miR Profiling Identifies Cyclin-Dependent Kinase 6 Downregulation as a Potential Mechanism of Acquired Cisplatin Resistance in Non-Small-Cell Lung Carcinoma.

UNLABELLED: To identify the mechanisms of cisplatin resistance, global microRNA (miR) expression was tested. The expression of miR-145 was consistently higher in resistant cells. The expression of cyclin-dependent kinase 6 (CDK6), a potential target of miR-145, was lower in resistant cells, and inhibition of CDK4/6 protected cells from cisplatin. Cell cycle inhibition, currently being tested in clinical trials, might be antagonistic to cisplatin and other cytotoxic drugs. BACKGROUND: Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death. Platinum-based chemotherapeutic drugs are the most active agents in treating advanced disease. Resistance to these drugs is common and multifactorial; insight into the molecular mechanisms involved will likely enhance efficacy. MATERIALS AND METHODS: A set of NSCLC platinum-resistant sublines was created from the Calu6 cell line. Cell viability was quantified using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Differentially expressed microRNAs (miRs) in these lines were identified using Affymetrix miR arrays. The potential genes targeted by these miRs were searched using the TargetScan algorithm. The expression levels of miRs and mRNA were tested using real-time polymerase chain reaction. RESULTS: miR-145 was reproducibly elevated in all the resistant sublines tested; however, modulation of miR-145 levels alone in these cells did not affect their response to cisplatin. A potential target of miR-145 is cyclin-dependent kinase 6 (CDK6), an important regulator of cell proliferation. The mRNA and protein levels of CDK6 were both downregulated in the resistant sublines. An inhibitor of CDK4/6 (PD0332991) protected parental NSCLC cells from cisplatin cytotoxicity. CONCLUSION: In the present study, we identified miRs differentially expressed in cisplatin-resistant cell lines, including miR-145. A predicted target of miR-145 is CDK6, and its expression was found to be downregulated in the resistant sublines, although not directly by miR-145. Inhibition of CDK6 antagonizes cisplatin-induced NSCLC cell cytotoxicity, suggesting that agents that inhibit CDK6 should be avoided during cisplatin therapy.

A survey of thrombosis experts evaluating practices and opinions regarding venous thromboprophylaxis in patients with active cancer hospitalized with an acute medical illness.

BACKGROUND: Current clinical practice guidelines recommend the use of prophylactic doses of low molecular weight heparins for cancer patients requiring hospitalization for acute medical illness. However, a recently published meta-analysis suggested that the risk-benefit ratio of current thromboprophylaxis regimens administered to all cancer patients admitted for medical illness is unclear. We sought to assess the clinical equipoise in using thromboprophylaxis for hospitalized medically ill cancer patients. METHODS: An electronic survey was conducted. The target sample included Thrombosis experts and members of Thrombosis Canada or the VECTOR research group. RESULTS: The survey was distributed 54 participants. The final response rate was 67% (36/54). The majority (75%; 95% CI: 60.3 to 85%) of responders indicated that the benefits of pharmacological parenteral thromboprophylaxis outweigh the risks. However, 63.9% (95% CI: 50.6 to 77.3%) believe that there is still clinical equipoise around the use of thromboprophylaxis in this patient population, and 88.9% (95% CI: 77.3 to 95.8%) would consider participating in a randomized trial-30.6% and 58.3% in a placebo-controlled or comparison of different agents/dosing-controlled randomized trial, respectively. For participants who would consider a randomized-controlled trial comparing different doses of thromboprophylaxis agents, the MCID was 2% between the two arms. The most common drug to be compared was enoxaparin (26%), and the two suggested doses were 30 mg and 40 mg SC twice daily. CONCLUSIONS: Our clinical survey of thrombosis experts confirms that there is equipoise regarding the use of current regimens of parenteral pharmacological thromboprophylaxis in medically ill cancer patients. A majority of physicians would participate in a randomized-controlled trial comparing different dose of LMWH. The MCID in the risk of VTE identified was 2%.

Kidney cancer survivorship survey of urologists and survivors: The gap in perceptions of care, but agreement on needs.

INTRODUCTION: There is lack of evidence-based literature addressing comprehensive long-term care for kidney cancer (KC) survivors. Additionally, it is unclear if the concerns of KC patients/caregivers are being adequately addressed. Therefore, Kidney Cancer Canada, a patient-led support organization for Canadians with KC, commissioned this first recorded survivorship survey specific to KC patients/caregivers. METHODS: We conducted a cross-sectional online survey of Canadian patients/caregivers diagnosed with localized KC, and a separate parallel survey of Canadian urologists. The primary objectives were to assess patient/caregivers' and urologists' perceptions of information provided, as well as the physical/psychological/emotional impact of KC treatment. RESULTS: Urologists recalled providing information about surgical complications (90%) and their management (63%), while patients/caregiver recalled much less (33% and 35%). Of the urologists, 93% recalled providing information on cancer recurrence, but only 42% of patients/caregivers remembered receiving this information. Concerns identified by patients/caregivers and urologists were similar: fear of recurrence, concerns about cancer, fatigue, and anxiety. Importantly, all agreed that survivorship information was paramount. Education of both patients/caregivers and physicians and the development of guidelines were factors identified to ensure optimal KC survivorship. Study limitations include potential biases in recall and selection of participants. CONCLUSION: There was some discordance between urologists' and patients/caregivers' rates of recall of information provided. Patients/caregivers would have desired more information about their cancer, long-term follow-up, and potential complications. A survivorship care plan (SCP) tailored to KC may be an effective measure to address these needs. The impact of this SCP on survivor outcomes should be rigorously assessed.

Lack of evidence to support thromboprophylaxis in hospitalized medical patients with cancer.

BACKGROUND: The administration of anticoagulant thromboprophylaxis for all patients with cancer who are hospitalized for acute medical illness is considered standard practice and strongly recommended in clinical guidelines. These recommendations are extrapolated from randomized controlled prophylaxis trials not specifically conducted in cancer cohorts. Because hospitalized patients with cancer constitute a unique population with increased risk of venous thromboembolic events and major hemorrhage, validation of the efficacy and safety of primary thromboprophylaxis in this population is critical. We sought to summarize the rates of venous thromboembolic events and major bleeding episodes among hospitalized patients with cancer who were receiving anticoagulant therapy compared with placebo. METHODS: A systematic literature search strategy was conducted using MEDLINE, EMBASE, and the Cochrane Register of Controlled Trials. Two reviewers independently extracted data onto standardized forms. The primary end points were all venous thromboembolic events. Secondary end points included major bleeding episodes and symptomatic venous thromboembolic events. Pooled analysis with relative risk using a random effect model was used as the primary measurement. RESULTS: A total of 242 citations were identified by the literature search. Of these, 3 placebo-controlled randomized trials included venous thromboembolic events as a primary outcome and were analyzed according to cancer subgroups. The pooled relative risk of venous thromboembolic events was 0.91 (95% confidence interval, 0.21-4.0; I(2): 68%) among hospitalized patients with cancer who were receiving thromboprophylaxis compared with placebo. None of the trials reported the rates of symptomatic venous thromboembolic events or major bleeding episodes according to cancer status. CONCLUSIONS: The risks and benefits of primary thromboprophylaxis with anticoagulant therapy in hospitalized patients with cancer are not known. This is especially relevant because numerous Medicare-type pay-for-performance incentives mandate prophylaxis specifically in patients with cancer.

Chemoradiotherapy for locoregional recurrence of non-small-cell lung cancer after surgical resection: a retrospective analysis.

BACKGROUND: Even if non-small-cell lung cancer (NSCLC) is diagnosed early and resected, recurrence is common. Uncertainty exists about the optimal treatment of locoregional recurrence. In fit patients with locoregional recurrence, chemoradiotherapy is sometimes offered, but no data exist about the feasibility and efficacy of this approach. We retrospectively collected data from patients treated this way to assess their outcomes and to identify prognostic factors. PATIENTS AND METHODS: Databases of The Ottawa Hospital Cancer Centre (TOHCC) (N = 5791) and the Princess Margaret Hospital (PMH) (N = 2225) were screened to identify patients with recurrent NSCLC after curative resection who were offered curative-intent chemoradiotherapy. Selected patients' charts were reviewed. RESULTS: Thirty patients fit our search criteria. The median disease-free interval was 15 months (2-33 months) and stage at recurrence was mainly T0 (n = 25 [83%]), N2 (n = 25 [83%]), and M0 (n = 29 [97%]). The median radiation dose given at recurrence was 63.5 Gy (26-66 Gy). Chemotherapy included a platinum agent in all cases, mostly a platinum-vinorelbine doublet (n = 14 [47%]), at a median of 3 cycles, (1-6 cycles) 2 of which were concurrent (0-3 cycles). Toxicities were as expected from thoracic chemoradiotherapy, with 7 cases of grade 4 toxicities and no treatment-related deaths. Median follow-up was 22 months (1.5-88 months). Median survival after recurrence was 26.9 months. No prognostic factors were identified. CONCLUSION: Chemoradiotherapy for locoregional recurrent NSCLC is practiced sporadically. This treatment is feasible for highly selected patients, and in our cohort, it allowed for a significantly higher than expected survival. No prognostic factors were identified. Chemoradiotherapy for locoregional NSCLC should be examined in a prospective trial.

Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin's lymphomas.

PURPOSE: This phase I study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the combination of decitabine with vorinostat. PATIENTS AND METHODS: Patients with advanced solid tumors or non-Hodgkin's lymphomas were eligible. Sequential and concurrent schedules were studied. RESULTS: Forty-three patients were studied in 9 different dose levels (6 sequential and 3 concurrent). The maximum tolerated dose (MTD) on the sequential schedule was decitabine 10 mg/m(2)/day on days 1 to 5 and vorinostat 200 mg three times a day on days 6 to 12. The MTD on the concurrent schedule was decitabine 10 mg/m(2)/day on days 1 to 5 with vorinostat 200 mg twice a day on days 3 to 9. However, the sequential schedule of decitabine 10 mg/m(2)/day on days 1 to 5 and vorinostat 200 mg twice a day on days 6 to 12 was more deliverable than both MTDs with fewer delays on repeated dosing and it represents the recommended phase II (RP2D) dose of this combination. Dose-limiting toxicities during the first cycle consisted of myelosuppression, constitutional and gastrointestinal symptoms and occurred in 12 of 42 (29%) patients evaluable for toxicity. The most common grade 3 or higher adverse events were neutropenia (49% of patients), thrombocytopenia (16%), fatigue (16%), lymphopenia (14%), and febrile neutropenia (7%). Disease stabilization for 4 cycles or more was observed in 11 of 38 (29%) evaluable patients. CONCLUSION: The combination of decitabine with vorinostat is tolerable on both concurrent and sequential schedules in previously treated patients with advanced solid tumors or non-Hodgkin's lymphomas. The sequential schedule was easier to deliver. The combination showed activity with prolonged disease stabilization in different tumor types.

Biochip arrays for the discovery of a biomarker surrogate in a phase I/II study assessing a novel anti-metastasis agent.

OBJECTIVE: Can biochip arrays identify which individuals with metastatic disease will respond to an anti-metastatic agent? DESIGN AND METHODS: Cytokine and cell adhesion arrays (Randox Ltd) were measured over 1 month in 9 research participants receiving CTCE-9908 in a Phase I/II study. RESULTS: Research participants with stable disease (n=2) had significantly higher soluble VCAM-1 as compared to those that progressed. DISCUSSION: VCAM-1 measurement early during CTCE-9908 treatment might be used as a surrogate for response.

Targeting apoptosis: preclinical and early clinical experience with mapatumumab, an agonist monoclonal antibody targeting TRAIL-R1.

In spite of the advances in survival with chemotherapy and radiotherapy, many cancer patients continue to experience failure with treatments. Advances in molecular oncology and the development of numerous targeted therapies, used by themselves or in combination with at present available treatments such as chemotherapy and radiation, will hopefully improve the fate of these patients. It has been well understood for many years now that deregulation of apoptosis is a major hallmark of cancer cells. Mapatumumab, a fully human agonistic monoclonal antibody to TNF-related apoptosis-inducing ligand receptor 1, has been developed to induce apoptosis in cancer cells although having minimal effects on normal cells. This paper reviews the preclinical and early clinical data of this exciting new agent and discusses options for future development of mapatumumab, mostly in combinations with other therapies.

Phase I study of decitabine in combination with vorinostat in patients with advanced solid tumors and non-Hodgkin's lymphomas.

PURPOSE: This phase I study evaluated the safety, tolerability, pharmacokinetics and preliminary efficacy of the combination of decitabine with vorinostat. PATIENTS AND METHODS: Patients with advanced solid tumors or non-Hodgkin's lymphomas were eligible. Sequential and concurrent schedules were studied. RESULTS: Forty-three patients were studied in 9 different dose levels (6 sequential and 3 concurrent). The maximum tolerated dose (MTD) on the sequential schedule was decitabine 10 mg/m(2)/day on days 1-5 and vorinostat 200 mg three times a day on days 6-12. The MTD on the concurrent schedule was decitabine 10 mg/m(2)/day on days 1-5 with vorinostat 200 mg twice a day on days 3-9. However, the sequential schedule of decitabine 10 mg/m(2)/day on days 1-5 and vorinostat 200 mg twice a day on days 6-12 was more deliverable than both MTDs with fewer delays on repeated dosing and it represents the recommended phase II (RP2D) dose of this combination. Dose-limiting toxicities during the first cycle consisted of myelosuppression, constitutional and gastrointestinal symptoms and occurred in 12/42 (29%) patients evaluable for toxicity. The most common ≥ grade 3 adverse events were neutropenia (49% of patients), thrombocytopenia (16%), fatigue (16%), lymphopenia (14%), and febrile neutropenia (7%). Disease stabilization for ≥ 4 cycles was observed in 11/38 (29%) evaluable patients. CONCLUSION: The combination of decitabine with vorinostat is tolerable on both concurrent schedules in previously treated patients with advanced solid tumors or non-Hodgkin's lymphomas. The sequential schedule was easier to deliver. The combination showed activity with prolonged disease stabilization in different tumor types.