Cetuximab plus carboplatin and paclitaxel with or without bevacizumab versus carboplatin and paclitaxel with or without bevacizumab in advanced NSCLC (SWOG S0819): a randomised, phase 3 study.

BACKGROUND: EGFR antibodies have shown promise in patients with advanced non-small-cell lung cancer (NSCLC), particularly with squamous cell histology. We hypothesised that EGFR copy number by fluorescence in-situ hybridisation (FISH) can identify patients most likely to benefit from these drugs combined with chemotherapy and we aimed to explore the activity of cetuximab with chemotherapy in patients with advanced NSCLC who are EGFR FISH-positive. METHODS: We did this open-label, phase 3 study (SWOG S0819) at 277 sites in the USA and Mexico. We randomly assigned (1:1) eligible patients with treatment-naive stage IV NSCLC to receive paclitaxel (200 mg/m2; every 21 days) plus carboplatin (area under the curve of 6 by modified Calvert formula; every 21 days) or carboplatin plus paclitaxel and bevacizumab (15 mg/kg; every 21 days), either with cetuximab (250 mg/m2 weekly after loading dose; cetuximab group) or without (control group), stratified by bevacizumab treatment, smoking status, and M-substage using a dynamic-balancing algorithm. Co-primary endpoints were progression-free survival in patients with EGFR FISH-positive cancer and overall survival in the entire study population. We analysed clinical outcomes with the intention-to-treat principle and analysis of safety outcomes included patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (number NCT00946712). FINDINGS: Between Aug 13, 2009, and May 30, 2014, we randomly assigned 1313 patients to the control group (n=657; 277 with bevacizumab and 380 without bevacizumab in the intention-to-treat population) or the cetuximab group (n=656; 283 with bevacizumab and 373 without bevacizumab in the intention-to-treat population). EGFR FISH was assessable in 976 patients and 400 patients (41%) were EGFR FISH-positive. The median follow-up for patients last known to be alive was 35·2 months (IQR 22·9-39·9). After 194 progression-free survival events in the cetuximab group and 198 in the control group in the EGFR FISH-positive subpopulation, progression-free survival did not differ between treatment groups (hazard ratio [HR] 0·92, 95% CI 0·75-1·12; p=0·40; median 5·4 months [95% CI 4·5-5·7] vs 4·8 months [3·9-5·5]). After 570 deaths in the cetuximab group and 593 in the control group, overall survival did not differ between the treatment groups in the entire study population (HR 0·93, 95% CI 0·83-1·04; p=0·22; median 10·9 months [95% CI 9·5-12·0] vs 9·2 months [8·7-10·3]). In the prespecified analysis of EGFR FISH-positive subpopulation with squamous cell histology, overall survival was significantly longer in the cetuximab group than in the control group (HR 0·58, 95% CI 0·36-0·86; p=0·0071), although progression-free survival did not differ between treatment groups in this subgroup (0·68, 0·46-1·01; p=0·055). Overall survival and progression-free survival did not differ among patients who were EGFR FISH non-positive with squamous cell histology (HR 1·04, 95% CI 0·78-1·40; p=0·77; and 1·02, 0·77-1·36; p=0·88 respectively) or patients with non-squamous histology regardless of EGFR FISH status (for EGFR FISH-positive 0·88, 0·68-1·14; p=0·34; and 0·99, 0·78-1·27; p=0·96; respectively; and for EGFR FISH non-positive 1·00, 0·85-1·17; p=0·97; and 1·03, 0·88-1·20; p=0·69; respectively). The most common grade 3-4 adverse events were decreased neutrophil count (210 [37%] in the cetuximab group vs 158 [25%] in the control group), decreased leucocyte count (103 [16%] vs 74 [20%]), fatigue (81 [13%] vs 74 [20%]), and acne or rash (52 [8%] vs one [<1%]). 59 (9%) patients in the cetuximab group and 31 (5%) patients in the control group had severe adverse events. Deaths related to treatment occurred in 32 (6%) patients in the cetuximab group and 13 (2%) patients in the control group. INTERPRETATION: Although this study did not meet its primary endpoints, prespecified subgroup analyses of patients with EGFR FISH-positive squamous-cell carcinoma cancers are encouraging and support continued evaluation of anti-EGFR antibodies in this subpopulation. FUNDING: National Cancer Institute and Eli Lilly and Company.

Risks and benefits of phase I liver dysfunction studies: should patients with severe liver dysfunction be included in these trials?

Introduction The goal of organ dysfunction Phase I trials is to characterize the safety and pharmacokinetics of novel agents in cancer patients with liver or kidney dysfunction, but the clinical benefit is not well established. Methods We reviewed 170 patients across 15 liver dysfunction studies at our institution, grouped based on the NCI-Organ Dysfunction Working Group criteria or Child-Pugh Score. Results The median survival for the entire cohort was two months and just one month amongst patients with severe liver dysfunction. Patients with normal or mild liver dysfunction, absence of tumor in liver, good performance status, higher serum albumin and lower bilirubin, aspartate transaminase and alkaline phosphatase had improved survival by univariate analysis. Serum albumin and liver function classification remained significant by multivariate analysis. Conclusion Given poor survival of patients with liver dysfunction, we need better criteria, such as albumin levels, for optimally selecting patients for liver dysfunction studies.

The impact of patient navigation on the delivery of diagnostic breast cancer care in the National Patient Navigation Research Program: a prospective meta-analysis.

Patient navigation is emerging as a standard in breast cancer care delivery, yet multi-site data on the impact of navigation at reducing delays along the continuum of care are lacking. The purpose of this study was to determine the effect of navigation on reaching diagnostic resolution at specific time points after an abnormal breast cancer screening test among a national sample. A prospective meta-analysis estimated the adjusted odds of achieving timely diagnostic resolution at 60, 180, and 365 days. Exploratory analyses were conducted on the pooled sample to identify which groups had the most benefit from navigation. Clinics from six medical centers serving vulnerable populations participated in the Patient Navigation Research Program. Women with an abnormal breast cancer screening test between 2007 and 2009 were included and received the patient navigation intervention or usual care. Patient navigators worked with patients and their care providers to address patient-specific barriers to care to prevent delays in diagnosis. A total of 4675 participants included predominantly racial/ethnic minorities (74 %) with public insurance (40 %) or no insurance (31 %). At 60 days and 180 days, there was no statistically significant effect of navigation on achieving timely diagnostic care, but a benefit of navigation was seen at 365 days (aOR 2.12, CI 1.36-3.29). We found an equal benefit of navigation across all groups, regardless of race/ethnicity, language, insurance status, and type of screening abnormality. Patient navigation resulted in more timely diagnostic resolution at 365 days among a diverse group of minority, low-income women with breast cancer screening abnormalities. Trial registrations clinicaltrials.gov Identifiers: NCT00613275, NCT00496678, NCT00375024, NCT01569672.

Classical Hematology Referrals at an National Cancer Institute-Designated Cancer Center: Lessons Learned.

PURPOSE: To understand the spectrum and volume of classical hematology (CH) referrals to hematology clinics at a National Cancer Institute (NCI)-designated cancer center (CC) to plan for the delivery of effective and equitable care for this population. METHODS: One referral office at the Academic CC located in Bexar County, TX, handles all adult hematology referrals. From October 1, 2021, to September 30, 2022, all nonmalignant hematology (MH) referrals were triaged daily to define the category of CH problem. Declined referrals (confirmed at triage that no CH problem was evident) are included as part of this analysis. Electronic consultation (opinion rendered without patient seen) at our CC is available and is not part of this analysis. RESULTS: One thousand nine hundred forty-five CH referrals were received in the 12-month period. Seventy-six referrals (3.9%) were declined. During the study period, there were 2,289 medical oncology referrals and 779 referrals for MH. CH referrals therefore comprise 39% of all hematology-oncology referrals and 71% of all hematology referrals at the CC. Anemia and thrombotic disorders were the most common categories of the accepted CH referrals at 487 (26%) and 393 (21%), respectively. Video visits were used for 447 of all CH referrals (23%), and the rest were in person. CONCLUSION: Nearly 40% of all referrals to hematology and medical oncology at our NCI-designated CC are for CH. Effective management of the CH population of patients will allow ideal care for CH problems and also allow cancer-focused care to improve.

Gemcitabine resistance of pancreatic cancer cells is mediated by IGF1R dependent upregulation of CD44 expression and isoform switching.

Chemoresistance in pancreatic cancer cells may be caused by the expansion of inherently resistant cancer cells or by the adaptive plasticity of initially sensitive cancer cells. We investigated how CD44 isoforms switching contributed to gemcitabine resistance. Treating CD44 null/low single-cell clones with increasing amounts of gemcitabine caused an increase in expression of CD44 and development of gemcitabine resistant (GR) cells. Drug sensitivity, invasiveness, and EMT process was evaluated by MTT, Matrigel invasion assays, and western blots. Genetic knockdown and pharmacological inhibitors were used to examine the roles of CD44 and IGF1R in mediating gemcitabine resistance. CD44 promoter activity and its interactive EMT-related transcription factors were evaluated by luciferase reporter assay and chromatin immunoprecipitation assay. Kaplan-Meier curve was created by log-rank test to reveal the clinical relevance of CD44 and IGF1R expression in patients. We found silence of CD44 in GR cells partially restored E-cadherin expression, reduced ZEB1 expression, and increased drug sensitivity. The gemcitabine-induced CD44 expressing and isoform switching were associated with an increase in nuclear accumulation of phosphor-cJun, Ets1, and Egr1 and binding of these transcription factors to the CD44 promoter. Gemcitabine treatment induced phosphorylation of IGF1R and increased the expression of phosphor-cJun, Ets1, and Egr1 within 72 h. Stimulation or suppression of IGF1R signaling or its downstream target promoted or blocked CD44 promoter activity. Clinically, patients whose tumors expressed high levels of CD44/IGF1R showed a poor prognosis. This study suggests that IGF1R-dependent CD44 isoform switching confers pancreatic cancer cells to undergo an adaptive change in response to gemcitabine and provides the basis for improved targeted therapy of pancreatic cancer.

Camidanlumab tesirine in patients with relapsed or refractory lymphoma: a phase 1, open-label, multicentre, dose-escalation, dose-expansion study.

BACKGROUND: Novel approaches are required to improve outcomes in relapsed or refractory classical Hodgkin lymphoma and non-Hodgkin lymphoma. We aimed to evaluate camidanlumab tesirine, an anti-CD25 antibody-drug conjugate, in this patient population. METHODS: This was a phase 1, dose-escalation (part 1), dose-expansion (part 2), multicentre trial done in 12 hospital sites (seven in the USA and five in the UK). Adults (≥18 years old) with pathologically confirmed relapsed or refractory classical Hodgkin lymphoma or non-Hodgkin lymphoma, an Eastern Cooperative Oncology Group performance status 0-2, who had no therapies available to them with established clinical benefit for their disease stage were enrolled. Camidanlumab tesirine was administered intravenously (3-150 µg/kg) once every 3 weeks. Primary objectives were to assess dose-limiting toxicity, determine maximum tolerated dose and recommended expansion dose(s), and assess safety of camidanlumab tesirine. Safety was assessed in all treated patients; antitumour activity was assessed in patients with one or more valid baseline and post-baseline disease assessment and in those who had disease progression or died after first study-drug dose. This trial was registered with ClinicalTrials.gov, NCT02432235. FINDINGS: Between Oct 5, 2015, and Jun 30, 2019, 133 patients were enrolled (77 [58%] had classical Hodgkin lymphoma and 56 (42%) had non-Hodgkin lymphoma). Median follow-up was 9·2 months (IQR 4·2-14·3). Eight dose-limiting toxicities were reported in five (6%) of 86 patients who were evaluable; the maximum tolerated dose was not reached. The recommended doses for expansion were 30 µg/kg and 45 µg/kg for patients with classical Hodgkin lymphoma and 80 µg/kg for patients with T-cell non-Hodgkin lymphomas. No recommended doses for expansion were defined for B-cell non-Hodgkin lymphomas. Grade 3 or worse treatment-emergent adverse events (reported by ≥10% of the 133 patients) included increased γ-glutamyltransferase (20 [15%] patients), maculopapular rash (16 [12%]), and anaemia (15 [11%]); 74 (56%) patients had serious treatment-emergent adverse events, most commonly pyrexia (16 [12%]). One (1%) fatal treatment-emergent adverse event and two (2%) deaths outside the reporting period were considered at least possibly study-drug related. Antitumoural activity was seen in classical Hodgkin and non-Hodgkin lymphomas; notably in all patients with classical Hodgkin lymphoma, the overall response was 71% (95% CI 60-81). INTERPRETATION: These results warrant evaluation of camidanlumab tesirine as a potential treatment option for relapsed or refractory lymphoma, particularly in patients with classical Hodgkin lymphoma. FUNDING: ADC Therapeutics.

Tumor response evaluation in oncology: current update.

Quantification of tumor burden and assessment of changes in tumor size after chemotherapy are commonly performed to evaluate treatment response in oncology trials. Validation and adoption of different criteria have been attempted in the past to achieve uniformity in scanning techniques and measurement metrics so that comparison of different oncological trials is feasible. Response assessment of solid tumors is usually consisted of either bidimensional (World Health Organization criteria) or unidimensional (Response Evaluation Criteria in Solid Tumors [RECIST] guidelines) measurement of tumors before and after chemotherapy. RECIST 1.1 criteria have been recently published. In this article, we try to provide a comprehensive review of the tumor response evaluation guidelines that were recently updated in attempts to overcome limitations of the previous criteria as well as incorporate recent advances in imaging techniques.

Cancer rates, medical comorbidities, and treatment modalities in the oldest patients.

Cancer disproportionately afflicts older patients, with 56% of incident diagnoses and 71% of deaths occurring in this population. Yet little is known about the "oldest of the old", oncology patients underrepresented in clinical trials. We examined elderly veterans diagnosed with lung, colorectal, prostate or head-neck cancer in 2005 (n=194,797), analyses comparing treatment receipt by age group, 70-84 versus 85-115. Treatment was more common among younger elders, including surgery (1.3% versus 0.6%), chemotherapy (2.1% versus 0.8%) and radiation (1.7% versus 0.7%). Differences were sharper for certain cancers, e.g., chemotherapy for lung (9.0% versus 2.9%), or colorectal surgery (5.8% versus 3.4%). Cancer prevalence is high among elders yet treatment rates appear extremely low, despite evidence of well-tolerated treatment. Toxicity concerns and comorbidities may inhibit pursuit of definitive treatment. As we reconcile definitions of 'elderly' with appropriate treatment options, compassionate care requires identifying geriatric oncology guidelines that improve survival and quality of life.

The biology and role of CD44 in cancer progression: therapeutic implications.

CD44, a non-kinase transmembrane glycoprotein, is overexpressed in several cell types including cancer stem cells and frequently shows alternative spliced variants that are thought to play a role in cancer development and progression. Hyaluronan, the main ligand for CD44, binds to and activates CD44 resulting in activation of cell signaling pathways that induces cell proliferation, increases cell survival, modulates cytoskeletal changes, and enhances cellular motility. The different functional roles of CD44 standard (CD44s) and specific CD44 variant (CD44v) isoforms are not fully understood. CD44v contain additional peptide motifs that can interact with and sequester growth factors and cytokines at the cell surface thereby functioning as coreceptors to facilitate cell signaling. Moreover, CD44v were expressed in metastasized tumors, whereas switching between CD44v and CD44s may play a role in regulating epithelial to mesenchymal transition (EMT) and in the adaptive plasticity of cancer cells. Here, we review current data on the structural and functional properties of CD44, the known roles for CD44 in tumorigencity, the regulation of CD44 expression, and the potential for targeting CD44 for cancer therapy.

Phase I Study of the Investigational Aurora A Kinase Inhibitor Alisertib plus Rituximab or Rituximab/Vincristine in Relapsed/Refractory Aggressive B-cell Lymphoma.

PURPOSE: The aurora A kinase inhibitor alisertib demonstrated single-agent clinical activity and preclinical synergy with vincristine/rituximab in B-cell non-Hodgkin lymphoma (B-NHL). This phase I study aimed to determine the safety and recommended phase II dose (RP2D) of alisertib in combination with rituximab ± vincristine in patients with relapsed/refractory aggressive B-NHL. PATIENTS AND METHODS: Patients with relapsed/refractory, diffuse, large, or other aggressive B-NHL received oral alisertib 50 mg b.i.d. days 1 to 7, plus i.v. rituximab 375 mg/m2 on day 1, for up to eight 21-day cycles (MR). Patients in subsequent cohorts (3 + 3 design) received increasing doses of alisertib (30 mg starting dose; 10 mg increments) b.i.d. days 1 to 7 plus rituximab and vincristine [1.4 mg/m2 (maximum 2 mg) days 1, 8] for 8 cycles (MRV). Patients benefiting could continue single-agent alisertib beyond 8 cycles. Cell-of-origin and MYC/BCL2 IHC was performed on available archival tissue. RESULTS: Forty-five patients participated. The alisertib RP2D for MR was 50 mg b.i.d. For MRV (n = 32), the RP2D was determined as 40 mg b.i.d. [1 dose-limiting toxicity (DLT) at 40 mg; 2 DLTs at 50 mg]. Drug-related adverse events were reported in 89% of patients, the most common was neutropenia (47%). Seven patients had complete responses (CR), 7 had partial responses (PRs); 9 of 20 (45%) patients at the MRV RP2D responded (4 CRs, 5 PRs), all with non-germinal center B-cell (GCB) diffuse large B-cell lymphoma (DLBCL). CONCLUSIONS: The combination of alisertib 50 mg b.i.d. plus rituximab or alisertib 40 mg b.i.d. plus rituximab and vincristine was well tolerated and demonstrated activity in non-GCB DLBCL.

Safety and Pharmacodynamics of the PDE4 Inhibitor Roflumilast in Advanced B-cell Malignancies.

Purpose: In this study, we aimed to validate our extensive preclinical data on phosphodiesterase 4 (PDE4) as actionable target in B-cell malignancies. Our specific objectives were to determine the safety, pharmacokinetics, and pharmacodynamics (PI3K/AKT activity), as well as to capture any potential antitumor activity of the PDE4 inhibitor roflumilast in combination with prednisone in patients with advanced B-cell malignancies.Experimental Design: Single-center, exploratory phase Ib open-label, nonrandomized study. Roflumilast (500 mcg PO) was given daily for 21 days with prednisone on days 8 to 14. Additional 21-day cycles were started if patients tolerated cycle 1 and had at least stable disease.Results: Ten patients, median age 65 years with an average of three prior therapies, were enrolled. The median number of cycles administered was 4 (range, 1-13). Treatment was well tolerated; the most common ≥grade 2 treatment-related adverse events were fatigue, anorexia (≥25%), and transient ≥ grade 2 neutropenia (30%). Treatment with roflumilast as a single agent significantly suppressed PI3K activity in the 77% of patients evaluated; on average, patients with PI3K/AKT suppression stayed in trial for 156 days (49-315) versus 91 days (28-139 days) for those without this biomarker response. Six of the nine evaluable patients (66%) had partial response or stable disease. The median number of days in trial was 105 days (range, 28-315).Conclusions: Repurposing the PDE4 inhibitor roflumilast for treatment of B-cell malignancies is safe, suppresses the oncogenic PI3K/AKT kinases, and may be clinically active. Clin Cancer Res; 23(5); 1186-92. ©2016 AACR.

Evaluation of Ki67, p53 and angiogenesis in patients enrolled in a randomized study of neoadjuvant chemotherapy with or without cystectomy: a Southwest Oncology Group Study.

In this prospective biomarker study, we evaluated the prognostic significance of Ki67, p53 and angiogenesis in patients with locally advanced bladder cancer. The patients were volunteers from a Southwest Oncology Group trial of locally advanced bladder cancer who were randomized to treatment with neoadjuvant chemotherapy plus cystectomy or cystectomy alone. Tissue specimens were obtained prior to neoadjuvant chemotherapy from 42 patients randomized to receive the combination-treatment arm and 52 randomized to cystectomy alone. The statistical power of the study was quite limited by the small sample size. The biomarkers were assayed by immunohistochemistry. Angiogenesis was determined using anti-CD34 immunostaining. Patients whose tumors had increased Ki67 expression had better progression-free survival that was marginally significant, p=0.063. The median survival in those with higher Ki67 expression was 73 months, and in those with lower expression was 38 months. However, this did not achieve statistical significance, p=0.25. There was a suggestion of worse survival among patients whose tumors exhibited altered p53 staining [hazard ratio (HR) = 1.48; p=0.15], but there was no difference in progression-free survival (HR=1.02; p=0.93). The enumeration of tumor microvessels did not provide prognostic information.

The role of positron emission tomography scans in the management of the N-positive neck in head and neck squamous cell carcinoma after chemoradiotherapy.

OBJECTIVE: The objective of this study was to determine the sensitivity, specificity, and predictive value of 18-fluorodeoxyglucose positron emission tomography (PET) in predicting residual cervical metastatic disease in patients with N-positive necks undergoing curative radiotherapy and chemoradiotherapy for squamous cell carcinoma (SCC) of the upper aerodigestive tract. METHODS: The authors studied a prospective case series of patients (2003-2005) of patients undergoing radiotherapy and chemoradiotherapy for advanced head and neck SSC. Study entry criteria included N-positive neck disease, a complete response to treatment at the primary tumor site, posttreatment PET scan (8-12 weeks after completion of treatment), followed by salvage neck dissection. The posttreatment PET scan neck findings were correlated to the salvage neck dissection pathology report. The sensitivity, specificity, and predictive values of the PET scan to predict residual cervical metastatic disease after curative chemoradiotherapy were calculated. RESULTS: Twenty-one neck dissections (pretreatment N1 = 5, N2a = 2, N2b = 8, N3 = 6) were entered into the protocol. Four (19.0%) of the 21 neck specimens were positive for residual cervical metastatic disease, whereas the remaining 17 (80.9%) specimens demonstrated no residual carcinoma. The overall sensitivity and specificity were 75.0% and 64.7%, respectively. The positive predictive value was 33% and the negative predictive value was 91.7%. CONCLUSIONS: Although the role of posttreatment neck dissection remains controversial, the surgeon must rely on clinical examination and imaging studies. Our practice has been to perform planned staged neck dissections on all N2 and N3 necks, as well as N1 necks with an incomplete response to treatment. Based on this small prospective study, it appears that PET imaging lacks adequate sensitivity and specificity to reliably predict the presence of residual cervical metastatic disease after completion of chemoradiotherapy. With a negative predictive value of 91.7%, however, a negative PET scan appears to be a reliable predictor of the absence of residual tumor.

Association Between the Number of Suppliers for Critical Antineoplastics and Drug Shortages: Implications for Future Drug Shortages and Treatment.

PURPOSE: Congress has identified the critical need to evaluate contributors to ongoing cancer drug shortages. Because increased competition may reduce drug shortages, we investigated the association between the number of suppliers for first-line breast, colon, and lung antineoplastics and drug shortages. DATA AND METHODS: Using the 2003 to 2014 Red Book and national drug shortage data from the University of Utah's Drug Information Service, we used exploratory analysis to quantify time trends in first-line drug suppliers and shortages by cancer site. Generalized mixed models were used to examine the association between the number of suppliers for individual drugs and resulting drug shortages. RESULTS: Among 35 antineoplastic drugs approved for first-line treatment of breast, colon, and lung cancer, the number of unique suppliers varied greatly (range, 1 to 19). In 2003, 12.5%,33.3%, and 0%of breast, colon, and lung cancer drugs, respectively, experienced shortages, which increased overall by 2014, to 40.0%, 37.5%, and 54.5%, respectively. Having as mall number of drug suppliers more than doubled the odds of shortages compared with a large number of suppliers (≥5), although the results were only statistically significant with three to four suppliers (odds ratio = 2.6, P = .049) but not with one to two suppliers (odds ratio = 3.49, P = .105). One of the strongest risk factors for drug shortages was the age of the drug, with older drugs significantly more likely to experience shortages (P<.001). CONCLUSION: Cancer drugs with a small number of suppliers had a higher risk of drug shortages than did those with$5 suppliers, but the relationship was nonlinear. Because the age of the drug is the strongest risk factor, future studies should explore underlying causes of shortages in older drugs.

CD44 Expression Level and Isoform Contributes to Pancreatic Cancer Cell Plasticity, Invasiveness, and Response to Therapy.

PURPOSE: A subpopulation of pancreatic ductal adenocarcinoma (PDAC) cells is thought to be inherently resistant to chemotherapy or to give rise to tumor cells that become resistant during treatment. Here we determined the role of CD44 expression and its isoforms as a marker and potential target for tumor cells that give rise to invasive and gemcitabine-resistant tumors. EXPERIMENTAL DESIGN: RT-PCR, Western blotting, and DNA sequencing was used to determine CD44 isoform and expression levels. Flow cytometry was used to sort cells on the basis of their CD44 expression level. CD44 expression was knocked down using shRNA. Tumorigenic properties were determined by clonogenic and Matrigel assays, IHC, tumor growth in vivo using luciferase imaging and by tumor weight. RESULTS: We identified an invasive cell population that gives rise to gemcitabine-resistant tumors. These cancer cells express a high level of CD44 standard isoform and have an EMT phenotype (CD44s/EMT). In vivo, CD44s/EMT engraft and expand rapidly and give rise to tumors that express high levels of CD44 isoforms that contain multiple exon variants. CD44low-expressing cells show continued sensitivity to gemcitabine in vivo and knockdown of CD44 in CD44s/EMT cells increases sensitivity to gemcitabine and decreases invasiveness. CONCLUSIONS: PDAC cells expressing high levels of CD44s with a mesenchymal-like phenotype were highly invasive and developed gemcitabine resistance in vivo Thus, initial targeting CD44 or reversing the CD44high phenotype may improve therapeutic response. Clin Cancer Res; 22(22); 5592-604. ©2016 AACR.

p53-based strategy to reduce hematological toxicity of chemotherapy: A proof of principle study.

p53 activation is a primary mechanism underlying pathological responses to DNA damaging agents such as chemotherapy and radiotherapy. Our recent animal studies showed that low dose arsenic (LDA)-induced transient p53 inhibition selectively protected normal tissues from chemotherapy-induced toxicity. Study objectives were to: 1) define the lowest safe dose of arsenic trioxide that transiently blocks p53 activation in patients and 2) assess the potential of LDA to decrease hematological toxicity from chemotherapy. Patients scheduled to receive minimum 4 cycles of myelosuppressive chemotherapy were eligible. For objective 1, dose escalation of LDA started at 0.005 mg/kg/day for 3 days. This dose satisfied objective 1 and was administered before chemotherapy cycles 2, 4, and 6 for objective 2. p53 level in peripheral lymphocytes was measured on day 1 of each cycle by ELISA assay. Chemotherapy cycles 1, 3, and 5 served as the baseline for the subsequent cycles of 2, 4, and 6 respectively. If p53 level for the subsequent cycle was lower (or higher) than the baseline cycle, p53 was defined as "suppressed" (or "activated") for the pair of cycles. Repeated measures linear models of CBC in terms of day, cycle, p53 activity and interaction terms were used. Twenty-six patients treated with 3 week cycle regimens form the base of analyses. The mean white blood cell, hemoglobin and absolute neutrophil counts were significantly higher in the "suppressed" relative to the "activated" group. These data support the proof of principle that suppression of p53 could lead to protection of bone marrow in patients receiving chemotherapy. This trial is registered in ClinicalTrials.gov. Identifier: NCT01428128.

Roles of c-Met and RON kinases in tumor progression and their potential as therapeutic targets.

c-Met and receptor originated from nantes (RON) are structurally related transmembrane phosphotyrosine kinase receptors. c-Met and RON show increased expression or activity in a variety of tumors leading to tumor progression and may play a role in acquired resistance to therapy. Although often co-expressed, the distinct functional roles of c-Met and RON are not fully understood. c-Met and RON form both activated homodimers and heterodimers with themselves and other families of phosphotyrosine kinase receptors. Inhibitors for c-Met and RON including small molecular weigh kinase inhibitors and neutralizing antibodies are in pre-clinical investigation and clinical trials. Several of the tyrosine kinase inhibitors have activity against both c-Met and RON kinases whereas the antibodies generally are target specific. As with many targeted agents used to treat solid tumors, it is likely that c-Met/RON inhibitors will have greater benefit when used in combination with chemotherapy or other targeted agents. A careful analysis of c-Met/RON expression or activity and a better elucidation of how they influence cell signaling will be useful in predicting which tumors respond best to these inhibitors as well as determining which agents can be used with these inhibitors for combined therapy.

Use of Milestones and Development of Entrustable Professional Activities in 2 Hematology/Oncology Training Programs.

BACKGROUND: The Next Accreditation System (NAS) increases the focus on educational outcomes and meaningful evaluation of learners. This requires that key clinical faculty develop new assessment formats such as entrustable professional activities (EPAs). OBJECTIVES: To build and develop milestone-based assessment tools supporting 5 EPAs for a hematology/oncology fellow continuity clinic, and to educate key clinical faculty regarding the Clinical Competency Committee (CCC) and the NAS. METHODS: Program directors from 2 hematology/oncology fellowship programs developed 5 EPAs for continuity clinic evaluation supported by milestone-based assessment. The program directors met to create a unified CCC charter. Key clinical faculty helped to develop a milestone-based evaluation of fellow continuity clinic through creation of 5 hematology/oncology-specific EPAs. Formal entrustment regarding EPAs was deliberated by the CCC. RESULTS: A total of 18 fellows were evaluated. Clinical Competency Committee deliberation at each institution took approximately 10 minutes per fellow for discussion and decision regarding entrustment for all 5 EPAs supporting continuity clinic. One-third of postgraduate year (PGY)-4s, 50% of PGY-5s, and 100% of PGY-6s were deemed competent in all 5 EPAs by the CCC. CONCLUSIONS: All hematology/oncology trainees in San Antonio were evaluated using milestone-based assessment for continuity clinic, and entrustment decisions regarding 5 EPAs were made by the CCC. This project may provide other programs with a sound basis for adoption and further development of the next generation of evaluation tools at their institutions. Entrustable professional activities that are rotation specific should be used as a starting point for linking to the competencies, subcompetencies, and the reporting milestones.

Breast cancer treatment delays in a majority minority community: is there a difference?

PURPOSE: Recent studies from large nationwide cancer databases have consistently shown that Hispanic women with breast cancer have delays in treatment initiation compared with non-Hispanic white women. However, time to treatment initiation has not been studied in a community where Hispanics are the majority. PATIENTS AND METHODS: We conducted a retrospective, observational study of 362 female patients with breast cancer treated at a large National Cancer Institute (NCI) -designated cancer center with a largely Hispanic population. We examined the relationship between race/ethnicity and time from mammogram to biopsy as well as time from biopsy to treatment initiation using Kaplan-Meier analyses and multivariable Cox proportional hazards regression. RESULTS: Half of the female patients with breast cancer were of Hispanic descent (50.0%; n = 181). Hispanic patients were more likely to be obese, have an Eastern Cooperative Oncology Group functional status ≥ 1, and have higher histologic grade disease (all P ≤ .05); no differences in American Joint Committee on Cancer stage at diagnosis were observed. After comprehensive adjustment for demographic and clinical characteristics, we found no significant differences between Hispanic versus non-Hispanic white patients in time from mammogram to biopsy (hazard ratio [HR], 0.91; 95% CI, 0.68 to 1.21) or time from biopsy to treatment (HR, 1.13; 95% CI, 0.69 to 1.88). CONCLUSION: Hispanic women and Non-Hispanic white women with breast cancer treated at an NCI-designated cancer center had similar times to biopsy and treatment initiation. These findings suggest that in majority minority communities with large cancer centers, racial disparities can be reduced. With a growing Hispanic population throughout the United States, future studies should examine the long-term impact on improved breast cancer survival in this population.

Acquired methemoglobinemia: a rare but serious complication.

Topical and local anesthetics are employed during minor invasive procedures to increase patient tolerance and to reduce the need for intravenous sedation. A potentially fatal complication of these anesthetics is methemoglobinemia (Met-Hgb). Met-Hgb should be suspected in patients with cyanosis that does not respond to administration of oxygen and who have a discrepancy in oxygen saturation measured by pulse oximetry compared with the arterial partial pressure of oxygen (PaO2) determined by blood gas analysis. We present a patient who developed life-threatening Met-Hgb from the local anesthesia required during percutaneous endoscopic gastrostomy tube placement.