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TPS208 Background: Castrate resistant prostate cancer (CRPC) is an immunologically cold tumor, with a 5% response rate reported to the PD-L1 inhibitor pembrolizumab. VEGF secreted by tumors may play a key role in hindering the anti-tumor immune response, leading to the development of an abnormal vasculature that may limit immune surveillance. VEGF also inhibits dendritic cell differentiation, limiting the presentation of tumor antigens. The inhibition of VEGF may therefore potentiate the effect of PD-1/L1 directed therapy by enabling immune surveillance and antigen presentation. VEGF-TKI and checkpoint inhibitor combinations are currently approved in the treatment of advanced kidney, cervical, and endometrial cancers. This signal-seeking study aims to determine whether the combination of the VEGF-TKI tivozanib and the PD-L1 inhibitor atezolizumab may be effective in CRPC and certain other immunologically cold tumors. Methods: The trial is a single center phase Ib/II basket study in multiple immunologically cold tumors. Co-primary endpoints are safety and the overall response rate as measured via RECIST v1.1. The tivozanib dose will be determined via a 3+3 dose de-escalation phase Ib portion. Patients treated in the phase Ib portion will be included as study subjects for phase the II portion. The study is designed to test for a 25%+ response rate as compared to a null hypothesis of

TPS280 Background: Patients with advanced colorectal cancer after progressing through first line therapy, have several FDA-approved systemic therapies that are associated with clinical benefit for a substantive minority of patients. Current clinical practice is to trial these various treatments in a step-wise fashion using CT scans every 3 months to evaluate effectiveness. This process requires 3-4 months between therapeutic interventions from which the patient may ultimately derive no clinical benefit, may have a performance status decline; limiting the number of possible interventions and increases risk for physical and financial toxicity. An alternative to the traditional CT-scan guided approach for disease assessment is a circulating tumor DNA (ctDNA) intervention. The Signatera ctDNA assay which utilizes 16 truncal mutations derived from a patient’s tumor, can be assessed every 2 weeks for a rapid determination of the effectiveness of a systemic therapy. This may allow patients to be exposed to many treatments during a short time, limiting toxicity, allowing for a quicker determination of clinical benefit and personalization of treatment. The aim of this study will be to compare the traditional scan-driven approach vs an intervention guided by ctDNA assessments, both arms using a pre-specified order of chemotherapy treatments. Methods: This is a phase 2 randomized study of patients with refractory metastatic adenocarcinoma of the colon or rectum. Participants are eligible after progression or intolerance to first line chemotherapy or recurrence within 6 months of adjuvant oxaliplatin based chemotherapy. They must have RECIST measurable metastatic disease that is not eligible for definitive management. Tissue from the primary and/or metastatic deposit is required for Signatera NGS analysis and subjects must have measurable ctDNA at sampling. Participants must be ≥18 years old without major organ dysfunction and have an ECOG performance status of 0 to 2. Subjects with Microsatellite High, deficient in DNA mismatch repair genes, or BRAF V600E mutations are excluded. Subjects will be randomized 1:1 to Arm A (ctDNA guided intervention) or Arm B (scan-guided control group). Patients in both arms will undergo systemic treatments in a standardized pre-specified order. Arm A will have ctDNA assessments every 2 weeks until an intervention shows a significant decrease, then every 4 weeks until Progressive Disease (PD) by scan or significant ctDNA increase. CT imaging will be performed every 12 weeks. Those in Arm B, will have CT imaging every 12 weeks and blood collected for post-hoc analysis every 4 weeks until PD by scan. The primary endpoint is overall survival. Secondary endpoints include progression free survival and overall response. Exploratory analysis with be performed of the microbiome. Enrollment continues to a maximum of 78 patients. Clinical trial information: NCT04786600 .

12129 Background: Depression, anxiety, and fear of cancer recurrence (FCR) constitute prevalent psychological concerns necessitating further attention in developing supportive care interventions for women with gynecologic, gastrointestinal, and thoracic cancers. Recent evidence indicates that such concerns may be especially severe among underserved women of color and women affected by low-socioeconomic status (SES). The purpose of the present study is to evaluate the magnitude of changes in depression, anxiety, and FCR associated with a mindfulness-based yoga intervention among a diverse sample of women with these cancers. A second aim is to identify how changes in these concerns may differ across sociodemographic groups. Methods: Women with gynecologic ( n=86), gastrointestinal ( n=17), or thoracic ( n=20) cancers were enrolled in a group-based 10-week yoga intervention utilizing mindfulness meditation, relaxation, and gentle yoga. Prior to and following intervention, participants were administered assessments, including the Beck Depression Inventory – Second Edition (BDI-II) to measure depression, the State-Trait Anxiety Inventory (STAI) to assess anxiety, and the Fear of Cancer Recurrence Inventory (FCRI) to evaluate aspects of FCR. Mixed-linear models evaluated change in outcomes from pre- to post-intervention, with conditional models assessing the effects of age, race/ethnicity, and SES on change. Analyses were conducted prior to trial completion due to approaching accrual period termination. Results: The sample demonstrated a mean age of 58.46 ( SD=10.82) and mean SES score of 3.98 ( SD=1.55) using a 1 to 7 composite scale. Twenty-six percent of participants were of racial and/or ethnic minority status ( n=32). Significant declines in total depressive symptoms, somatic depressive symptoms, state anxiety, and psychological distress due to FCR were observed across the sample. Higher SES was associated with significantly greater reductions in total depressive symptoms and affective depressive symptoms, specifically. Women of color experienced significantly greater declines in somatic symptoms compared to non-Hispanic White women. Conclusions: This mindfulness-based yoga intervention was associated with significant reductions in depressive symptoms, state anxiety, and psychological distress related to FCR among women with gynecologic, gastrointestinal, and thoracic cancers. Higher SES and underserved race/ethnicity status moderated some of these effects. Future research should explore the efficacy of this intervention among diverse women in a randomized clinical trial context. Clinical trial information: NCT03385577.

3122 Background: BRCA1-Associated Protein 1 (BAP1) acts as a tumor suppressor and critical regulator of the cell cycle and DNA damage response (DDR). PARP inhibitors (PARPi) demonstrate synthetic lethality in BAP1 mutant (mBAP1) preclinical models, independent of underlying germline BRCA status. mBAP1 leads to a loss of functional protein in several solid tumors. This study aimed to explore the clinical activity of niraparib in patients (pts) with advanced tumors likely to harbor mBAP1. Methods: Eligible adult pts with measurable metastatic solid tumors having exhausted approved therapies, adequate organ function, and ECOG PS 0-1 were assigned to Cohort A (histology-specific): tumors likely to harbor mBAP1 (i.e., cholangiocarcinoma, uveal melanoma, mesothelioma, or clear cell renal cell carcinoma) with tissue available for mBAP1 confirmation; or Cohort B (histology-agnostic): tumors with other known non-BRCA confirmed DDR mutations. Known BRCA1 or 2 mutations or prior PARPi exposure were excluded. All pts received niraparib 200-300mg daily, depending on weight and/or platelet count. Radiographic response was assessed by RECIST v1.1 measured every 8 weeks while on treatment. The primary endpoint was ORR with secondary endpoints of PFS, OS, clinical benefit (CR+PR+SD), toxicity, and exploratory biomarker determinations. Cohort A employed Simon's optimal two-stage design to assess a 30% ORR increase (a = 0.05; power = 90%). Cohort B aimed to assess a 40% ORR increase for this molecularly selected/enriched patient population. Results: From 08/13/2018 to 12/21/2021, 37 pts enrolled from two different centers, with 32 evaluable for response (Cohort A n = 18; Cohort B n = 14). In Cohort A, best ORR was 1 PR (6%), 8 SD (44%; median 5.7 mo; range 2 - 9.4 mo), and 9 PD (50%). Cohort A was stopped at the first stage following the pre-specified Simon’s design. mBAP1 was confirmed in 7/9 pts (78%) with PR or SD but in only 2/9 (22%) in those with PD. In Cohort B, best ORR was 6 SD (43%; median 7.5 mo; range 3.3 - 8.6 mo) and 8 PD (57%). Mutations in those with SD included ATM, CHEK2, PTEN, RAD50, and ARID1A. Common grade 3/4 AEs observed were anemia (16%), thrombocytopenia (16%), nausea (11%), and vomiting (8%). There were no unexpected nor grade 5 toxicities. Conclusions: The use of niraparib was well tolerated in pts with advanced treatment refractory solid tumors but failed to meet pre-specified efficacy threshold of ORR. However, clinical benefit was identified in 78% of patients in cohort A who had a confirmed mBAP1 tumor. Further correlative analyses are ongoing and additional clinical development restricted to mBAP1 tumors may be justified. Clinical trial information: NCT03207347.

e24125 Background: Gynecologic, gastrointestinal (GI), and thoracic cancers account for significant morbidity and mortality in the U.S. Women with these types of cancers frequently experience psychological distress, among other poor outcomes. Previous research has indicated that mindfulness-based interventions, such as yoga, can be effective in decreasing distress in cancer patients. Notably, this research has primarily been conducted in a breast cancer population with limited research assessing the feasibility, acceptability, and/or efficacy of this type of intervention in other prevalent and impactful cancers among women. The purpose of the present study was to assess the Feasibility and Acceptability of a yoga intervention for women with gynecologic, GI, or thoracic cancers. Methods: A total of 124 women diagnosed with a gynecologic, GI, or thoracic cancer in the prior year were recruited via outpatient oncology clinics to participate in a 10-week, group-based manualized yoga intervention entitled “Stilling the Waters of Uncertainty” (Author: E. Kacel) that is nearing the end of accrual. Participants completed an Acceptability evaluation following each yoga session with ratings on a 5-point Likert scale from “not at all” to “extremely.” Feasibility of the study was operationalized as percentage of eligible participants who (a) enrolled, (b) attended sessions, and (c) completed post-intervention assessment. Acceptability was operationalized as the percentage of participants with average session ratings of “very” or “extremely” for intervention usefulness, enjoyableness, safety, clarity, relevance, and likelihood of continuing to practice skills. Criteria for operationalizing Feasibility and Acceptability for this study were defined a priori based on recommendations of Bowen and colleagues (2009). A minimum of 80% for each measure of feasibility and acceptability was set as the a priori threshold of success in each domain. Results: All measures of Feasibility were below the a priori benchmark of 80%: Of the 318 eligible patients approached for participation, (a) 124 patients (39.0%) enrolled; 49/124 (39.5%) attended at least 1 yoga session; 44/124 (35.4%) attended at least 8 sessions; and (c) 41/124 (33.1%) completed post-intervention assessment procedures. At least 80% of attendees rated the intervention as “very” or “extremely” useful, enjoyable, safe, and clear; 75.5% and 79.6% of attendees rated the intervention as “very” or “extremely” relevant and likely to be continued to be practiced. Conclusions: The results of this study indicate that a yoga intervention for women with prevalent non-breast cancer types did not meet a priori criteria for feasibility. However, participants who attended at least 1 session rated the intervention as generally acceptable. Future research is needed to improve study/intervention feasibility in this population. Clinical trial information: NCT03385577.

PURPOSE: Some elderly patients (≥ 65 years old) with small-cell lung cancer (SCLC) do not receive chemotherapy likely because of fear of toxicity and uncertainty regarding benefits. Thus, we aimed to study real-world trends in utilization of antineoplastics over the years and predictors of utilization, survival, and Medicare expenditure in elderly patients with extensive-stage (ES) SCLC. PATIENTS AND METHODS: Using the linked SEER and Medicare database, we identified elderly patients with newly diagnosed ES-SCLC between 2001 and 2013. The Wald test was used to determine the significance of trends. Cox proportional hazards models were applied for survival analyses. We used SAS, version 9.4 (SAS Institute, Cary, NC). RESULTS: We identified 15,763 patients with newly diagnosed ES-SCLC. Approximately 6,838 patients (43.38%) received antineoplastics, and 8,925 patients (56.61%) received supportive care only. Every year since 2001, the percentage of patients receiving antineoplastics has decreased (45.8% v 36.6% in 2001 and 2013, respectively; Ptrend < .0001). Patients with advanced age ( P < .001), patients from high-poverty areas ( P < .001) or rural areas ( P = .005), patients with Charlson comorbidity index ≥ 3 ( P < .001), and non-Hispanic blacks ( P = .003) and Hispanics ( P = .001) were less likely to receive antineoplastics. Mean Medicare spending per patient decreased over the study period for patients treated with antineoplastics ($45,998 in 2001 and $35,053 in 2013; Ptrend < .001) and for those receiving supportive care only ($34,197 in 2001 and $25,265 in 2013; Ptrend < .001). CONCLUSION: Decreasing utilization of antineoplastics in elderly patients with ES-SCLC since 2001 could be partly secondary to higher comorbidities and physiologic age, leading to poor candidacy. Medicare expenditures decreased likely as a result of value-based treatment initiatives by the Centers for Medicaid and Medicare Services. However, expenditures are likely to increase with use of expensive novel agents.

TPS223 Background: Patients with advanced colorectal cancer after progressing through first line therapy, have several FDA-approved systemic therapies that are associated with clinical benefit for a substantive minority of patients. Current clinical practice is to trial these various treatments in a step-wise fashion using CT scans every 3 months to evaluate effectiveness. This process requires 3-4 months between therapeutic interventions from which the patient may ultimately derive no clinical benefit, may have a performance status decline; limiting the number of possible interventions and increases risk for physical and financial toxicity. An alternative to the traditional CT-scan guided approach for disease assessment is a circulating tumor DNA (ctDNA) intervention. The Signatera ctDNA assay which utilizes 16 truncal mutations derived from a patient’s tumor, can be assessed every 2 weeks for a rapid determination of the effectiveness of a systemic therapy. This may allow patients to be exposed to many treatments during a short time, limiting toxicity, allowing for a quicker determination of clinical benefit and personalization of treatment. The aim of this study will be to compare the traditional scan-driven approach vs an intervention guided by ctDNA assessments, both arms using a pre-specified order of chemotherapy treatments. Methods: This is a phase 2 randomized study of patients with refractory metastatic adenocarcinoma of the colon or rectum. Participants are eligible after progression or intolerance to first line chemotherapy or recurrence within 6 months of adjuvant oxaliplatin based chemotherapy. They must have RECIST measurable metastatic disease that is not eligible for definitive management. Tissue from the primary and/or metastatic deposit is required for Signatera NGS analysis and subjects must have measurable ctDNA at sampling. Participants must be ≥18 years old without major organ dysfunction and have an ECOG performance status of 0 to 2. Subjects with Microsatellite High, deficient in DNA mismatch repair genes, or BRAF V600E mutations are excluded. Subjects will be randomized 1:1 to Arm A (ctDNA guided intervention) or Arm B (scan-guided control group). Patients in both arms will undergo systemic treatments in a standardized pre-specified order. Arm A will have ctDNA assessments every 2 weeks until an intervention shows a significant decrease, then every 4 weeks until Progressive Disease (PD) by scan or significant ctDNA increase. CT imaging will be performed every 12 weeks. Those in Arm B, will have CT imaging every 12 weeks and blood collected for post-hoc analysis every 4 weeks until PD by scan. The primary endpoint is overall survival. Secondary endpoints include progression free survival and overall response. Exploratory analysis with be performed of the microbiome. Enrollment continues to a maximum of 78 patients. Clinical trial information: NCT04786600.

TPS354 Background: BRCA1-Associated Protein 1 (BAP1) is a critical regulator of the cell cycle, cellular differentiation, cell death, and DNA damage response. It also acts as a tumor suppressor. Preclinical models demonstrate significant synthetic lethality in BAP1 mutant cell lines and patient xenografts when treated with PARP inhibitors, independent of underlying BRCA status, suggesting this mutation confers a BRCA-like phenotype. BAP1 is mutated, leading to a loss of functional protein, in up to 30% of cholangiocarcinomas as well as several other solid tumors. Methods: This phase 2, open-label, single arm multicenter study aims to exploit the concept of synthetic lethality with the use of the PARP inhibitor niraparib in pts with metastatic relapsed or refractory solid tumors. Eligible pts with measurable metastatic and incurable solid tumors are assigned to one of two cohorts: Cohort A (histology-specific): tumors harboring suspected BAP1 mutations including cholangiocarcinoma, uveal melanoma, mesothelioma or clear cell renal cell carcinoma with tissue available for BAP1 mutational assessment via NGS or Cohort B (histology-agnostic): tumors with known DNA damage response (DDR) mutations (Table) confirmed by CLIA-approved NGS. Other key eligibility criteria include age ≥18 years, adequate cardiac, renal, hepatic function and Eastern Cooperative Oncology Group performance status of 0 to 1. Pts with known BRCA1 or BRCA2 mutations or prior PARPi exposure are excluded. Pts receive niraparib 200-300mg daily (depending on weight and/or platelet count) continuously. Primary endpoint is objective response rate with secondary endpoints of PFS, OS, toxicity and exploratory biomarker determinations. Radiographic response by RECIST criteria is measured every 8 weeks while on treatment. Cohort A has fully enrolled. Cohort B enrollment continues to a maximum of 47 total evaluable subjects with expansion cohorts allowable for histologic or molecular subtypes meeting pre-specified responses. NCT03207347 Clinical trial information: NCT03207347. [Table: see text]

e22061 Background: BRCA-associated protein-1 (BAP1) is a ubiquitin ligase associated with regulating cell cycle, cell proliferation, DNA damage pathway, and cell death. It also acts as a tumor suppressor gene as seen in hereditary cancer syndrome associated with germline mutations in BAP1. Preclinical studies have shown that PARP-inhibitor treatment of BAP1 mutant cell lines demonstrated significant synthetic lethality, independent of underlying BRCA status suggesting this mutation confers a BRCA-like phenotype. BAP1 is mutated, leading to a loss of functional protein, in up to 30% of several solid tumors including cholangiocarcinoma, mesothelioma, uveal melanoma, and clear cell renal cell carcinoma. Methods: This phase 2, open-label, single arm study aims to exploit the concept of synthetic lethality with the use of the PARP inhibitor niraparib in two biologically distinct cohorts. Eligible patients (pts) with measurable metastatic and incurable solid tumors are assigned to one of the two cohorts: Cohort A (histology-specific): tumors harboring suspected BAP1 mutations including cholangiocarcinoma, uveal melanoma, mesothelioma or clear cell renal cell carcinoma with tissue available for BAP1 mutational assessment via Next Generation Sequencing (NGS); or Cohort B (histology-agnostic): tumors with known DNA damage response (DDR) mutations (Table) confirmed by CLIA-approved NGS. Key inclusion criteria also include age ≥18 years, adequate cardiac, renal, hepatic function and ECOG PS of 0 to 1. Key exclusion criteria include known BRCA1 or BRCA2 mutations or prior PARPi exposure. Pts receive niraparib 200-300mg daily (depending on weight and/or platelet count) continuously. Primary endpoint is objective response rate (ORR), and secondary endpoints are progression free survival (PFS), overall survival (OS), toxicity and exploratory biomarker determinations. Radiographic response by RECIST criteria is measured every 8 weeks while on treatment. Cohort B enrollment is closed. Enrollment in Cohort A continues. A maximum of 47 evaluable subjects is planned with expansion cohorts allowable for histologic or molecular subtypes meeting pre-specified responses. Clinical trial information: NCT03207347. [Table: see text]

Defects in DNA repair can result in oncogenic genomic instability. Cancers occurring from DNA repair defects were once thought to be limited to rare inherited mutations (such as BRCA1 or 2). It now appears that a clinically significant fraction of cancers have acquired DNA repair defects. DNA repair pathways operate in related networks, and cancers arising from loss of one DNA repair component typically become addicted to other repair pathways to survive and proliferate. Drug inhibition of the rescue repair pathway prevents the repair-deficient cancer cell from replicating, causing apoptosis (termed synthetic lethality). However, the selective pressure of inhibiting the rescue repair pathway can generate further mutations that confer resistance to the synthetic lethal drugs. Many such drugs currently in clinical use inhibit PARP1, a repair component to which cancers arising from inherited BRCA1 or 2 mutations become addicted. It is now clear that drugs inducing synthetic lethality may also be therapeutic in cancers with acquired DNA repair defects, which would markedly broaden their applicability beyond treatment of cancers with inherited DNA repair defects. Here we review how each DNA repair pathway can be attacked therapeutically and evaluate DNA repair components as potential drug targets to induce synthetic lethality. Clinical use of drugs targeting DNA repair will markedly increase when functional and genetic loss of repair components are consistently identified. In addition, future therapies will exploit artificial synthetic lethality, where complementary DNA repair pathways are targeted simultaneously in cancers without DNA repair defects.

Smokers experience aberrant gene promoter methylation in their bronchial cells, which may predispose to the development of neoplasia. Hydralazine is a DNA demethylating agent, and valproic acid is a histone deacetylase inhibitor, and both have modest but synergistic anticancer activity in vitro. We conducted a phase I trial combining valproic acid and hydralazine to determine the maximally tolerated dose (MTD) of hydralazine in combination with a therapeutic dose of valproic acid in patients with advanced, unresectable, and previously treated solid cancers. Twenty females and nine males were enrolled, with a median age of 57 years and a median ECOG performance status of 0. Grade 1 lymphopenia and fatigue were the most common adverse effects. Three subjects withdrew for treatment-related toxicities occurring after the DLT observation period, including testicular edema, rash, and an increase in serum lipase accompanied by hyponatremia in one subject each. A true MTD of hydralazine in combination with therapeutic doses of valproic acid was not reached in this trial, and the planned upper limit of hydralazine investigated in this combination was 400 mg/day without grade 3 or 4 toxicities. A median number of two treatment cycles were delivered. One partial response by Response Evaluation Criteria In Solid Tumors criteria was observed, and five subjects experienced stable disease for 3 to 6 months. The combination of hydralazine and valproic acid is simple, nontoxic, and might be appropriate for chemoprevention or combination with other cancer treatments. This trial supports further investigation of epigenetic modification as a new therapeutic strategy.

Background: Nicotine promotes the proliferation of human squamous cell lung cancer (SCC-L) via the α7-nicotinic receptor (nAChR). Results: Nicotine increases α7-nAChR expression via transcriptional mechanisms involving Sp1 and GATA proteins. Conclusion: Nicotine-induced up-regulation of α7-nAChR accelerates the growth of human SCC-L. Significance: SCC-L patients exposed to nicotine display fast growing lung tumors and worse clinical outcomes., Nicotine, the addictive component of cigarettes, promotes lung cancer proliferation via the α7-nicotinic acetylcholine receptor (α7-nAChR) subtype. The present manuscript explores the effect of nicotine exposure on α7-nAChR levels in squamous cell carcinoma of the lung (SCC-L) in vitro and in vivo. Nicotine (at concentrations present in the plasma of average smokers) increased α7-nAChR levels in human SCC-L cell lines. Nicotine-induced up-regulation of α7-nAChR was confirmed in vivo by chicken chorioallantoic membrane models. We also observed that the levels of α7-nAChR in human SCC-L tumors (isolated from patients who are active smokers) correlated with their smoking history. Nicotine increased the levels of α7-nAChR mRNA and α7-nAChR transcription in human SCC-L cell lines and SCC-L tumors. Nicotine-induced up-regulation of α7-nAChR required GATA4 and GATA6. ChIP assays showed that nicotine induced the binding of GATA4 or GATA6 to Sp1 on the α7-nAChR promoter, thereby inducing its transcription and increasing its levels in human SCC-L. Our data are clinically relevant because SCC-L patients smoked for decades before being diagnosed with cancer. It may be envisaged that continuous exposure to nicotine (in such SCC-L patients) causes up-regulation of α7-nAChRs, which facilitates tumor growth and progression. Our results will also be relevant to many SCC-L patients exposed to nicotine via second-hand smoke, electronic cigarettes, and patches or gums to quit smoking.

Non

Introduction S-1 is a rationally designed oral agent that combines the 5-fluorouracil prodrug tegafur with gimeracil and oteracil, which inhibit 5-fluorouracil degradation by dihydropyrimidine dehydronase and phosphorylation within the gastrointestinal tract, respectively, to increase antineoplastic activity while reducing gastrointestinal toxicity. We investigated the activity and toxicity of S-1 in combination with cisplatin in patients with unresectable non-small cell lung cancer (NSCLC). Methods Cisplatin, 75 mg/m 2 , was administered intravenously on day 1, with S-1, 25 mg/m 2 PO two times a day, days 1 to 14, every 21 days for a maximum of six cycles. Primary end point was overall response. Results A total of 58 patients received at least one cycle of protocol-specified therapy. The best overall response rate was 23.2% (95% confidence interval: 13.0–36.4), and the disease control rate was 67.9%. The median progression-free survival was 4.0 months (95% confidence interval: 3.3–5.5). There did not appear to be any relationship between response to therapy and tumor histology. The most frequently reported adverse events of G3 or more (≥10%) were neutropenia (28%), hyponatremia (19%), diarrhea (17%), hypokalemia (12%), fatigue (10%), dehydration (10%), and deep vein thrombosis (10%). Conclusions Although the S-1 + cisplatin regimen used in this study appeared to have a similar level of antitumor activity and toxicity to that of established cisplatin-based doublets in NSCLC, the protocol-specified criteria of sufficient efficacy to warrant further study with an objective response rate ≥30% was not achieved. Therefore, while S-1 appears to be a promising agent in NSCLC, further evaluation should be conducted to determine the optimal S-1-based regimen to take forward for additional study.

Background: Motexafin gadolinium (MGd) disrupts redox-dependent pathways by inhibiting oxidative stress-related proteins leading to apoptosis. MGd selectively targets tumor cells, disrupting energy metabolism and repair mechanisms, rendering cells more prone to apoptosis. Preclinical studies with MGd and pemetrexed show significant tumor growth delay in lung cancer cell lines. Methods: Patients with non-small cell lung cancer, Eastern Cooperative Oncology Group performance status 0 to 1, who had received one previous platinum containing regimen and normal organ function were treated with MGd 15 mg/kg and pemetrexed 500 mg/m 2 q21days. Patients were allowed to receive more than one regimen if the initial treatment was in the adjuvant or curative setting and administered >12 months earlier. The primary end point was to demonstrate a 40% rate of 6-month progression free survival (PFS). Results: Seventy-two patients (30 women, 42 men), performance status 0/1 (30/42), and a median age of 63 years were enrolled. Most patients (96%) were current or former smokers. All histologic types were represented (squamous/adenocarcinoma/other: 28%, 42%, 31%). Number of prior regimens: 1: 69%; 2: 26%, and >2: 4%. Median number of cycles administered was (range) 2 (1–12). Toxicity: grade 3/4 neutropenia was noted in 8.3% with febrile neutropenia in 1.4%, thrombocytopenia in 8.3%, fatigue in 9.7%, and pneumonia in 11.1%. There were no complete responses, 8.1% had partial response, 56.5% had stable disease, and 35.5% had progressive disease as their best response. Twenty-three percent of patients were progression free at 6 months and the median PFS was 2.6 months with an overall survival of 8.1 months. Conclusions: The combination of MGd and pemetrexed was well tolerated with toxicity similar to that of pemetrexed alone. However, the study did not achieve its end point of 40% 6-month PFS. The response rate, PFS, and overall survival did not seem markedly different than prior phase II and phase III studies of pemetrexed alone. Consequently, there are no further plans for development of this combination.

Although the incidence of gastric cancer has been decreasing in the United States, it remains a leading cause of cancer death in the world, only lung cancer causes more deaths worldwide. The combination of relatively low prevalence, lack of pathognomonic symptoms, and lack of defined risk factors are associated with a delay in diagnosis leading to a dismal prognosis. For localized disease, surgery remains a cornerstone of treatment but much controversy remains regarding optimal peri-operative therapy. For advanced disease, several new agents and new combination chemotherapies have offered encouraging results. This paper seeks to review the major topics surrounding gastric cancer and cover the results of recently reported and ongoing trials.

Over the past three decades, numerous randomized controlled trials have demonstrated that chemotherapy improves both recurrence-free survival and overall survival for women with early-stage breast cancer (1–5). However, the efficacy of adjuvant chemotherapy has been shown to decrease with age. For example, the pooled analysis of 47 randomized trials by the Early Breast Cancer Trialists' Collaborative Group showed that chemotherapy provided a 27% proportional reduction in 10-year mortality for women with early-stage operable breast cancer aged

The understanding of mesenchymal neoplasms of the gastrointestinal tract has evolved dramatically over the last two decades since gastrointestinal stromal tumor (GIST) was described as the most common stromal tumor arising anywhere from the esophagus to the ano-rectum. Although morphologically similar to other benign and malignant smooth muscle and neural stromal neoplasms, GIST constitutes a distinct group of rare gastrointestinal tract tumors that originate from the interstitial cells of Cajal, regulators of gut peristalsis that normally express CD117, which is the product of the c-KIT proto-oncogene that encodes a tyrosine kinase receptor that regulates cellular proliferation in GISTs. Virtually all GISTs occur from mutations of the c-KIT oncogene and exhibit consistent expression of c-KIT (CD117), which is considered the most specific criterion for a diagnosis of GIST. Gastrointestinal stromal tumors vary in their behavior and several features have to be considered to assess their malignant potential. The advent of sophisticated imaging techniques for the evaluation and sampling of stromal tumors of the gastrointestinal tract has resulted in improved detection of GISTs. The identification of a novel tumor-specific target in c-KIT resulted in the development of a tyrosine kinase-inhibitor (imatinib mesylate) that provides an encouraging option for treating GISTs. This article reviews recent advances in the understanding of the cell biology, diagnosis, and therapy of GISTS.

Mortality from colon cancer could be reduced with routine screening, yet screening rates are low. Current screening tools are limited by expense and suboptimal acceptance. A retrospective case–control study of all cases of colon cancer diagnosed at our institution over a 5-year period was performed to determine the frequency of blood count abnormalities in these patients upon presentation. One hundred twenty-seven patients had right-sided colon cancer: 107 (84%) had an elevated red cell distribution width (RDW); 87 (69%) had anemia; and 70 (55%) had a low mean corpuscular volume (MCV). Ninety-eight patients had left-sided colon cancer: 49 (50%) had an elevated red cell distribution width; 43 (44%) had anemia; and 22 (22%) had a low mean corpuscular volume. The red cell distribution width was 84% sensitive and 88% specific for right-sided colon cancer. An elevated red cell distribution width may help better identify those patients who should be referred for full colonoscopy.

Smoking has a strong association with the development of squamous cell carcinomas of the lung (SCC-L). Nicotine, the addictive component of cigarettes, promotes the proliferation of SCC-Ls via the ...

Brain metastases are seen in a considerable number of patients with non-small cell lung cancer (NSCLC) and when they occur will pose a negative impact on patients’ survival. Diverse therapeutic options are being used to treat brain metastases including surgical excision, stereotactic radiosurgery, whole brain radiotherapy and systemic therapy. Of systemic therapies, gefitinib and erlotinib, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), have shown benefit in treatment of brain metastases in patients with NSCLC. They are particularly effective in those whose lesions harbor activating EGFR mutations, as well as those selected with certain clinical features including young non-smokers, females, and those with East-Asian ethnicity or with adenocarcinoma histology. Gefitinib and erlotinib also have the advantage of exerting their antitumor activity with a favorable toxicity profile. However, they may fail after months of continuous use due to development of drug resistance. In these situations, adopting other treatment strategies such as switching drugs or dose escalation may be suitable alternatives. Several clinical trials in different phases are currently evaluating the efficacy of gefitinib or erlotinib in larger populations of NSCLC patients with brain metastases. On the other hand, new drugs such as afatinib, icotinibor crizotinib have shown benefit in patients with corresponding molecular alterations, at least in case reports or in early phase trials, and are awaiting further study in larger populations.

Thrombocytopenia following myelotoxic therapy is a common problem and when severe (20,000/microl) can lead to severe morbidity and mortality. Thrombopoietin (TPO) is a naturally occurring glycosylated peptide which stimulates the differentiation of bone marrow stem cells into megakaryocyte progenitor cells, induces the expression of megakaryocyte differentiation markers, promotes megakaryocyte proliferation, polyploidization and, ultimately, the formation of increased numbers of platelets in the circulation. TPO has now been produced by recombinant technology and has entered clinical trials. This open label phase I study was designed to determine the safety, tolerance and pharmacokinetics of recombinant thrombopoietin (rhTPO) when administered to patients after undergoing high-dose chemotherapy followed by autologous bone marrow transplantation. rhTPO was administered intravenously by bolus injection at doses ranging from 0.3 to 4.8 microg/kg/day every 3 days to 30 patients and 0.6 microg/kg daily to three patients. rhTPO was begun the day after marrow infusion and continued until platelet recovery to20,000/microl. G-CSF was concomitantly administered to promote myeloid recovery. Serious adverse events or neutralizing antibodies to rhTPO were not observed during the study. Median platelet recovery after ABMT was 19 days (range, 11-41). Neither the dose nor the schedule of rhTPO appeared to have any impact upon the time course of platelet recovery. In this phase I study, rhTPO was found to be well tolerated without the development of neutralizing antibodies and without compromising neutrophil recovery. Platelet recovery was similar for all doses studied warranting further evaluation in phase II and III trials designed to test for platelet recovery efficacy.

Brain metastases are a common occurrence in non–small-cell lung cancer (NSCLC). The standard treatment is radiation therapy with or without resection, but chemotherapy is only modestly palliative for recurrence within the brain. We describe a 60-year-old nonsmoking Native American woman who presented with left-sided weakness due to a stage IV adenocarcinoma of the lung with multiple brain metastases. The patient received whole-brain radiotherapy (33 Gy in 11 fractions) with resolution of her symptoms, but deferred subsequent chemotherapy. Within 3 months, she became symptomatic again with vertigo, anorexia, and a decrease in her performance

Summary Objectives The epidermal growth factor receptor (EGFR) is a validated target in head and neck squamous cell carcinoma (HNSCC). In recurrent and/or metastatic (R/M) HNSCC, resistance to anti-EGFR therapy inevitably occurs. Downstream activation of the PI3K/Akt/mTOR pathway is an established resistance mechanism. Concurrent mTOR blockade may improve efficacy of anti-EGFR therapy. Materials and methods Erlotinib 150 mg daily and temsirolimus 15 mg weekly were administered to patients with platinum-refractory R/M HNSCC and ECOG performance status 0–2. The primary endpoint was progression-free survival (PFS). Correlative studies determined PIK3CA and HRAS mutation status; p16, EGFR, pS6K, pAkt and PTEN expression; and pre- and post-treatment plasma levels of 20 immunomodulatory cytokines. Results Twelve patients enrolled; six withdrew within 6 weeks due to toxicity or death, prompting early closure of the trial. Grade ⩾ 3 toxicities included fatigue, diarrhea, gastrostomy tube infection, peritonitis, pneumonia, dyspnea, and HN edema. Median PFS was 1.9 months. Median overall survival was 4.0 months. Six/12 tumors were p16(+), 9/11 lacked measurable PTEN expression, and 1/12 harbored a PIK3CA mutation. On exploratory analysis, high baseline plasma VEGF and interferon-gamma levels marginally associated with tumor progression. Conclusions The combination of erlotinib and temsirolimus was poorly tolerated. Low prevalence of PTEN expression and 8% incidence of PIK3CA mutations indicate biological relevance of this pathway in R/M disease. Investigation of more tolerable combinations of EGFR and PI3K/Akt/mTOR pathway inhibitors in selected HNSCC patients is warranted.

Background. Metastatic colorectal cancer is generally incurable. The most active regimen available, 5-fluorouracil(5-FU) and folinic acid (Leucovorin), produces response rates of approximately 25% to 30%. Methyl-lomustine is a nitrosourea with modest activity against colorectal cancer. A randomized trial was undertaken to evaluate the impact the addition of methyl-lomustine would have on response, duration of survival, and survival rates in patients with advanced colorectal cancer. Methods. The methyl-lomustine/5-FU/Leucovorin (MFL) regimen consisted of methyl-lomustine (110 mg/ m2), administered on Day 1 of each 8-week cycle with six weekly boluses of 5-FU (600 mg/m2), and Leucovorin (500 mg/mz). The FL treatment arm consisted of the administration of 5-FU and Leucovorin as described above. Patients were evaluated for response and toxicity after each 8-week cycle.

Background In non-small cell lung cancer (NSCLC), interstitial hypertension is a barrier to chemotherapy delivery, and is mediated by platelet derived growth factor receptor (PDGFR). Antagonizing PDGFR with imatinib may improve intra-tumoral delivery of paclitaxel, increasing response rate (RR). Methods This single-stage, open-label phase II study evaluated pulse dose imatinib and weekly paclitaxel in elderly patients with advanced NSCLC. Eligible patients were aged ≥ 70 with untreated, stage IIIB-IV NSCLC and ECOG performance status 0-2. Primary endpoint was RR. Secondary endpoints included median progression free and overall survival (PFS, OS) and correlatives of PDGFR pathway activation. Baseline Charlson Comorbidity Index (CCI) and Vulnerable Elder Survey-13 (VES-13) were correlated with outcomes. Results Thirty-four patients with median age 75 enrolled. Eleven of 29 (38%) were frail by VES-13 score. Overall RR was 11/34 (32%; 95% CI 17%-51%), meeting the primary endpoint. Median PFS and OS were 3.6 and 7.3 months, respectively. High tumoral PDGF-B expression predicted inferior PFS. Frail patients by VES-13 had significantly worse median PFS (3.2 vs. 4.5 months; p=0.02) and OS (4.8 vs. 12 months; p=0.02) than non-frail. Conclusions The combination of imatinib and paclitaxel had encouraging activity as measured by the primary endpoint of RR. However, PFS and OS were typical for elderly patients treated with single agent chemotherapy and the regimen is not recommended for further study. Adjunct imatinib did not overcome the established association of tumoral PDGF-B expression with inferior PFS. VES-13 was a powerful predictor of poor survival outcomes. Frailty should be further studied as a predictor of non-benefit from chemotherapy. Trial Registration ClinicalTrials.gov NCT01011075

Head and neck cancers are a common spectrum of diseases, accounting for over one-third of a million deaths worldwide each year, and over 11,000 annual US deaths. Most head and neck cancers have traditionally been diagnosed in older males who abuse tobacco and/or alcohol. With increasing public awareness of the dangers of tobacco exposure and excessive alcohol intake, the incidence of many subgroups of head and neck cancer is now decreasing in the West. However, over the past several decades, the rates of carcinomas of the tonsil and base of tongue are increasing, and are affecting a different demographic group consisting mainly of younger, nonsmoking, males. These lesions are caused by infections with the same high-risk human papillomaviruses (HPV) genotypes as those responsible for cervical cancer and other anogenital neoplasms. These HPV-induced head and neck cancers differ in their biology and prognosis from those neoplasms induced by tobacco or ethanol. Understanding the biology of these lesions will allow for the development of selective preventive and treatment strategies, and better outcomes, for this subpopulation of patients.

PURPOSE To determine the activity and evaluate the toxicity of uracil and tegafur in a 4:1 molar concentration (UFT; Taiho Pharmaceutical Ltd, Tokyo, Japan) plus oral calcium leucovorin in the treatment of patients with advanced colorectal carcinoma. PATIENTS AND METHODS Forty-five patients with advanced, bidimensionally measurable metastatic colorectal carcinoma were enrolled onto the trial. None of the patients had received prior chemotherapy or biologic therapy for advanced disease. Patients received either 350 or 300 mg/m2/d UFT plus 150 mg/d leucovorin administered orally in divided daily doses every 8 hours for 28 days followed by a 7-day rest period. Response was evaluated after two courses of therapy. RESULTS Eighteen patients (three treated at 350 mg/m2/d and 15 at 300 mg/m2/d) had partial responses, and one patient had a complete response (response rate, 42.2%; 95% confidence interval, 28% to 58%). Responses were observed in sites that included liver (n = 18), lung (n = 6), and bone (n = 1). Of seven patients who received 350 mg/m2 UFT, prolonged grade 3 diarrhea developed in five; this resulted in a reduction in the UFT starting dose to 300 mg/m2/d in the remaining 38 patients. Grade 1 or 2 toxic effects included diarrhea, nausea, vomiting, abdominal cramping, anorexia, fatigue, oral mucositis, excessive lacrimation, and rash. Among 38 patients who received the 300-mg/m2/d dose, grade 3 toxic reactions included diarrhea (n = 4), vomiting (n = 2), abdominal cramping (n = 1), and fatigue (n = 2). CONCLUSION UFT 300 mg/m2/d plus oral leucovorin 150 mg/d administered for 28 days demonstrated significant activity against metastatic colorectal carcinoma. This oral regimen was well tolerated and devoid of the neutropenia or significant oral mucositis that complicates intravenous schedules of fluorouracil (5-FU) plus leucovorin. The results of this clinical trial will serve as the basis for a randomized phase III study to compare this oral schedule of UFT plus leucovorin with intravenous 5-FU plus leucovorin to determine the relative efficacy, impact on quality of life, and cost of the two regimens.

Cytogenetic abnormalities in acute myelogenous leukemia have been identified as one of the most important prognostic factors. Favorable chromosomal changes such as inv(16), t(8;21), and t(15;17) are associated with higher rates of complete remission and event-free survival. Translocation t(15;17) characterizes acute promyelocytic leukemia (APL) (French-American-British [FAB] class M3) in almost all patients. Secondary chromosomal abnormalities are also present in approximately one-third of patients with newly diagnosed APL. We present a 26-year-old Hispanic man diagnosed with the microgranular variant of APL (FAB class M3v) whose initial cytogenetics included t(15;17) and trisomy 21. The prognostic implications of trisomy 21 and other secondary cytogenetic aberrations in APL are reviewed. To our knowledge, this is the first reported case of trisomy 21 with t(15;17) in the microgranular variant of APL.

Background. Mitoxantrone is an anthraquinone derivative that has demonstrated encouraging preclinical and clinical activity against a variety of human carcinoma cell lines and malignancies. Three Phase II studies of systemically administered mitoxantrone in patients with colorectal carcinoma failed to demonstrate any therapeutic activity, as did four Phase II studies of intravenous mitoxantrone in hepatocellular carcinoma. Two additional trials demonstrated limited activity when administered intravenously to patients with hepatocellular carcinoma. However, because this drug exhibits a steep dose-response curve, a Phase I-II trial of mitoxantrone by hepatic arterial infusion was initiated. Methods. Patients with hepatocellular carcinoma and metastatic colorectal carcinoma with liver only or liver-predominant disease were eligible for therapy. All patients underwent the placement of a percutaneous hepatic arterial catheter before each course of therapy, and the first cohort of patients was treated at 10 mg/m2/ course on day 1 on a 28-day cycle. Dosages were escalated in increments of 2 mg/m2/course based on side effects and tolerance. Results. Twenty-eight patients with bidimensionally measurable unresectable, liver-predominant disease were entered into this trial. The therapy was well tolerated, with only 5 courses of 55 being complicated by neutropenia and none associated with fever. Only one patient required a dosage reduction on the basis of toxicity (neutropenia). No complete or partial responses were observed. Conclusion. These data are consistent with a lack of therapeutic activity of mitoxantrone when administered by hepatic arterial infusion for the treatment of hepatocellular carcinoma or metastatic colorectal cancer.

Bronchiolitis obliterans organizing pneumonia (BOOP) is an adverse event known to occur after cancer chemotherapy and radiotherapy. We present a case of a 47-year-old patient who was diagnosed with BOOP after treatment for metastatic rectal cancer with oxaliplatin/capecitabine/bevacizumab. Removal of oxaliplatin from the regimen and replacement with irinotecan resulted in a resolution of his pulmonary symptoms.

A cDNA clone designated pPDC-1 was isolated from a cDNA library prepared against poly(A+)RNA isolated from the human pancreatic adenocarcinoma cell line, Capan-2. The cDNA corresponds to a 1.7-kilobase mRNA that is expressed at higher levels in seven of nine pancreatic tumors than in their corresponding normal tissues. It is also expressed in normal human kidney, intestine, pancreas, stomach, placenta, lung, brain, spleen, and liver. A computer search of the Intelligenetics System of all available nucleotide sequences revealed a 60% homology between the nucleotide sequence of the pPDC-1 cDNA and that of elongation factor-1 gamma from Artemia. The deduced amino acid sequence shared 53% identity with the amino acid sequence for the Artemia elongation factor-1 gamma.

Background In general, prognosis and impact of prognostic/predictive factors are assessed with Kaplan-Meier plots and/or the Cox proportional hazard model. There might be substantive differences from the results using these models for the same patients, if different statistical methods were used, for example, Boag log-normal (cure-rate model), or log-normal survival analysis. Methods Cohort of 244 limited-stage small-cell lung cancer patients, were accrued between 1981 and 1998, and followed to the end of 2005. The endpoint was death with or from lung cancer, for disease-specific survival (DSS). DSS at 1-, 3- and 5-years, with 95% confidence limits, are reported for all patients using the Boag, Kaplan-Meier, Cox, and log-normal survival analysis methods. Factors with significant effects on DSS were identified with step-wise forward multivariate Cox and log-normal survival analyses. Then, DSS was ascertained for patients with specific characteristics defined by these factors. Results The median follow-up of those alive was 9.5 years. The lack of events after 1966 days precluded comparison after 5 years. DSS assessed by the four methods in the full cohort differed by 0–2% at 1 year, 0–12% at 3 years, and 0–1% at 5 years. Log-normal survival analysis indicated DSS of 38% at 3 years, 10–12% higher than with other methods; univariate 95% confidence limits were non-overlapping. Surgical resection, hemoglobin level, lymph node involvement, and superior vena cava (SVC) obstruction significantly impacted DSS. DSS assessed by the Cox and log-normal survival analysis methods for four clinical risk groups differed by 1–6% at 1 year, 15–26% at 3 years, and 0–12% at 5 years; multivariate 95% confidence limits were overlapping in all instances. Conclusion Surgical resection, hemoglobin level, lymph node involvement, and superior vena cava (SVC) obstruction all significantly impacted DSS. Apparent DSS for patients was influenced by the statistical methods of assessment. This would be clinically relevant in the development or improvement of clinical management strategies.

Cigarette smoking is a major risk factor for all types of lung cancers. Nicotine, the addictive component of cigarettes, accelerates the growth and angiogenesis of human lung cancers. The biological activity of nicotine is mediated by nicotinic acetylcholine receptors (nAChRs). The endogenous ligand of nAChRs is acetylcholine (ACh). We show that both human SCLCs and NSCLCs contain all proteins of the acetylcholine signaling pathway, namely nAChRs, choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), choline transporter (ChT1) and acetylcholinesterase (AChE). ACh functions as an autocrine growth factor for human lung cancer cells. Lung adenocarcinoma (LAC), squamous cell carcinoma (SCC-L) and invasive mucinous adenocarcinoma (IMA) express a diverse array of nAChRs. In addition, normal human lung cells also express nAChRs and other ACh signaling proteins. Nicotine amplifies the ACh signaling loop in human lung cancer cells. It increases the levels of alpha7-nAChR subunit in human SCC-Ls. The alpha7-nAChR is responsible for the proliferative and pro-angiogenic activity of nicotine in lung cancer. The level of alpha7-nAChR was analyzed in human SCC-L samples isolated from patients. It was found that the level of alpha7-nAChR in SCC-L patients (who are heavy smokers) was much higher than that of moderate smoker suffering from SCC-Ls. Nicotine was also found to elevate the levels of ChAT and VAChT in human lung cancers. The acetylcholine signaling pathway may be a useful molecular target for the diagnosis and therapy of human lung cancers in smokers. Our results are also relevant to lung cancer patients who are exposed to nicotine via secondhand smoke, nicotine patches, gums or electronic cigarettes. Citation Format: Kathleen C. Brown, Jamie K. Lau, Haley E. Perry, Brent A. Thornhill, Cathryn D. Stevenson, William D. Rollyson, Cody A. Stover, Dennie V. Jones, Joseph F. Pulliam, Piyali Dasgupta. The acetylcholine signaling pathway: A novel molecular target for lung cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1032. doi:10.1158/1538-7445.AM2015-1032

Activation of the hedgehog pathway is reported in lung cancer, but its frequency remains unknown. We examine activation of this pathway in lung cancers by in situ hybridization and immunohistochemstry, and find that less than 10% of the tumors have elevated hedgehog target gene expression. We further identify a cell line NCI-H209 and two primary tumors with no detectable Su(Fu), a negative regulator of the pathway. Ectopic expression of Su(Fu) in NCI-H209 cells down-regulates hedgehog target gene expression and leads to inhibition of cell proliferation. These data indicate that activation of the hedgehog pathway is activated through Shh over-expression or Su(Fu) inactivation in only a subset of lung cancers.

The expression of selected gene products involved in cell differentiation and cell growth and genetic polymorphism of detoxi- fying genes was examined in 105 surgically resected nonsmall cell lung cancer (NSCLC) patients, and the relationship of these factors was correlated with cigarette smoking and patient survival. Genotyp- ing of peripheral blood lymphocytes from 87 patients was performed for CYP2E1, GSTM1, GSTT1, mEH, and MPO detoxifying genes using polymerase chain reaction. Formalin-fixed, paraffin-embedded tissue was immunostained with antibodies to p53, p27, phospho-AKT, and bcl-2 using the avidin-biotin-peroxidase method and tissue mi- croarray technique. Tumors were assigned a positive or negative score based on more than 10% of tumor cells staining positive with the antibody. The subtypes of NSCLC included 48 adenocarcinomas, 47 squamous cell carcinomas, and 10 large cell undifferentiated car- cinomas. A total of 54 tumors were pathologic stage I, 23 were stage II, and 26 were stage III. All subjects smoked (range, 10-175 pack- years; mean, 60 pack-years). The mean overall survival was 112 weeks (median, 129 weeks). Patients with p53-positive tumors had significantly fewer pack-years of smoking (52 pack-years vs 72 pack- years; P = 0.021), smoked fewer years (34 years vs 40 years; P = 0.018), and had significantly better survival compared with those with p53-negative tumors (P = 0.045). When smoking history was further analyzed, the authors found that p53 expression was associated with the number of years smoked and not the number of packs smoked per day. Patients with squamous cell carcinoma had smoked longer com- pared with those with adenocarcinoma (P = 0.011). Significant asso- ciation was seen between the CYP2E1 wild-type allele and better sur- vival (P = 0.016). Patients with stage I tumors had better survival compared with stages II and III (P = 0.032). No association was found between survival and tumor type; tumor differentiation; expression of phospho-AKT, p27, and bcl-2; and polymorphic metabolizing genes other than CYP2E1. The significant association of long duration of smoking (>40 years) with loss of p53 expression and poor survival suggests inactivation of the protective p53 pathway in those who had a history of more than 40 years of smoking.

The combination of interferons (IFNs) and retinoids in antineoplastic therapy is based upon preclinical, in vitro, and in vivo observations. Retinoid-IFN combinations have shown significant antitumor activity against advanced cutaneous and cervical squamous cell carcinoma (SCC), and the toxic effects do not appear to overlap. Based on in vitro evidence of synergy and observed clinical activity, we conducted a pilot phase II trial of 13-cis-retinoic acid (1 mg/kg/day) and IFN alpha (6 million units/day) in patients with advanced pancreatic adenocarcinoma. No objective responses occurred among six evaluable patients. The toxicities were mild and reversible, and grade 3 fatigue occurred in only one patient. No objective antitumor activity was noted against pancreatic adenocarcinomas at the dose and schedule utilized. Further exploration of this this purely biological approach is not warranted for pancreatic adenocarcinomas.

This study assessed the ability of various schedules of recombinant human thrombopoietin (rhTPO) to enhance mobilization of peripheral blood progenitor cells (PBPCs) in 134 patients with cancer undergoing high-dose chemotherapy and autologous PBPC transplantation. Patients received the study drug on days 1, 3, and 5 before initiation of granulocyte colony-stimulating factor (G-CSF) 10 microg/kg/day on day 5 and pheresis starting on day 9. Randomly assigned treatments on days 1, 3, and 5 were: group 1 (n=27) placebo, placebo, rhTPO 1.5 microg/kg; group 2 (n=27) rhTPO 1.5 microg/kg, placebo, placebo; groups 3 (n=28) and 4 (n=22) rhTPO 0.5 microg/kg on all 3 treatment days; and group 5 (n=30) placebo on all 3 treatment days. After high-dose chemotherapy and PBPC transplantation, groups 1 through 4 received rhTPO 1.5 microg/kg days 0, +2, +4, and +6 with either G-CSF 5 microg/kg/day (groups 1-3) or granulocyte-macrophage colony-stimulating factor 250 microg/m(2)/day (group 4). Group 5 received placebo plus G-CSF 5 microg/kg/day. The addition of rhTPO to G-CSF increased median CD34+ cell yield/pheresis in cohorts in which rhTPO was started before day 5, with higher yields in groups 2 (2.67 x 10(6)/kg) and groups 3 and 4 (3.10 x 10(6)/kg) than in group 1 (1.86 x 10(6)/kg) or group 5 (1.65 x 10(6)/kg) (P=.006 across groups). Comparing rhTPO to placebo, higher percentages of patients achieved the minimum yield of CD34+or =2 x 10(6)/kg (92% v 75%; P=.050) as well as the target yield of CD34+or =5 x 10(6)/kg (73% v 46%; P= .041). rhTPO-treated patients required fewer phereses to achieve minimum (P= .011) and target (P= .015) CD34+ cell values. rhTPO given after transplantation did not speed platelet recovery. No neutralizing antibodies were observed. We conclude that rhTPO can safely enhance mobilization of PBPC, reduce the number of leukapheresis, and allow more patients to meet minimal cell yield requirements to receive high-dose chemotherapy with PBPC transplantation.

Pulmonary synovial sarcoma is a rare neoplasm recently recognized as a distinct entity and characterized by t(X;18) translocation and production of at least 2 fusion genes, SYT-SSX1 and SYT-SSX2. We report a case of primary pulmonary synovial sarcoma with the SYT-SSX2 phenotype and a rapidly progressive downhill course. Previous reports have suggested that the soft tissue synovial sarcomas with SYT-SSX2 phenotype have a favorable clinical outcome. To the best of our knowledge, this is also the first report of CD117 (c-Kit) expression in a pulmonary synovial sarcoma. A 45-year-old woman presented with left chest pain and was found to have a left lower lobe tumor that was originally diagnosed as a sarcomatoid carcinoma. After the patient underwent chemotherapy and brachytherapy, the specimen from a left pneumonectomy showed a large spindle cell tumor, which was reclassified as a synovial sarcoma based on the results of immunophenotyping and molecular genetic studies. Differentiation between sarcoma and carcinosarcoma is crucial for implementing appropriate therapy. Furthermore, if the tumor expresses c-Kit, it may respond to target-based therapy.

Didemnin B is a depsipeptide derived from a Caribbean tunicate (sea squirt) that has demonstrated antineoplastic activity against a variety of murine tumor models, including the L1210 and P388 leukemia, the B16 melanoma, and M5076 sarcoma cell lines. Based on these data, we designed a phase II trial in which 15 patients with measureable, unresectable colorectal cancer were treated with Didemnin B at an initial dosage of 3.47 mg/m2 over 30 minutes administered by intravenous infusion every 28 days; the dosage was altered in accordance with the toxicity observed, with only one patient requiring a dosage reduction for pronounced nausea and vomiting. No hematologie or nonhematologic toxicity developed. No complete or partial responses were observed. These results do not compare favorably with results of treatments using other single agents or combinations that are currently available for the treatment of advanced colorectal cancers. However, because of the tolerable levels of toxicity experienced by in our patients, it is possible that an insufficient dose of the medication was delivered. We concluded that Didemnin B is not active against of colorectal cancers at the dosage and schedule at which it was administered in this study.

Patients undergoing anticancer therapy are often at risk for developing severe and/or prolonged posttreatment thrombocytopenia. This can be associated with significant bleeding; currently, it is treated with supportive platelet transfusions. Frequent platelet transfusions can cause alloimmunization which requires HLA-matched donors and more frequent blood transfusions, and transmission of both viral and bacterial infections via platelet transfusions remains a concern. Furthermore, thrombocytopenia can mandate a decrease in the dose intensity of cytotoxic therapy by causing either delays or dose reductions in therapy administration. An intervention that reduces the risk or shortens the duration of severe thrombocytopenia would represent an important medical advance. Thrombopoietin (TPO), a naturally occurring, glycosylated polypeptide that was cloned by Genentech in 1994, is capable of inducing differentiation of stem cells into megakaryocytes and accelerating the maturation of megakaryocytes, thereby increasing the platelet count. Recombinant human TPO (rHuTPO) is currently undergoing testing in phase 1 and 2 studies in patients receiving myelosuppressive or myeloablative therapy. For the purposes of illustration, preliminary safety and activity data from one ongoing phase 1 myelosuppression trial (rHuTPO in women with advanced gynecologic malignancies receiving carboplatin) and one ongoing phase 1 myeloablation trial (rHuTPO for peripheral blood progenitor cell mobilization prior to myeloablative chemotherapy for high risk breast cancer) will be presented.

Thrombocytopenia is a significant problem in the treatment of cancer.To assess the clinical safety of therapy with recombinant human thrombopoietin (rhTPO) and its ability to ameliorate chemotherapy-induced severe thrombocytopenia.Phase I/II clinical cohort study.The University of Texas M.D. Anderson Cancer Center, Houston, Texas.29 patients with gynecologic cancer.Recombinant human thrombopoietin was given before chemotherapy and after a second cycle of carboplatin therapy.Peripheral blood counts and platelet transfusions.Administration of rhTPO after chemotherapy significantly reduced the degree and duration of thrombocytopenia and enhanced platelet recovery. In patients who received the optimal biological dose of rhTPO (1.2 microg/kg of body weight) in cycle 2 (carboplatin plus rhTPO), the mean platelet count nadir was higher (44x10(9) cells/L and 20x10(9) cells/L; P = 0.002) and the duration of thrombocytopenia was shorter (days with a platelet count20x10(9) cells/L, 1 and 4 [P = 0.002]; days with a platelet count50x10(9) cells/L, 4 and 7 [P = 0.006]) than in cycle 1 (carboplatin only). The need for platelet transfusion in this group was reduced from 75% of patients in cycle 1 to 25% of patients in cycle 2 (P = 0.013).Therapy with rhTPO seems to be safe and may attenuate chemotherapy-induced severe thrombocytopenia and reduce the need for platelet transfusions.

BACKGROUND & AIMS: The nonspecific cross-reacting antigen (NCA) is a cell adhesion molecule, and the messenger RNA for NCA is overexpressed in 92% of colorectal carcinomas. The aim of this study was to determine the cis-acting elements that may be responsible for the expression of NCA. METHODS: Deletion mutants of the 5' flanking sequence and first intron were ligated into chloramphenicol acetyltransferase expression vectors, transfected into Chinese hamster ovary (CHO), DiFi, and HT-29 human colorectal carcinoma cells, and BxPC-3 and MDAPanc-28 human pancreatic carcinoma cells. The amount of acetylated chloramphenicol was determined to show the presence and activity of cis-acting sequences. RESULTS: The 5' flanking sequence functions as a promoter in all of cell lines and contains negative regulatory and enhancer sequences. The minimal promoter is active in Chinese hamster ovary and HT-29, though not in MDAPanc-28 cells. The first intron contains a silencer capable of suppressing a heterologous promoter. CONCLUSIONS: The results show cis-acting sequences within and 5' to the NCA gene, which appear to play a role in the expression of this gene in malignant tissues. Some of these sequences function in a cell type-specific manner. Further studies of these elements may provide insight into the mechanisms of the abnormal growth patterns of malignant cells. (Gastroenterology 1997 Mar;112(3):776-82)

5549 Background: The Epidermal Growth Factor Receptor (EGFR) is a validated target in HNSCC. In R/M disease, primary or acquired resistance to anti-EGFR therapy inevitably occurs. Downstream activation of the PI3K/Akt/mTOR pathway is an established resistance mechanism. We hypothesized that concurrent mTOR blockade may improve efficacy of anti-EGFR therapy and conducted this phase II study. Methods: We evaluated the combination of erlotinib 150 mg po daily and temsirolimus 15 mg IV weekly in pts with platinum-refractory R/M HNSCC and ECOG PS 0-2. The exact, single-stage phase II design had 80% power (5% significance level) to detect improvement in progression-free survival (PFS) from 2.3 to 4.4 mos with 35 evaluable pts. Correlatives included determination of PIK3CA mutation (mut) status; p16, EGFR and PTEN expression; and immunomodulatory cytokine levels. Results: From Dec 2009 – Mar 2011, 12 pts enrolled. Six pts withdrew prior to first planned response assessment, due to toxicity (5) or death (1), prompting referral to the Data Safety and Monitoring Committee and early closure. Grade ≥ 3 toxicities included fatigue (5), diarrhea (2), GI infection/peritonitis (2), dyspnea (2), HN edema (2), and neutropenia (1). Among 8 progression-evaluable pt, median PFS was 1.9 mos. Median OS was 4.1 mos. 4/12 tumors were p16(+); 4/10 were EGFR(+); 11/11 showed no PTEN expression. PIK3CA mut was present in 1/11; the mut(+) pt withdrew after 3 wk for diarrhea/peritonitis with minor response. There were no associations between tumor p16, EGFR or PTEN status and oncologic outcomes. Five of 6 toxicity-related withdrawals occurred in p16(-) pts. Immunomodulatory cytokine levels in pre- and post-temsirolimus plasma did not significantly differ or associate with toxicity. Two pts with ≥ 4.4 mos PFS were p16(-) and PIK3CA mut(-). Conclusions: The combination of erlotinib and temsirolimus was poorly tolerated in this population, with toxicities predominant in p16(-) pts. Although the sample size was small, this R/M cohort demonstrated lack of PTEN expression and 9% PIK3CA mut, justifying further investigation of PI3K/Akt/mTOR pathway inhibitors in selected HNSCC pts.