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The article offers a perspective on variants of unknown significance (VUS) in precision oncology and their impact on treatment choice. It presents clinical cases of patients with pancreatic cancer, a family history of cancer, and germline or somatic VUS, to illustrate the challenges of VUS in clinical practice. It considers pathogenic, germline mutations as loss-of-function mutations in tumor suppressors and presents data regarding pathogenic TET3 mutations and VUS.

The authors discuss the impact of exuberance on equipoise in oncology clinical trials. Topics include factors that have contributed to the loss of equipoise which lead to early withdrawals from study and informative censoring, the use of progression-free survival (PFS) as an endpoint, and importance of effective lines of therapy in oncology.

Considering presentations at this year's ASCO annual meeting, this editorial highlights a number of studies of interest, from adjuvant therapy studies to tumor agnostic therapy. [ABSTRACT FROM AUTHOR]

Background: Methods for screening agents earlier in development and strategies for conducting smaller randomized controlled trials (RCTs) are needed. Methods: We retrospectively applied a tumor growth model to estimate the rates of growth of pancreatic cancer using radiographic tumor measurements or serum CA 19-9 values from 3033 patients with stages III-IV PDAC who were enrolled in 8 clinical trials or were included in 2 large real-world data sets. Results: g correlated inversely with OS and was consistently lower in the experimental arms than in the control arms of RCTs. At the individual patient level, g was significantly faster for lesions metastatic to the liver relative to those localized to the pancreas. Regardless of regimen, g increased toward the end of therapy, often by over 3-fold. Conclusions: Growth rates of PDAC can be determined using radiographic tumor measurement and CA 19-9 values. g is inversely associated with OS and can differentiate therapies within the same trial and across trials. g can also be used to characterize changes in the behavior of an individual's PDAC, such as differences in the growth rate of lesions based on metastatic site, and the emergence of chemoresistance. We provide examples of how g can be used to benchmark phase II and III clinical data to a virtual reference arm to inform go/no go decisions and consider novel trial designs to optimize and accelerate drug development. Novel trial designs, requiring smaller sample sizes, are needed to screen therapies earlier in development and to inform go/no go decisions more accurately. This article describes a kinetic analysis of clinical trial and real-world data from therapies used in the management of metastatic pancreatic ductal adenocarcinoma, using a novel method of analysis indifferent to intervals of assessment to compare data from disparate sources. [ABSTRACT FROM AUTHOR]

Background Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare neoplasms with an increasing annual incidence and prevalence. Many are metastatic at presentation or recur following surgical resection and require systemic therapy, for which somatostatin analogs such as octreotide or lanreotide comprise typical first-line therapies. Nonetheless, treatment options remain limited. Epigenetic processes such as histone modifications have been implicated in malignant transformation and progression. In this study, we evaluated the anti-proliferative effects of a histone deacetylase (HDAC) inhibitor, entinostat, which was computationally predicted to show anti-cancer activity, as confirmed in in vitro and in vivo models of GEP-NETs. Methods This was a phase II study to evaluate the efficacy and safety of entinostat in patients with relapsed or refractory abdominal NETs. The primary objective was to estimate the objective response rate to entinostat. Additionally, with each patient as his/her own control we estimated the rates of tumor growth prior to enrollment on study and while receiving entinostat. Patients received 5 mg entinostat weekly until disease progression or intolerable toxicity. The dose could be changed to 10 mg biweekly for patients who did not experience grade ≥ 2 treatment-related adverse events (AEs) in cycle 1, but was primarily administered at the starting 5 mg weekly dose. Results The study enrolled only 5 patients due to early termination by the drug sponsor. The first patient that enrolled had advanced disease and died within days of enrollment before follow-up imaging due to a grade 5 AE unrelated to study treatment and was considered non-evaluable. Best RECIST response for the remaining 4 patients was stable disease (SD) with time on study of 154+, 243, 574, and 741 days. With each patient as his/her own control, rates of tumor growth on entinostat were markedly reduced with rates 17%, 20%, 33%, and 68% of the rates prior to enrollment on study. Toxicities possibly or definitely related to entinostat included grade 2/3 neutrophil count decrease [2/4 (50%)/ 2/4 (50%)], grade 3 hypophosphatemia [1/4, (25%)], grade 1/2 fatigue [1/4 (25%)/ 2/4 (50%)], and other self-limiting grade 1/2 AEs. Conclusion In the treatment of relapsed or refractory abdominal NETs, entinostat 5 mg weekly led to prolonged SD and reduced the rate of tumor growth by 32% to 83% with an acceptable safety profile (ClinicalTrials.gov Identifier: NCT03211988). [ABSTRACT FROM AUTHOR]

HER2 amplification, which results in overexpression of the receptor tyrosine kinase HER2, has been described in a wide variety of malignancies. HER2‐targeting agents have been incorporated into the treatment paradigms for HER2‐overexpressing breast and gastric cancer. More recently, these agents have shown promise in other gastrointestinal malignancies, such as colon cancer and biliary tract tumors. This study discusses two patients with gallbladder carcinoma and a third with ampullary carcinoma who were able to achieve marked responses to HER2‐directed therapy. These cases underscore the importance of molecular analysis for HER2 amplification/HER2 overexpression, irrespective of tumor histology, and highlight a need for further investigation of HER2‐directed therapy beyond breast and gastroesophageal cancers. Key Points: Current guidelines recommend molecular assessment for HER2 overexpression exclusively in breast and gastric adenocarcinoma.The focus of this report is on three cases (two biliary tract and one ampullary carcinoma) in which amplification of HER2 or overexpression of HER2 was detected and treatment with HER2‐directed therapy resulted in robust responses.These cases exemplify responsiveness of non‐breast/gastric histologies to HER2‐directed therapies, highlighting several promising new settings for these agents.Testing for amplification of HER2 or overexpression of HER2 should be considered especially in rare diseases with limited treatment options. This article presents three unique cases, two patients with gallbladder carcinoma and one patient with ampullary carcinoma, whose tumors overexpressed HER2 and responded remarkably well to HER2‐directed therapy. [ABSTRACT FROM AUTHOR]

STK11 was first recognized as a tumor suppressor gene in the late 1990s based on linkage analysis of patients with Peutz‐Jeghers syndrome. STK11 encodes LKB1, an intracellular serine‐threonine kinase involved in cellular metabolism, cell polarization, regulation of apoptosis, and DNA damage response. Recurrent somatic loss‐of‐function mutations occur in multiple cancer types, most notably in 13% of lung adenocarcinomas. Recent reports indicate that KRAS‐mutant non‐small cell lung cancers harboring co‐mutations in STK11 do not respond to PD‐1 axis inhibitors. We present three patients with STK11‐mutated tumors and discuss the proposed mechanisms by which germline and somatic alterations in STK11 promote carcinogenesis, potential approaches for therapeutic targeting, and the new data on resistance to immune checkpoint inhibitors. Key Points: STK11 is a tumor suppressor gene, and loss‐of‐function mutations are oncogenic, due at least in part to loss of AMPK regulation of mTOR and HIF‐1‐α. Clinical trials are under way, offering hope to patients whose STK11‐mutated tumors are refractory and/or have progressed on chemotherapeutic regimens. Whether gastrointestinal cancers with STK11 loss of function will show the same outcome and potential refractoriness to immune therapy that were reported for lung cancer is unknown. However, physicians managing such patients should consider the experience in lung cancer, particularly outside the context of a clinical trial.In the CheckMate‐057 trial lung tumors harboring co‐mutations in KRAS and STK11 had an inferior response to PD‐1 axis inhibitors. Coupled with the observation that STK11‐mutated tumors were found to have a cold immune microenvironment regardless of KRAS status, the conclusion could extend to KRAS wild‐type tumors with STK11 mutation. Current data suggest that the use of PD‐1 axis inhibitors may be ill advised in the presence of STK11 mutation. This article reports three cases of different cancer types harboring somatic STK11 mutations, focusing on the mechanism of tumorigenesis in cancers harboring this particular tumor suppressor gene and the currently available therapeutic options. [ABSTRACT FROM AUTHOR]

Venous thromboembolism (VTE) frequently occurs in patients with cancer, and particularly those with pancreatic ductal adenocarcinoma (PDAC). Therapeutic anticoagulation with either low‐molecular‐weight heparin or a direct oral anticoagulant is clearly beneficial in patients who develop a VTE. However, whether thromboprophylaxis improves patient outcomes remains unclear. Studies assessing this risk show a 10%–25% risk of VTE, with reduction to 5%–10% with thromboprophylaxis but no impact on survival. To aid in the risk stratification of patients, several tools have been developed to identify those at highest risk for a VTE event. However, the clinical application of these risk stratification models has been limited, and most patients, even those at the highest risk, will never have a VTE event. New oral anticoagulants have greatly improved the feasibility of prophylaxis but do show increased risk of bleeding in patients with the underlying gastrointestinal dysfunction frequently found in patients with pancreatic cancer. Recently, several completed clinical trials shed new light on this complicated risk versus benefit decision. Here, we present this recent evidence and discuss important considerations for the clinician in determining whether to initiate thromboprophylaxis in patients with PDAC. Implications for Practice: Given the high risk of venous thromboembolism in patients with pancreatic adenocarcinoma (PDAC), whether to initiate prophylactic anticoagulation is a complex clinical decision. This review discusses recent evidence regarding the risk stratification and treatment options for thromboprophylaxis in patients with PDAC, with the goal of providing practicing clinicians with updates on recent developments in the field. This article also highlights important considerations for individualizing the treatment approach for a given patient given the lack of general consensus of uniform recommendations for this patient population. Venous thromboembolism (VTE) frequently occurs in patients with cancer, especially pancreatic ductal adenocarcinoma (PDAC). Several tools have been developed to identify those at highest risk for a VTE event; however, whether thromboprophylaxis improves patient outcomes remains unclear. This article presents evidence and important considerations for the clinician in determining whether to initiate thromboprophylaxis in patients with PDAC. [ABSTRACT FROM AUTHOR]

Background: Concurrent chemoradiotherapy is an established component of the nonoperative management of locally advanced head and neck squamous cell carcinoma (HNSCC), but the standard dose of 100 mg/m2 cisplatin every 3 weeks is associated with clinically significant toxicity. Interest in a more tolerable regimen has led to the widespread use of weekly lower dose cisplatin, but few randomized trials have compared these approaches.Methods: We examined outcomes of patients with stage III-IVb HNSCC treated with definitive intent chemoradiotherapy using either high-dose cisplatin (HDC) or low-dose cisplatin (LDC), using population-based Veterans Affairs data. In an intent-to-treat analysis, patients were assigned to the HDC vs LDC group according to the dose of their first cycle. Variables potentially influencing treatment decisions including cancer site, stage, smoking/alcohol use, and comorbidities were used to generate propensity scores (PS) for the use of HDC. We compared overall survival (OS) by treatment group using Cox regression, adjusting for PS. We then determined the risk of toxicities using PS-adjusted logistic regression.Results: A total of 2901 patients were included in the analysis; 2200 received HDC (mean initial dose 100 mg/m2). The mean initial dose of LDC was 40 mg/m2. After PS adjustment, HDC was not associated with improved OS over LDC (hazard ratio = 0.94, 95% confidence interval = 0.80 to 1.04). Adjusting for PS, HDC was associated with an increased risk of acute kidney injury, neutropenia, dehydration/electrolyte disturbance, and hearing loss.Conclusion: In this large, population-based study of US military veterans, LDC was associated with similar survival to HDC in the nonoperative definitive management of locally advanced HNSCC of the oral cavity, oropharynx, and hypopharynx/larynx. HDC was associated with statistically significantly more toxicity than LDC. Adoption of LDC may reduce toxicity burden while maintaining OS. [ABSTRACT FROM AUTHOR]

Better adherence to supportive care guidelines is needed, especially for common challenges such as chemotherapy‐induced nausea and vomiting. This commentary remarks on recently published data on adherence to guidelines, considering treatment options and new strategies to reduce chemotherapy complications. [ABSTRACT FROM AUTHOR]

Background Multiple preclinical studies have shown cytotoxic synergy involving combinations of poly (ADP-ribose) polymerase (PARP) inhibitors and topoisomerase 1 (TOP1) inhibitors, but such combinations have proven too toxic in clinical trials. Liposomal irinotecan (nal-IRI) achieved similar intratumoral exposure with better antitumor activity than the conventional TOP1 inhibitor irinotecan in preclinical models. Tumor targeted delivery of TOP1 inhibitor using nal-IRI and an intermittent schedule of administration of PARP inhibitor may provide a tolerable combination. Methods A phase I study was performed to evaluate the safety and tolerability of escalating doses of nal-IRI and the PARP inhibitor veliparib in patients with solid tumors resistant to standard treatments. Nal-IRI was administered on days 1 and 15 and veliparib on days 5-12 and 19-25 in 28-day cycles. Results Eighteen patients were enrolled across 3 dose levels. Five patients encountered dose–limiting toxicities, including grade 3 diarrhea lasting more than 72 h in 3 patients and 1 patient each with grade 4 diarrhea and grade 3 hyponatremia. The most common grade 3 or 4 toxicities included diarrhea (50% of patients), nausea (16.6%), anorexia, and vomiting (11.1% each) (Table 1). There was no difference in frequencies of adverse events based on UGT1A1*28 status or prior opioid use (Table 1). Conclusion The clinical trial was terminated due to high frequency of unacceptable gastrointestinal toxicities, which precluded dose escalation of veliparib in combination with nal-IRI (ClinicalTrials.gov Identifier: NCT02631733). [ABSTRACT FROM AUTHOR]

This editorial describes the results of discussions between the U.S. FDA Oncology Center of Excellence and members of six pharmaceutical companies—a forum aptly named PD‐1 Pandemonium—regarding development and regulatory approvals of immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

As the challenge of proper reporting of potential financial conflicts of interest is once again brought into the national spotlight, this editorial considers the recent events, expands on current systems for enforcing accurate reporting of financial disclosures, and considers ways to move forward. [ABSTRACT FROM AUTHOR]

The author comments on the editorial "Back to the Future for Clinical Oncology," by Doctor Bruce Chabner, published in February 1996. Topics covered include the importance of providing multimodality care for individuals with cancer, concerns regarding market forces undermining cancer care and the move of the Veterans Administration Medical Centers to launch a series of clinical pathways that offer a decision support tool.

In this issue of The Oncologist, Agarwal et al. report negative results from a phase I trial of LFA102. Although “negative” in terms of antitumor activity, the study provides useful pharmacokinetic and pharmacodynamic information. Future trials evaluating PRLR blockers alone and in combination with other agents may still be warranted in patients with breast and prostate cancer. [ABSTRACT FROM AUTHOR]

Background. Despite the ethical imperative to publish clinical trials when human subjects are involved, such data frequently remain unpublished. The objectives were to tabulate the rate and ascertain factors associated with eventual publication of clinical trial results reported as abstracts in the Proceedings of the American Society of Clinical Oncology (American Society of Clinical Oncology). Materials and Methods. Abstracts describing clinical trials for patients with breast, lung, colorectal, ovarian, and prostate cancer from 2009 to 2011 were identified by using a comprehensive online database (http://meetinglibrary.asco. org/abstracts). Abstracts included reported results of a treatment or intervention assessed in a discrete, prospective clinical trial. Publication status at 426 years was determined by using a standardized search of PubMed. Primary outcomes were the rate of publication for abstracts of randomized and nonrandomized clinical trials. Secondary outcomes included factors influencing the publication of results. Results. A total of 1,075 abstracts describing 378 randomized and 697 nonrandomized clinical trials were evaluated. Across all years, 75% of randomized and 54% of nonrandomized trials were published, with an overall publication rate of 61%. Sample size was a statistically significant predictor of publication for both randomized and nonrandomized trials (odds ratio [OR] per increase of 100 participants 5 1.23 [1.11-1.36], p < .001; and 1.64 [1.15-2.34], p = .006, respectively). Among randomized studies, an industry coauthor or involvement of a cooperative group increased thelikelihoodofpublication(OR2.37, p = .013; and 2.21, p = .01, respectively). Among nonrandomized studies, phase II trials were more likely to be published than phase I (p < .001). Use of an experimental agent was not a predictor of publication in randomized (OR 0.76 [0.38-1.52]; p = .441) or nonrandomized trials (OR 0.89 [0.61-1.29]; p = .532). Conclusion. This is the largest reported study examining why oncology trials are not published. The data show that 426 years after appearing as abstracts, 39% of oncology clinical trials remain unpublished. Larger sample size and advanced trial phase were associated with eventual publication; among randomized trials, an industry-affiliated author or a cooperative group increased likelihood of publication. Unfortunately, we found that, despite widespread recognition of the problem and the creation of central data repositories, timely publishing of oncology clinical trials results remains unsatisfactory. [ABSTRACT FROM AUTHOR]

Many investigators have turned their efforts toward improving the gemcitabine/nab‐paclitaxel combination by the addition of a third agent. This commentary highlights efforts to date, including the Clinical Trial Results by Ko et al.: A Randomized Double‐Blinded Phase II Trial of Gemcitabine and Nab‐Paclitaxel Plus Apatorsen or Placebo in Patients with Metastati Pancreatic Cancer: The RAINIER Trial. [ABSTRACT FROM AUTHOR]

In the article, the author discusses updates in the operation of the journal, including the resignation of Bruce Chabner as editor-in-chief of the journal and the journal's mission to present the best therapies to the clinics.

The author comments on the draft opinion of the U.S. Supreme Court in the case Dobbs v. Jackson Women's Health Organizaion, which supports to overturn of the constitutional right to abortion ruling in Roe v. Wade. The author points out the lack of clarity as to what will be considered as life-saving situation. The author views that a woman's decision to terminate her pregnancy is a constitutional right and that the prohibition of abortion is a threat to the rational practice of medicine.

Policies promoting open access publishing have resulted in a startling increase in the number of gold open‐access publishing groups, some of which have been identified as “predatory” in nature. This commentary aims toward a better understanding of the characteristics of predatory publishing groups, discusses the negative aspects of accepting spam e‐mail invitations to publish in their journals, and encourages thought about an alternative direction for biomedical publishing. [ABSTRACT FROM AUTHOR]

Background. To hasten cancer drug development, new paradigms are needed to assess therapeutic efficacy. In a randomized phase II study in patients with renal cell carcinoma, 10 µg/kg bevacizumab (Avastin®; Genentech, Inc., South San Francisco, CA) administered every 2 weeks resulted in a longer time to progression but a statistically significant difference in overall survival could not be demonstrated. Methods. We developed a novel two-phase equation to estimate concomitant rates of tumor regression (regression rate constant) and tumor growth (growth rate constant). This method allows us to assess therapeutic efficacy using tumor measurements gathered while a patient receives therapy in a clinical trial. Results. The growth rate constants of renal cell carcinomas were significantly lower during therapy with 10 µg/kg bevacizumab than those of tumors in patients receiving placebo. In all cohorts the tumor growth rate constants were correlated with survival. That a survival advantage was not demonstrated with bevacizumab appears to have been a result of early discontinuation of bevacizumab. Conclusions. Single-agent bevacizumab significantly affects the growth rate constants of renal cell carcinoma. Extrapolating from the growth rate constants, we conclude that the failure to demonstrate a survival advantage in the original study was a result of premature discontinuation of bevacizumab. The mathematical model described herein has applications to many tumor types and should aid in evaluating the relative efficacies of different therapies. Quantitating tumor growth rate constants using data gathered while patients are enrolled in a clinical trial, as in the present study, may streamline and assist in drug development. [ABSTRACT FROM AUTHOR]

Purpose. The slow progress in developing new cancer therapies can be attributed in part to the long time spent in clinical development. To hasten development, new paradigms especially applicable to patients with metastatic disease are needed. Patients and Methods. We present a new method to predict survival using tumor measurement data gathered while a patient with cancer is receiving therapy in a clinical trial. We developed a two-phase equation to estimate the concomitant rates of tumor regression (regression rate constant d) and tumor growth (growth rate constant g). Results. We evaluated the model against serial levels of prostate-specific antigen (PSA) in 112 patients undergoing treatment for prostate cancer. Survival was strongly correlated with the log of the growth rate constant, log(g) (Pearson r=-0.72) but not with the log of the regression rate constants, log(d) (r=-0.218). Values of log(g) exhibited a bimodal distribution. Patients with log(g) values above the median had a mortality hazard of 5.14 (95% confidence interval, 3.10-8.52) when compared with those with log(g) values below the median. Mathematically, the minimum PSA value (nadir) and the time to this minimum are determined by the kinetic parameters d and g, and can be viewed as surrogates. Conclusions. This mathematical model has applications to many tumor types and may aid in evaluating patient outcomes. Modeling tumor progression using data gathered while patients are on study, may help evaluate the ability of therapies to prolong survival and assist in drug development. [ABSTRACT FROM AUTHOR]

Hoechst 33342 side population (SP) analysis is a common method for identifying stem cells in mammalian hematopoietic and nonhematopoietic tissues. Although widely employed for stem cell analysis, this method requires an ultraviolet (UV) laser to excite Hoechst 33342. Flow cytometers equipped with UV sources are not common because of the cost of both the laser and optics that can transmit light UV light. Violet laser sources are inexpensive and are now common fixtures on flow cytometers, but have been previously shown to provide insufficient Hoechst dye excitation for consistent resolution of SP cells. One solution to this problem is to identify additional fluorescent substrates with the same pump specificity as Hoechst 33342, but with better violet excitation characteristics. DyeCycle Violet reagent has emission characteristics similar to those of Hoechst 33342, but with a longer wavelength excitation maxima (369 nm). When this dye is loaded into hematopoietic cells, a sharply resolved side population was also observed, similar in appearance to that seen with Hoechst 33342. Unlike Hoechst SP, DCV SP was similar in appearance with both violet and UV excitation. DCV SP could be inhibited fumitremorgin C, and showed the same membrane pump specificity as Hoechst 33342. Simultaneous immunophenotyping with stem cell markers in mouse bone marrow demonstrated that DCV SP was restricted to the stem cell lineage- Sca-1+ c-kit+ cells population, as is Hoechst SP. Pending confirmation by functional analysis of DCV SP cells, these results suggest that DCV efflux identified approximately the same stem cell population as did Hoechst 33342 efflux. Substituting DCV for Hoechst 33342 in the SP technique may, therefore, allow side population analysis on flow cytometers with violet lasers. [ABSTRACT FROM AUTHOR]

The era of COVID19 reflects the importance, perhaps now more than ever, of transparency in the outcomes of trials small and large. The Oncologist Clinical Trial Results (CTR) section has endeavored to provide a remedy for the persistent problem of underreporting in clinical trials in oncology and the subsequent publication bias that this practice necessarily creates. As The Oncologist celebrates its 25th Anniversary, we focus not only on the ethical and moral imperatives behind CTR, but also on the practical goal of informing the practice of treating physicians. [ABSTRACT FROM AUTHOR]

Lessons Learned: Staphylococcus aureus infection in cutaneous T‐cell lymphoma (CTCL) is thought to contribute to disease progression; thus, adjunctive treatment with antibiotics warrants further investigation.This trial of antibiotic therapy followed by imiquimod in early stage CTCL was not completed because of difficulties with patient accrual. Background: Cutaneous T‐cell lymphoma (CTCL), a form of non‐Hodgkin lymphoma, is a heterogeneous group of malignancies of mature memory T lymphocytes. It has an annual age‐adjusted incidence of 7.5 per million persons in the U.S. population [1]. The etiology of CTCL is unknown, but epidemiological studies have reported potential associations with environmental and occupational factors, including Agent Orange exposure in Vietnam Veterans [2]. Both topical and systemic therapies have been identified as effective in CTCL; the choice of treatment is dependent on disease stage, with the overall goal of improving symptoms given the chronic and recurrent nature of the disease. Several studies have suggested that CTCL is exacerbated by the presence of Staphylococcus aureus in the skin and can be ameliorated by treatment with antibiotics [3]. Methods: Our study was designed to assess the effects of antibiotics and imiquimod on early stage CTCL. Patients between the ages of 30–89 years with stage I and II CTCL were eligible for enrollment. They could not be receiving concurrent therapy, and the study design included a 14‐day washout period after discontinuation of CTCL therapy. The washout period was followed by doxycycline 100 mg p.o. b.i.d. for 14 days and then two packets (250 mg per packet) of imiquimod 5% cream topically to the most clinically active lesions 3 days a week (Monday, Wednesday, and Friday) for 28 days. Skin lesions were measured using the modified Severity Weighted Assessment Tool (mSWAT). Results: Our study enrolled only two patients with early stage CTCL because of difficulty locating patients with active CTCL able to discontinue all therapy. The two enrolled patients completed all therapy. One patient had a complete response after imiquimod, whereas the other patient had stable disease. Conclusion: Antibiotics and imiquimod have reported activity as single agents in CTCL; we did not enroll enough patients to assess value in the sequence of antibiotic therapy followed by imiquimod. [ABSTRACT FROM AUTHOR]

The development of new treatment options for central nervous system metastases from breast cancer and from other solid tumors lags far behind progress in other areas of oncology. Despite this lag, a series of paradigm shifts have made it possible to renew our efforts to make progress. [ABSTRACT FROM AUTHOR]

Objective: An increase in stimulation frequency can facilitate or depress cardiac Ca2+ current (ICa). The aim was to examine the Ca2+ dependence of these effects, to determine if facilitation is sustained, and to elucidate the mechanism by which isoprenaline modulates facilitation. Methods: We examined the effects of increasing the stimulation frequency for 1 min, from 0.05 to 1 Hz, on ICa recorded from guinea-pig ventricular myocytes, using the whole-cell, voltage-clamp technique. Results: 1 Hz stimulation caused a facilitation of ICa that peaked in 5 s and was followed by depression towards the basal level. Metabolic inhibitors or replacement of extracellular Ca2+ with Ba2+ abolished facilitation without affecting depression, implying that they are independent processes and that facilitation required ATP and Ca2+. Subtraction of the depression observed in either condition, from the response to 1 Hz stimulation recorded under control conditions, revealed that ICa facilitation was well maintained during 1 Hz stimulation. Increased intracellular Ca2+ buffering reduced both phases of the response. Furthermore, varying the extracellular Ca2+ concentration ([Ca2+]o) revealed a Ca2+-dependent enhancement of depression and a bell-shaped dependence of facilitation on [Ca2+]o. Facilitation increased with [Ca2+]o up to 1 mM, then declined at higher concentrations due to partial masking by the overlapping depression. Isoprenaline produced concentration-dependent inhibition of facilitation and enhancement of depression when pipettes contained 2 mM EGTA, but not BAPTA. For an equivalent increase in ICa amplitude, the effects of isoprenaline and elevated [Ca2+]o on the response to 1 Hz stimulation were quantitatively the same. Conclusions: Facilitation is sustained during increased activity, but appears transient due to overlapping depression. Both responses are promoted by increased submembrane [Ca2+]. Isoprenaline appears to modulate facilitation and depression as a consequence of increased Ca2+ influx, rather than cAMP-dependent phosphorylation. The apparent block of facilitation by isoprenaline may result from masking by the enhanced depression. [ABSTRACT FROM PUBLISHER]

Multidrug resistance (MDR) mediated by high levels of mdr-I (also known as PGYl)/P-glycoprotein (Pgp) has been studied in tissue culture systems; however, most tumor samples which express mdr-l/Pgp have much lower levels. We wanted to determine if levels seen clinically could be detected by commonly used methods and to determine if these levels conferred MDR reversible by Pgp antagonists. We studied multi-drug-resistant cell lines and sublines with levels of mdr-l/Pgp expression comparable to those seen clinically. We evaluated the expression of mdr-l RNA by Northern blot analysis, slot blot analysis, polymerase chain reaction (PCR) analysis, and in situ hybridization. We evaluated protein expression by immunofluorescence, immunohis-tochemistry, fluorescence-activated cell sorting, and immunoblotting analyses. Drug resistance and reversibility were determined by cell growth during continuous drug exposure. In most cases, the low level of mdr-l/Pgp present in these cell lines could be detected by each method, but the assays were at the limit of sensitivity for all methods except the PCR method. These low levels of mdr-l/Pgp are capable of conferring MDR, which can be antagonized by verapamil. Levels of mdr-l/Pgp similar to those found in clinical samples can be detected by each of these methods, but the PCR method was the most sensitive and most reliably quantitative. In vitro sensitization by the addition of verapamil in cell lines with these low levels of mdr-1/Pgp suggests that clinically detected levels may confer drug resistance in vivo. [J Natl Cancer Inst 84:711–716, 1992] [ABSTRACT FROM PUBLISHER]

Communication of clinical trial outcomes is important, but the results of many clinical trials are never published. If we do not publish the results of clinical trials, the lessons learned from those trials will perish. The Oncologist offers a powerful solution through the Clinical Trial Results publishing platform, which uses an established template for authors to easily build a manuscript by simply providing the essential trial data. Through it, every patient's legacy of clinical trial enrollment can matter. [ABSTRACT FROM AUTHOR]

The Editors of The Oncologist remark on recent national events and call for new strategies for the New Year. [ABSTRACT FROM AUTHOR]

As recruitment for oncology clinical trials has become more difficult, there appears to have been an increase in the number of studies that allow patients in the control arm to “crossover” and receive the experimental therapy after disease progression. Although some researchers worry that allowing such crossover may abolish gains in progression-free survival in the experimental arm, the possibility that crossover might inadvertently benefit the experimental arm has not been addressed. In clinical trials in which the experimental agent has little or no intrinsic activity and is used to modulate an active combination, such crossover might negatively affect the overall survival of the control arm. Because resistance to the active combination—manifested as disease progression—has occurred, the likelihood of benefit from adding the experimental drug is reduced. Consequently, patients who were randomly assigned to the control arm continue to receive the now inactive combination after crossover, whereas patients in the experimental arm who discontinue study participation may seek out potentially effective salvage regimens. This difference in subsequent therapies may confer an advantage to the experimental arm that is manifested as gains beyond those achieved in progression-free survival, gains that occur not because the experimental therapy induced a change in tumor biology that persists beyond treatment discontinuation but because the control arm suffers by continuing to receive a therapy on which their tumor is progressing. Such an outcome may explain the recently reported trial results for iniparib in triple-negative breast cancer. Given that allowing patients in the control arm to receive the experimental agent may confound interpretation of overall survival, such crossover should not be used indiscriminately, especially if the experimental agent has little or no intrinsic activity. [ABSTRACT FROM PUBLISHER]

The article comments on the issue of linguistic precision in medical oncology raised by the use of the phrase, the patient has failed. A review of the early issues of the "Cancer" periodical has found that the phrase, the patient has failed therapy, was not in general use in the early days of experimental therapy. It is explained that the term is the most concise manner to state the fact that a given treatment proved to be of limited value to the patient.

Background. Ixabepilone is a microtubule-stabilizing agent approved for metastatic breast cancer. Preclinical data have shown that ixabepilone is active in taxane-sensitive and -resistant cells. Metastatic cervical carcinoma (mCC) has a poor prognosis and no established second-line therapies. This study assessed the efficacy and safety of ixabepilone in previously treated mCC. Methods. Patients with histologically confirmed mCC and at least one prior cisplatin-containing regimen were treated with ixabepilone [6 mg/m² per day for 5 days] every 21 days. The primary endpoint was progression-free survival (PFS) according to the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints were response rate, rate of tumor growth, overall survival (OS), and safety. Levels of gluterminated and acetylated tubulin, markers of microtubule stabilization, and surrogates for target engagement were assessed by Western blot. Results. In total, 41 patients were enrolled; 34 had tumors with primarily squamous histology. The median number of prior therapies was 2 (range 1-6). Four patients (9.7%) had a partial response. Median PFS in months was 2.3 for all, 3.84 for taxane-naïve, and 2.03 for taxane-pretreated patients (p = .13). Consistent with this, we found statistically similar (p = 1) rates of growth in taxane-naive patients (0.0035 per day) and taxane pretreated patients (0.0053 per day). Median OS was 5.84 months. G1/2 toxicities included vomiting (43%), sensory neuropathy (21%), and fatigue (60%). Bowel fistulas were observed in 7% of patients. Glu and acetylated tubulin were assessed in tumor samples from 11 patients during the first cycle of treatment. Although there was clear evidence of "target engagement" and microtubule stabilization in all tumors, a correlation between the extent of tubulin stabilization and response to therapy could not be demonstrated. Conclusion. Ixabepilone was well tolerated but showed very modest activity in second- or later-line mCC and cannot be recommended as a therapy. Target engagement was demonstrated but was not correlated with responses, suggesting that other factors mediate drug sensitivity. New strategies are needed for refractory mCC. [ABSTRACT FROM AUTHOR]

The Oncologist's Clinical Trial Results section welcomes both positive and negative results in an effort to share information, speed discovery, and inform the field. Clinical Trial Results submissions have shown how succinctly the salient features of a submission can be presented, with more in‐depth information to be found online. [ABSTRACT FROM AUTHOR]

The article reflects on the Clinical Trial Results (CTR) section of the periodical which addresses the need of both positive and negative reporting clinical trial results. It mentions that many trial outcomes go unreported whereas some are reported late which causes loss of valuable information, redundant control groups and a waste of other resources. It states that clinical trials outcome related to drug efficacy in breast and liver cancer have been reported in 2012 issue of the journal.

The authors respond to the comments made on their article "Potential Pitfalls of Crossover and Thoughts on Iniparib in Triple-Negative Breast Cancer." They appreciate the discusser for his concern with the trend in randomized clinical trials in oncology that allows patient access to experimental drug through crossover following disease progression on the control arm. They also argue that the concept of therapeutic equipoise was not foremost in the design of the iniparib trial.