonstrated characteristic changes in alopecia areata, AGA and telogen effluvium. CONCLUSIONS: Our study demonstrated the feasibility of using morphometric and 3D reconstruction software to evaluate scalp biopsies. With further validation, this technique may prove to be more sensitive to detect subtle quantitative and qualitative follicular changes in non-cicatricial alopecias.

Reduced inositol content in lymphocyte-derived cell lines from bipolar patients.

OBJECTIVES: The study aimed to determine whether low inositol content and uptake previously reported in brain and peripheral tissue of bipolar patients are also reflected in lymphocyte-derived cell lines from these patients. METHODS: Inositol content and uptake were studied in lymphocyte-derived cell lines grown in vitro for at least five generations to eliminate influences of drug treatment. Inositol content was studied gas chromatographically and inositol uptake by following 3H-inositol incorporation at various concentrations. RESULTS: Inositol levels of cell lines derived from bipolar patients were significantly lower than those of cell lines from controls. CONCLUSIONS: Low inositol content in lymphocyte-derived cell lines from bipolar patients corroborates previous findings in frontal cortex and in lymphoblastoid cell lines and are consistent with the notion that the phosphatidylinositol signaling system is involved in the pathophysiology of this disorder.

Phase I and pharmacokinetic trial of weekly oral fluorouracil given with eniluracil and low-dose leucovorin to patients with solid tumors.

PURPOSE: Fluorouracil (5-FU) given as a weekly, high-dose 24-hour infusion is active and tolerable. We evaluated an oral regimen of eniluracil (which inactivates dihydropyrimidine dehydrogenase [DPD]), 5-FU, and leucovorin to simulate this schedule. PATIENTS AND METHODS: Patients received a single 24-hour infusion of 5-FU (2,300 mg/m(2) on day 2) with leucovorin (15 mg orally [PO] bid on days 1 through 3) to provide reference pharmacokinetic data. Two weeks later, patients began treatment with eniluracil (20 mg) and leucovorin (15 mg) (PO bid on days 1 through 3) and 5-FU (10 to 15 mg/m(2) PO bid on day 2). RESULTS: Dose-limiting toxicity (diarrhea, neutropenia, and fatigue) was seen with 5-FU 15 mg/m(2) PO bid on day 2 given weekly for either 6 of 8 weeks or 3 of 4 weeks, whereas five of seven patients tolerated 5-FU 10 mg/m(2) PO bid given weekly for 3 of 4 weeks. Eniluracil led to a 35-fold reduction in 5-FU clearance. Fluoro-beta-alanine, a 5-FU catabolite, was not detected in plasma during oral 5-FU-eniluracil therapy. DPD activity was markedly suppressed in all patients during eniluracil therapy; the inactivation persisted after the last eniluracil dose; percentages of baseline values were 1.8% on day 5, 4.5% on day 12, and 23.6% on day 19. CONCLUSION: The recommended oral dosage of 5-FU (10 mg/m(2) PO bid) given with eniluracil and leucovorin is approximately 115-fold lower than the reference dosage for 24-hour infusional 5-FU. This difference is greater than expected given the reduction in 5-FU clearance. DPD inactivation persisted for several weeks after completion of eniluracil therapy.

Scyllo-inositol in post-mortem brain of bipolar, unipolar and schizophrenic patients.

Inositol levels measured in postmortem brain of unipolar, bipolar and schizophrenic patients, suicide victims and normal controls showed no difference in scyllo-inositol levels in frontal or occipital cortex between any of the groups. We could not replicate previous reports of low myo-inositol levels in the frontal cortex of unipolar, bipolar and schizophrenic patients and suicide victims. There was no correlation between myo-inositol levels and estimated chlorpromazine equivalents in neuroleptic-treated subjects, and no effect of chronic haloperidol treatment on rat brain myo-inositol levels.

Alopecia areata update.

Alopecia areata (AA) is a nonscarring hair loss condition. Among the many factors under investigation in the pathogenesis of AA, the main areas of concentration have been genetic constitution as well as nonspecific immune and organ-specific autoimmune reactions. Treatment with intralesional corticosteroid injections for localized patchy AA and topical immunotherapy for extensive AA have proven successful in the majority of patients, although all treatments are palliative and do not change the prognosis of the disease.