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Background Cancer stem cells (CSCs) are purported to be responsible for tumor initiation, treatment resistance, disease recurrence, and metastasis. CXCR1, one of the receptors for CXCL8, was identified on breast cancer (BC) CSCs. Reparixin, an investigational allosteric inhibitor of CXCR1, reduced the CSC content of human BC xenograft in mice. Methods In this multicenter, single-arm trial, women with HER-2-negative operable BC received reparixin oral tablets 1000 mg three times daily for 21 days before surgery. Primary objectives evaluated the safety of reparixin and the effects of reparixin on CSC and tumor microenvironment in core biopsies taken at baseline and at treatment completion. Signal of activity was defined as a reduction of ≥ 20% in ALDH + or CD24 − /CD44 + CSC by flow cytometry, with consistent reduction by immunohistochemistry. Results Twenty patients were enrolled and completed the study. There were no serious adverse reactions. CSC markers ALDH + and CD24 − /CD44 + measured by flow cytometry decreased by ≥ 20% in 4/17 and 9/17 evaluable patients, respectively. However, these results could not be confirmed by immunofluorescence due to the very low number of CSC. Conclusions Reparixin appeared safe and well-tolerated. CSCs were reduced in several patients as measured by flow cytometry, suggesting targeting of CXCR1 on CSC. Clinical trial registration Clinicaltrials.gov, NCT01861054. Registered on April 18, 2013.

An amendment to this paper has been published and can be accessed via the original article.

The pharmacokinetics and potential drug–drug interactions between cetuximab and cisplatin or carboplatin from two studies (JXBA and JXBB) were evaluated. These studies were multicenter, open‐label phase II trials designed to evaluate the drug–drug interactions between cetuximab (400 mg m−2 initial dose) and cisplatin (JXBA; 100 mg m−2) or carboplatin (JXBB; area under the curve [AUC] = 5 mg × min mL−1) with or without 5‐fluorouracil (5FU) in patients with advanced solid tumors. Concentrations of cetuximab, cisplatin and carboplatin were determined using analytical methods. The safety and tolerability of cetuximab in combination with cisplatin or carboplatin was also determined in all treated patients. The JXBA study showed that cetuximab serum concentrations were similar when cetuximab was administered alone or in combination with cisplatin. The Cmax, tmax and overall AUC for the cetuximab group (194 µg mL−1, 2.0 hour, 14 900 µg × h mL−1) and the cetuximab and cisplatin combination group (192 µg mL−1, 1.99 hour, 16 300 µg × h mL−1) were similar. The JXBB study showed that mean cetuximab serum concentrations were similar when cetuximab was administered alone or in combination with carboplatin. The Cmax, tmax and overall AUC for the cetuximab group (199 µg mL−1, 1.15 hour, 17 200 µg × h mL−1) and the cetuximab and carboplatin combination group (199 µg mL−1, 3.17 h, 16 800 µg × h mL−1) were similar. Both studies showed that the safety profile was consistent with known side effects of cetuximab, platinum–based therapies and 5‐FU. There was no clinically relevant change in cetuximab pharmacokinetics when it was administered in combination with cisplatin or carboplatin.

Use of electronic clinical trial portals has increased in recent years to assist with sponsor-investigator communication, safety reporting, and clinical trial management. Electronic portals can help reduce time and costs associated with processing paperwork and add security measures; however, there is a lack of information on clinical trial investigative staff's perceived challenges and benefits of using portals. The Clinical Trials Transformation Initiative (CTTI) sought to (1) identify challenges to investigator receipt and management of investigational new drug (IND) safety reports at oncologic investigative sites and coordinating centers and (2) facilitate adoption of best practices for communicating and managing IND safety reports using electronic portals. CTTI, a public-private partnership to improve the conduct of clinical trials, distributed surveys and conducted interviews in an opinion-gathering effort to record investigator and research staff views on electronic portals in the context of the new safety reporting requirements described in the US Food and Drug Administration's final rule (Code of Federal Regulations Title 21 Section 312). The project focused on receipt, management, and review of safety reports as opposed to the reporting of adverse events. The top challenge investigators and staff identified in using individual sponsor portals was remembering several complex individual passwords to access each site. Also, certain tasks are time-consuming (eg, downloading reports) due to slow sites or difficulties associated with particular operating systems or software. To improve user experiences, respondents suggested that portals function independently of browsers and operating systems, have intuitive interfaces with easy navigation, and incorporate additional features that would allow users to filter, search, and batch safety reports. Results indicate that an ideal system for sharing expedited IND safety information is through a central portal used by all sponsors. Until this is feasible, electronic reporting portals should at least have consistent functionality. CTTI has issued recommendations to improve the quality and use of electronic portals.

Background A recent study reviewed phase III trials of first‐line advanced non‐small cell lung cancer (NSCLC) conducted from 1981 to 2010, and provided trends in the study outcome. However, such trials have never been analyzed in detail for design and stratification factors. Methods Phase III studies of systemic treatment for first‐line advanced or metastatic NSCLC published in English literature between 1981 and 2010 were identified. Characteristics, including sample size, number of trials, region, rate of meeting accrual goal, primary endpoint, type of phase III, interim analysis, allocation method, and stratification factors, were determined for each decade. Results A total of 162 studies met the criteria. The number of studies and sample size increased over the three decades. The primary endpoint was reported more frequently in recent decades, and non‐overall survival endpoints were chosen in European and Asian studies. Interim analysis was conducted more commonly during the 2000s. Allocation method was rarely reported throughout the three decades. The number of stratification factors increased significantly from one in 1980s to three in 2000s. Performance status, stage, and institution were most frequently selected, and at least one of the three factors was used in most of the studies in the 2000s. However, there are many other stratification factors that were used infrequently. Conclusions Despite Consolidated Standards of Reporting Trials guidelines, allocation method has rarely been reported. The choice of stratification factor remains inconsistent across studies.

Pancreatic cancer remains highly lethal. Previous attempts with neoadjuvant therapy in this disease have been inconclusive, but a potential for benefit exists. We conducted a phase II trial of dose-intense docetaxel and gemcitabine followed by twice-weekly gemcitabine and external beam radiotherapy in patients with pancreatic adenocarcinoma. Patients with stage I to III disease were eligible. Docetaxel 65 mg/m(2) intravenously over 1 hour and gemcitabine 4000 mg/m(2) given intravenously over 30 minutes were given on days 1, 15, and 29. On day 43, radiotherapy was begun at 50.4 Gy with gemcitabine 50 mg/m(2) intravenously over 30 minutes twice weekly for 12 doses. After treatment, patients were considered for resection. Twenty-four assessable patients were recruited onto the trial. All but one patient completed a full 12 weeks of therapy. Grade 3 and 4 hematological and nonhematological toxicities were common but manageable, and neutropenic fever did not occur. No patient had local tumor progression. Twelve patients (50%) responded by Response Evaluation Criteria in Solid Tumors Group (RECIST) criteria, including one radiographic complete response. Seventeen patients underwent resection after therapy. Margin-negative resections were performed in 13 patients, including 9 patients whose disease was borderline or unresectable before treatment. A treatment effect was seen in all resection specimens. There have been no local recurrences of tumor, and several patients remain alive without evidence of disease. Docetaxel/gemcitabine followed by gemcitabine/radiotherapy is active in the treatment of pancreatic adenocarcinoma, with manageable toxicity. Tumor downstaging occurs in some patients to allow complete resection. Further investigation of this regimen is warranted.

To determine the maximum tolerated dose and dose-limiting toxicity (DLT) of the novel anticancer agent, motexafin gadolinium (MGd), administered concurrently with radiation therapy (RT) in patients with locally advanced pancreatic or biliary tumors. The pharmacokinetics of MGd were also evaluated. Cohorts of three to six patients were treated with escalating doses of MGd, administered three times per week for a total of 16 doses concurrent with RT. The dose of RT was fixed at 5,040 cGy, and given in 28 fractions, from Monday to Friday of every week. Plasma MGd concentrations were measured by high performance liquid chromatography. Eight patients were treated at dose level 1 (2.9 mg/kg), with one DLT (grade 3 fever). Three patients were treated at dose level 2 (3.6 mg/kg), and two DLTs were noted. One DLT was grade 3 nausea and vomiting (N/V), and the other was grade 3 skin toxicity. The most common toxicity was N/V. There were no objective responses. The median survival was 6 months. The MGd plasma concentration versus time profile in each patient was best fit by a two-compartment, open, linear model. There was minimal accumulation of MGd in plasma with the three-times/week dosing schedule. Simulation of the time course of MGd in the peripheral compartment indicated that maximal MGd concentrations of 1-2 micromol/kg occurred between 4 and 6 h after MGd infusion. Dose level 1 (2.9 mg/kg of MGd) is the recommended dose for combination with (RT) in phase II studies for locally advanced pancreatic and biliary cancers. Patient tolerance might be improved by modification of the RT schedule and antiemetic prophylaxis.

BackgroundA recent study reviewed phase III trials of first‐line advanced non‐small cell lung cancer (NSCLC) conducted from 1981 to 2010, and provided trends in the study outcome. However, such trials have never been analyzed in detail for design and stratification factors.MethodsPhase III studies of systemic treatment for first‐line advanced or metastatic NSCLC published in English literature between 1981 and 2010 were identified. Characteristics, including sample size, number of trials, region, rate of meeting accrual goal, primary endpoint, type of phase III, interim analysis, allocation method, and stratification factors, were determined for each decade.ResultsA total of 162 studies met the criteria. The number of studies and sample size increased over the three decades. The primary endpoint was reported more frequently in recent decades, and non‐overall survival endpoints were chosen in European and Asian studies. Interim analysis was conducted more commonly during the 2000s. Allocation method was rarely reported throughout the three decades. The number of stratification factors increased significantly from one in 1980s to three in 2000s. Performance status, stage, and institution were most frequently selected, and at least one of the three factors was used in most of the studies in the 2000s. However, there are many other stratification factors that were used infrequently.ConclusionsDespite Consolidated Standards of Reporting Trials guidelines, allocation method has rarely been reported. The choice of stratification factor remains inconsistent across studies.

Increased physician awareness of soft tissue sarcomas, a relatively rare tumor, may lead to earlier diagnosis and improved results. Clinical presentation, diagnosis, pathology and treatment of soft tissue sarcomas in adults are examined.

Sebaceous carcinomas (SeC) are cutaneous malignancies that, in rare cases, metastasize and prove fatal. Here we report whole-exome sequencing on 32 SeC, revealing distinct mutational classes that explain both cancer ontogeny and clinical course. A UV-damage signature predominates in 10/32 samples, while nine show microsatellite instability (MSI) profiles. UV-damage SeC exhibited poorly differentiated, infiltrative histopathology compared to MSI signature SeC ( p  = 0.003), features previously associated with dissemination. Moreover, UV-damage SeC transcriptomes and anatomic distribution closely resemble those of cutaneous squamous cell carcinomas (SCC), implicating sun-exposed keratinocytes as a cell of origin. Like SCC, this UV-damage subclass harbors a high somatic mutation burden with >50 mutations per Mb, predicting immunotherapeutic response. In contrast, ocular SeC acquires far fewer mutations without a dominant signature, but show frequent truncations in the ZNF750 epidermal differentiation regulator. Our data exemplify how different mutational processes convergently drive histopathologically related but clinically distinct cancers. Sebaceous carcinomas (SeC) are cutaneous malignancies that sometimes metastasize and cause death. Here the authors perform whole-exome sequencing on 32 SeC and report distinct mutational classes that may explain cancer ontogeny and clinical outcome.