The role of histological subtypes in the survival of patients diagnosed with cutaneous or mucosal melanoma in the United States of America.

BACKGROUND: Literature presents limited information on histological subtypes and their association with other factors influencing the survival of melanoma patients. To explore the risk of death due to melanoma associated with histological subtypes, this retrospective study used the Surveillance, Epidemiology, and End Results program (SEER) data from 1998 to 2019. METHODS: A total of 27,532 patients consisting of 15,527 males and 12,005 females. The Hypertabastic Accelerated Failure Time model was used to analyze the impact of histology on the survival of patients with cutaneous or mucosal melanoma. RESULTS: The median survival time (MST) for cutaneous patients was 149 months, whereas those diagnosed with mucosal melanoma was 34 months. Nodular melanoma had a hazard ratio of 3.40 [95% CI: (2.94, 3.94)] compared to lentigo maligna melanoma. Across all histological subtypes, females had a longer MST, when compared to males. The hazard ratio (HR) of distant to localized melanoma was 9.56 [95% CI: (7.58, 12.07)]. CONCLUSIONS: Knowledge of patients' histological subtypes and their hazard assessment would enable clinicians and healthcare providers to perform personalized treatment, resulting in a lower risk of complication and higher survivability of melanoma patients. Significant factors were stage of the disease, age, histology, sex, and income. Focus should be placed on high-risk populations with severe and aggressive histological subtypes. Programs that emphasize preventive measures such as awareness, education, and early screening could reduce risk.

Analysis of Nonbattle Deaths Among U.S. Service Members in the Deployed Environment.

OBJECTIVE: Describe etiologies and trends in non-battle deaths (NBD) among deployed U.S. service members to identify areas for prevention. BACKGROUND: Injuries in combat are categorized as battle (result of hostile action) or nonbattle related. Previous work found that one-third of injured US military personnel in Iraq and Afghanistan had nonbattle injuries and emphasized prevention. NBD have not yet been characterized. METHODS: U.S. military casualty data for Iraq and Afghanistan from 2001 to 2014 were obtained from the Defense Casualty Analysis System (DCAS) and the Department of Defense Trauma Registry (DoDTR). Two databases were used because DoDTR does not capture prehospital deaths, while DCAS does not contain clinical details. Nonbattle injuries and NBD were identified, etiologies classified, and NBD trends were assessed using a weighted moving average and time-series analysis with autoregressive integrated moving average. Future NBD rates were forecast. RESULTS: DCAS recorded 59,799 casualties; 21.0% (n = 1431) of all deaths (n = 6745) were NBD. DoDTR recorded 29,958 casualties; 11.5% (n = 206) of all deaths (n = 1788) were NBD. After early fluctuations, NBD rates for both Iraq and Afghanistan stabilized at approximately 21%. Leading causes of NBD were gunshot wounds and vehicle accidents, accounting for 66%. Approximately 25% was self-inflicted. A 24% NBD rate was forecasted from 2015 through 2025. CONCLUSIONS: Approximately 1 in 5 deaths were NBD. The majority were potentially preventable, including a significant proportion of self-inflicted injuries. A single comprehensive data repository would facilitate future mortality monitoring and performance improvement. These data may assist military leaders with implementing targeted safety strategies.

Author Correction: Cancer Testis Antigen Promotes Triple Negative Breast Cancer Metastasis and is Traceable in the Circulating Extracellular Vesicles.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cisplatin combined with laser­activated nanotherapy as an adjuvant therapy for head and neck cancer.

Head and neck cancers (HNCs), in general, have a poor prognosis with a worldwide 5­year survival rate of <50%. Numerous HNC patients with locoregionally advanced, difficult­to­treat, inoperable, recurrent and drug­resistant tumors may require additional treatment options when the standard of care surgery, chemotherapy and radiation are not viable. The poor outcomes justify exploring strategies to increase the efficacy of lower doses of drugs, such as cisplatin, by combining these drugs with other treatment modalities and manipulating the dosing schedule. Cisplatin is a standard and effective anticancer drug; however, some patients cannot tolerate the side­effects or exhibit drug resistance. Adjuvant therapies may lower the effective dose, decrease side­effects, address drug resistance and improve overall survival outcomes, particularly for patients with difficult­to­treat tumors. The present study focuses on combining cisplatin with laser­activated nanotherapy (LANT), as an adjuvant HNC therapy, with the aim of enhancing the therapeutic efficacy of lower doses of cisplatin and decreasing treatment times. The results demonstrate the potential of cisplatin and LANT co­therapy as a possible addition to the adjuvant therapy options for HNC using 3 cell lines: Detroit 562, FaDu and CAL 27 cells. Combining cisplatin with LANT demonstrated up to a 5.4­fold greater therapeutic efficacy than with cisplatin monotreatment. The most effective combination in the present study was 1 µM Cis + 5 nM LANT, which demonstrated cell death comparable to 5.9, 4.2 and 5.3 µM of Cis monotreatment, in Detroit 562, FaDu and CAL 27 cells, respectively. This result suggests that a lower cisplatin dose may be combined with LANT to achieve the same therapeutic efficacy as that obtained with higher doses of cisplatin monotreatment. The combination of LANT and cisplatin suggests that LANT may enhance the therapeutic efficiency of low doses of cisplatin, decrease treatment times and improve patient outcomes.

Return on Investment of Free Colorectal Cancer Screening Tests in a Primarily Rural Uninsured or Underinsured Population in Northeast Texas.

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer in the USA. Its economic impact is extensive, and preventive screening services are warranted to help prevent it. OBJECTIVE: We sought to examine the return on investment, in terms of reduced costs attributed to cancer prevention, of a CRC screening outreach program providing education and screening in a primarily rural region targeting the uninsured and underinsured. METHODS: The expenditures of the Northeast Texas CRC screening program were calculated for the years of 2016 and 2017. Prices ($US) were adjusted for inflation and converted to year 2017 values. The costs saved were calculated using the estimated costs of CRC care present in the literature. RESULTS: For fiscal years 2016 and 2017, the program provided an average return of $US1.46-2.06 for every tax dollar spent. Estimated cost avoidance was $US165,080 per avoided case and estimated cost avoidance of $US245,601 among early-stage cancer cases detected, resulting in potential savings ranging from $US3,893,676 to $US4,837,923. CONCLUSION: A CRC outreach program providing education and screening operating in less densely populated regions yields a positive return on investment.

Cervical Cancer Prevention in Racially Disparate Rural Populations.

Background: Undergoing a timely Pap smear, high-risk human papilloma virus (HPV)- and colposcopy-based testing can reduce HPV-associated cervical cancer (CC) development in women. However, in rural areas, women and minorities without insurance do not undergo periodic assessment and remain at greater risk of HPV infection and CC. Methods: In this study, 173 women from rural East Texas with various ethnic backgrounds were examined thorough HPV/Pap-based testing and colposcopic assessment. Results: Of the 113 informative cases, 77% (87/113) were positive for high-risk HPV infection and 23% of subjects (26/113) were negative. Associations between HPV positivity with young age (p = 0.002), and a low number of pregnancy (p = 0.004) and births (p = 0.005) were evident. Women with long-term use of contraceptives (OR 1.93, 95% CI, 0.80-4.69) were associated with increased risk of HPV infection. African-American women had a higher risk of abnormal Pap outcome compared to Caucasians (OR 5.31, 95% CI, 0.67-42.0). HPV seemed to be a predictor of abnormal Pap outcome (OR 1.77, 95% CI, 0.48-6.44) in these subjects. Unmarried/widowed/divorced women had an increased abnormal Pap test outcome compared to married women or women living with a partner (p = 0.01), with over 278% increased odds (OR 3.78 at 95% CI, 1.29-11.10). Insured women undergoing periodic checkups were detected early with high-risk HPV infection and abnormal Pap test/colposcopic outcome. Conclusions: Comprehensive and timely screening of uninsured women and minorities in rural East Texas are warranted, which could potentially prevent the onset of HPV-associated CC.

Cancer Testis Antigen Promotes Triple Negative Breast Cancer Metastasis and is Traceable in the Circulating Extracellular Vesicles.

Triple negative breast cancer (TNBC) has poor survival, exhibits rapid metastases, lacks targeted therapies and reliable prognostic markers. Here, we examined metastasis promoting role of cancer testis antigen SPANXB1 in TNBC and its utility as a therapeutic target and prognostic biomarker. Expression pattern of SPANXB1 was determined using matched primary cancer, lymph node metastatic tissues and circulating small extracellular vesicles (sEVs). cDNA microarray analysis of TNBC cells stably integrated with a metastasis suppressor SH3GL2 identified SPANXB1 as a potential target gene. TNBC cells overexpressing SH3GL2 exhibited decreased levels of both SPANXB1 mRNA and protein. Silencing of SPANXB1 reduced migration, invasion and reactive oxygen species production of TNBC cells. SPANXB1 depletion augmented SH3GL2 expression and decreased RAC-1, FAK, A-Actinin and Vinculin expression. Phenotypic and molecular changes were reversed upon SPANXB1 re-expression. SPANXB1 overexpressing breast cancer cells with an enhanced SPANXB1:SH3GL2 ratio achieved pulmonary metastasis within 5 weeks, whereas controls cells failed to do so. Altered expression of SPANXB1 was detected in the sEVs of SPANXB1 transduced cells. Exclusive expression of SPANXB1 was traceable in circulating sEVs, which was associated with TNBC progression. SPANXB1 represents a novel and ideal therapeutic target for blocking TNBC metastases due to its unique expression pattern and may function as an EV based prognostic marker to improve TNBC survival. Uniquely restricted expression of SPANXB1 in TNBCs, makes it an ideal candidate for targeted therapeutics and prognostication.

Reproductive factors and breast cancer risk: A meta-analysis of case-control studies in Indian women.

BACKGROUND/OBJECTIVE: India is the world's most biodiverse region and is undergoing a period of dramatic social and economic change. Due to population's explosion, climate change and lax implementation of environmental policies, the incidence of breast cancer is increasing. From population-based cancer registry data, breast cancer is the most common cancer in women in urban registries where it constitutes more than 30% of all cancers in females. We conducted a meta-analysis of all breast cancer case-control studies conducted in India during 1991-2018 to find pooled estimates of odds ratio (OR). MATERIALS AND METHODS: Eligible studies were identified through a comprehensive literature search of PubMed, EMBASE, and HINARI databases from 1991 to January 2018. This analysis included 24 observational studies out of 34 that reported the case-control distribution of reproductive factors, body mass index (BMI) and type of residence. The analysis was performed using RevMan 5.3 (Review Manager, 2017) applying the random-effects model. RESULTS: A total of 21,511 patients (9889 cases and 11,622 controls) were analyzed, resulting in statistically significant association between breast cancer and the following reproductive factors: never breastfeed (OR: 3.69; 95% confidence interval [CI]: 1.70, 8.01), menopausal age >50 years (OR: 2.88; 95% CI: 1.85, 3.85), menarche age <13 years (OR: 1.83; 95% CI: 1.34, 2.51), null parity (OR: 1.58; 95% CI: 1.21, 2.06), postmenopause (OR: 1.35; 95% CI: 1.13, 1.62), and age at the 1st pregnancy >25 years (OR: 1.57; 95% CI: 1.37, 1.80). Family history (FH) of breast cancer (OR: 5.33; 95% CI: 2.89, 9.82), obesity (OR: 1.19; 95% CI: 1.00, 1.42), and urban residence (OR: 1.22; 95% CI: 1.03, 1.44) were also found to be significant risk factors. CONCLUSION: The results of this meta-analysis are indicative of significant associations between reproductive factors and breast cancer risk, profoundly so among women experiencing menopause after the age of 50, women who never breastfeed and FH of breast cancer.

A Longitudinal Pilot Study for Examining Symptom Reduction in Patients With Cancer in a Palliative Care Program: A Primarily Rural Northeast Texas Population.

Many patients with cancer live in rural areas and research is lacking on the efficacy of palliative care programs in rural community settings. This pilot study was conducted in a primarily rural setting where healthcare professionals delivered palliative care to 52 mostly lower income patients with a variety of cancers. They were assessed for physical, financial, psychosocial and overall symptom intensity at baseline and at three consequent assessments. This pilot study demonstrated the potential efficacy of an outpatient palliative care program in a mostly rural setting in the reduction of physical, psychosocial, and overall symptom intensity in patients with cancer.

Microbiome Diversity in Sputum of Nontuberculous Mycobacteria Infected Women with a History of Breast Cancer.

BACKGROUND/AIMS: The nontuberculous mycobacterial lung disease (NTM), caused by Mycobacterium avium complex (MAC) is an increasing health problem in the USA and worldwide. The NTM disease is prevalent in Caucasian women with a current diagnosis or history of breast cancer (BCa), posing a significant challenge towards treatment. We hypothesize that NTM affected women with considerable therapeutic resistance may harbor pathogenic microbes other than nontuberculous mycobacterium, aiding in disease progression and therapeutic resistance. METHODS: We assessed microbiome diversity in sputa from healthy women, women with nontuberculous mycobacterial lung disease (NTM) and women with both nontuberculous mycobacterial lung disease and breast cancer (NTM-BCa). First, we collected sputa and isolated DNA from sputa of these healthy women and women with NTM and NTM-BCa. We also isolated DNA from sera derived extracellular vesicles from women with NTM-BCa. To identify diverse pathogenic microbes in various groups of subjects, we then performed 16S rDNA sequencing. Data analysis was performed utilizing the analytical pipelines at the Center for Metagenomic and Microbiome Research (CMMR), Baylor College of Medicine. RESULTS: A large community of resident microbes, including bacteria, virus, Archeas and Fungi live in the human body are being increasingly recognized as the key components of human health and disease. We identified a diverse microbiome community in the sputa and the extracellular vesicles dominated by Streptococcus, Haemophillus, Veillonella, Neisseria, Prevotella, Fusobacterium, Bacteroides, Allistipes, Faecalibacterium and Staphylococcus in women with nontuberculous mycobacterial lung disease as well as women with both nontuberculous mycobacterial lung disease and breast cancer. Some of these genera, including Fusobacterium, Bacteroides, and Allistipes have estrobolome activity and associated with breast and other neoplasms. CONCLUSION: This work confirms the presence of a distinct pathogenic microbiome other than nontuberculous mycobacteria in the sputa and the circulating extracellular vesicles of these patients. This information could be useful for better therapeutic design to treat the NTM patients.

Sputum Detection of Predisposing Genetic Mutations in Women with Pulmonary Nontuberculous Mycobacterial Disease.

Nontuberculous mycobacterial lung disease (NTM), including Mycobacterium avium complex (MAC), is a growing health problem in North America and worldwide. Little is known about the molecular alterations occurring in the tissue microenvironment during NTM pathogenesis. Utilizing next generation sequencing, we sequenced sputum and matched lymphocyte DNA in 15 MAC patients for a panel of 19 genes known to harbor cancer susceptibility associated mutations. Thirteen of 15 NTM subjects had a diagnosis of breast cancer (BCa) before or after NTM infection. Thirty three percent (4/12) of these NTM-BCa cases exhibited at least 3 somatic mutations in sputa compared to matched lymphocytes. Twenty four somatic mutations were detected with at least one mutation in ATM, ERBB2, BARD1, BRCA1, BRCA2, AR, TP53, PALB2, CASP8, BRIP1, NBN and TGFB1 genes. All four NTM-BCa patients harboring somatic mutations also exhibited 15 germ line BRCA1 and BRCA2 mutations. The two NTM subjects without BCa exhibited twenty somatic mutations spanning BRCA1, BRCA1, BARD1, BRIP1, CHEK2, ERBB2, TP53, ATM, PALB2, TGFB1 and 3 germ line mutations in BRCA1 and BRCA2 genes. A single copy loss of STK11 and AR gene was noted in NTM-BCa subjects. Periodic screening of sputa may aid to develop risk assessment biomarkers for neoplastic diseases in NTM patients.

Postoperative radiosurgery for the treatment of metastatic brain tumor: Evaluation of local failure and leptomeningeal disease.

In patients undergoing surgical resection of a metastatic brain tumor, whole brain radiation therapy reduces the risk of recurrence and neurologic death. Focal radiation has the potential to mitigate neurocognitive side effects. We present an institutional experience of postoperative radiosurgery for the treatment of brain metastases. A retrospective review of a prospectively maintained institutional radiosurgery database was performed for the years 2005-2015 identifying all adult patients treated with postoperative radiosurgery to the tumor bed. Primary endpoints include local recurrence and postoperative LMD. Kaplan-Meier curves and Cox regression were used to evaluate time to local recurrence and postoperative LMD. Ninety-one patients received adjuvant focal radiation for a brain metastasis. Median radiographic follow-up among patients who had not developed a local failure was 9 months. Of the 91 patients, 20 (22%) developed local recurrence and 32 (35%) experienced postoperative LMD. Freedom from local recurrence and LMD at 1 year was 84% and 69%, respectively. In multivariable models, predictors of local failure included the presence of more than one brain metastasis (HR = 2.65, p = .04) with a preoperative tumor diameter of >3 cm (HR = 4.16, p = .06) trending toward significance. There was a trend to a higher risk of LMD with >1 tumor (HR 2.07, p = .06) and breast cancer (HR 2.37, p = .07). More than one metastasis is an independent predictor of local and leptomeningeal failure following postoperative radiosurgery. The high rate of LMD was likely related to the liberal definition of LMD to include focal dural recurrences.

Pilot phase II study of metronomic chemotherapy in combination with bevacizumab in patients with advanced non-squamous non-small cell lung cancer.

INTRODUCTION: The goal of this study was to explore the efficacy and tolerability of metronomic chemotherapy, a novel anti-angiogenic treatment strategy, in combination with bevacizumab in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Subjects with newly diagnosed stage IV NSCLC were treated with 4-week cycles of paclitaxel 80mg/m2 and gemcitabine 300mg/m2 weekly for three weeks, plus bevacizumab 10mg/kg every two weeks. Radiologic assessments were performed every 8 weeks. The primary endpoint was progression free survival (PFS). An exploratory objective was to correlate plasma levels of angiogenic biomarkers with treatment response. RESULTS: Thirty-nine subjects were included in the intent to treat (ITT) analysis. The objective response rate (ORR) was 56%, the median PFS was 8.5 months, and median overall survival (OS) was 25.5 months. The PFS rate at 6, 12, and 24 months was 61%, 21%, and 11% respectively. The OS rate at 12 and 24 months was 74% and 53% respectively. Treatment was well tolerated, without significant myelosuppressive, gastrointestinal, or neurologic events. Subjects with less than median baseline values of angiopoietin-2 and IL-8 experienced significantly longer PFS. Longer OS was associated with subjects with less than the median baseline values for PLGF and angiopoietin-2. There were statistically significant differences in median values of several biomarkers between cycles 1 and 3 in subjects with objective responses. CONCLUSIONS: The combination of paclitaxel and gemcitabine, delivered in a metronomic schedule, in combination with bevacizumab, appears to be an effective and tolerable treatment strategy in patients with advanced NSCLC.

Sociodemographic Patterns of Chronic Disease: How the Mid-South Region Compares to the Rest of the Country.

INTRODUCTION: States in the Mid-South region are among the least healthy in the nation. This descriptive study examines sociodemographic differences in the distribution of chronic diseases and health-related behaviors in the Mid-South versus the rest of the U.S., identifying subgroups at increased risk of chronic disease. METHODS: Data were obtained from the 2013 Behavioral Risk Factor Surveillance System; analyses were completed in January 2016. Twelve chronic health conditions were assessed: obesity, diabetes, high blood pressure, coronary heart disease, myocardial infarction, stroke, chronic kidney disease, cancer, arthritis, asthma, chronic obstructive pulmonary disease, and depression. Evaluated health-related behaviors included smoking, physical activity, and fruit and vegetable consumption. Age-standardized percentages were reported using complex survey design parameters to enhance generalizability. RESULTS: The Mid-South population had increased rates of chronic disease and worse health-related behaviors than the rest of the U.S. POPULATION: Mid-South blacks had the highest percentages of obesity, diabetes, high blood pressure, and stroke of all subgroups, along with lower physical activity and fruit and vegetable consumption. In both races and regions, individuals with lower income and education had higher rates of chronic disease and unhealthy behaviors than those with higher income and education. However, black men in both regions had higher obesity and cancer rates in the higher education category. In general, education-level disparities were more pronounced in health-related behaviors, whereas income-level disparities were more pronounced in chronic health conditions. CONCLUSIONS: Future studies should test tailored interventions to address the specific needs of population subgroups in order to improve their health.

Racial and Gender Disparities in Incidence of Lung and Bronchus Cancer in the United States: A Longitudinal Analysis.

BACKGROUND: Certain population groups in the United States carry a disproportionate burden of cancer. This work models and analyzes the dynamics of lung and bronchus cancer age-adjusted incidence rates by race (White and Black), gender (male and female), and prevalence of daily smoking in 38 U.S. states, the District of Columbia, and across eight U.S. geographic regions from 1999 to 2012. METHODS: Data, obtained from the U.S. Cancer Statistics Section of the Centers for Disease Control and Prevention, reflect approximately 77% of the U.S. population and constitute a representative sample for making inferences about incidence rates in lung and bronchus cancer (henceforth lung cancer). A longitudinal linear mixed-effects model was used to study lung cancer incidence rates and to estimate incidence rate as a function of time, race, gender, and prevalence of daily smoking. RESULTS: Between 1999 and 2012, age-adjusted incidence rates in lung cancer have decreased in all states and regions. However, racial and gender disparities remain. Whites continue to have lower age-adjusted incidence rates for this cancer than Blacks in all states and in five of the eight U.S. geographic regions. Disparities in incidence rates between Black and White men are significantly larger than those between Black and White women, with Black men having the highest incidence rate of all subgroups. Assuming that lung cancer incidence rates remain within reasonable range, the model predicts that the gender gap in the incidence rate for Whites would disappear by mid-2018, and for Blacks by 2026. However, the racial gap in lung cancer incidence rates among Black and White males will remain. Among all geographic regions, the Mid-South has the highest overall lung cancer incidence rate and the highest incidence rate for Whites, while the Midwest has the highest incidence rate for Blacks. Between 1999 and 2012, there was a downward trend in the prevalence of daily smokers in both genders. However, males have significantly higher rates of cigarette smoking than females at all time points. The highest and lowest prevalence of daily smoking are found in the Mid-South and New England, respectively. There was a significant correlation between lung cancer incidence rates and smoking prevalence in all geographic regions, indicating a strong influence of cigarette smoking on regional lung cancer incidence rates. CONCLUSION: Although age-adjusted incidence rates in lung cancer have decreased throughout the U.S., racial and gender disparities remain. This longitudinal model can help health professionals and policy makers make predictions of age-adjusted incidence rates for lung cancer in the U.S. in the next five to ten years.

Mitochondrial Reprogramming Regulates Breast Cancer Progression.

PURPOSE: The goal of this study was to understand the role of altered mitochondrial function in breast cancer progression and determine the potential of the molecular alteration signature in developing exosome-based biomarkers. EXPERIMENTAL DESIGN: This study was designed to characterize the critical components regulating mitochondrial function in breast tumorigenesis. Experiments were conducted to assess the potential of these molecules for exosome-based biomarker development. RESULTS: We observed a remarkable reduction in spontaneous metastases through the interplay in mitochondria by SH3GL2, vesicular endocytosis-associated protein and MFN2, an important regulator of mitochondrial fusion. Following its overexpression in breast cancer cells, SH3GL2 translocated to mitochondria and induced the production of superoxide and release of cytochrome C from mitochondria to the cytoplasm. These molecular changes were accompanied by decreased lung and liver metastases and primary tumor growth. SH3GL2 depletion reversed the above phenotypic and associated molecular changes in nontumorigenic and tumorigenic breast epithelial cells. Loss of SH3GL2 and MFN2 expression was evident in primary human breast cancer tissues and their positive lymph nodes, which was associated with disease progression. SH3GL2 and MFN2 expression was detected in sera exosomes of normal healthy women, but barely detectable in the majority of the women with breast cancer exhibiting SH3GL2 and MFN2 loss in their primary tumors. CONCLUSIONS: This study identified a new mitochondria reprogramming pathway influencing breast cancer progression through SH3GL2 and MFN2. These proteins were frequently lost in breast cancer, which was traceable in the circulating exosomes. Clin Cancer Res; 22(13); 3348-60. ©2016 AACR.

PI3K/AKT/mTOR and sonic hedgehog pathways cooperate together to inhibit human pancreatic cancer stem cell characteristics and tumor growth.

Cancer stem cells (CSCs) play major roles in cancer initiation, progression, and metastasis. It is evident from growing reports that PI3K/Akt/mTOR and Sonic Hedgehog (Shh) signaling pathways are aberrantly reactivated in pancreatic CSCs. Here, we examined the efficacy of combining NVP-LDE-225 (PI3K/mTOR inhibitor) and NVP-BEZ-235 (Smoothened inhibitor) on pancreatic CSCs characteristics, microRNA regulatory network, and tumor growth. NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting pancreatic CSC's characteristics and tumor growth in mice by acting at the level of Gli. Combination of NVP-LDE-225 and NVP-BEZ-235 inhibited self-renewal capacity of CSCs by suppressing the expression of pluripotency maintaining factors Nanog, Oct-4, Sox-2 and c-Myc, and transcription of Gli. NVP-LDE-225 co-operated with NVP-BEZ-235 to inhibit Lin28/Let7a/Kras axis in pancreatic CSCs. Furthermore, a superior interaction of these drugs was observed on spheroid formation by pancreatic CSCs isolated from Pankras/p53 mice. The combination of these drugs also showed superior effects on the expression of proteins involved in cell proliferation, survival and apoptosis. In addition, NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting EMT through modulation of cadherin, vimentin and transcription factors Snail, Slug and Zeb1. In conclusion, these data suggest that the combined inhibition of PI3K/Akt/mTOR and Shh pathways may be beneficial for the treatment of pancreatic cancer.

Phase I/IIa study of sequential chemotherapy regimen of bendamustine/irinotecan followed by etoposide/carboplatin in untreated patients with extensive disease small cell lung cancer (EDSCLC).

PURPOSE: The sequence bendamustine (B) + Irinotecan (I) followed by etoposide (E) + carboplatin (C) was hypothesized to increase progression-free survival (PFS) and overall survival (OS) in untreated extensive-disease small cell lung cancer (EDSCLC) patients compared to historical controls by exploiting mitotic catastrophe. Absent expression of ERCC-1 and expression of topoisomerases were hypothesized to be predictive for PFS and OS. METHODS: This was a phase I/IIa trial in 30 patients to determine the maximum tolerated dose (MTD) of B + I and the PFS of B + I E + C with secondary end points including overall response rate (ORR) and OS. Biomarkers measured by immunohistochemistry (IHC) obtained from diagnostic specimens were correlated with outcome. RESULTS: The MTD of B + I was not reached. During treatment with B + I, there were two grade 5 toxicities from neutropenic sepsis and metabolic encephalopathy. Other toxicities included fatigue, nausea/vomiting, diarrhea, and weight loss. For the sequence, the PFS and OS were 6.0 months and 10 months, respectively. The ORR for B + I and the sequence were 82% and 83%, respectively. Topoisomerase-2 expression was predictive for TTP and OS, but absent ERCC-1 expression was not, contrary to our hypothesis. CONCLUSIONS: B + I is an active regimen in EDSCLC. Toxicities included two grade 5 events but were otherwise manageable. The novel sequence B + I E + C increased PFS and OS compared to historical controls. Correlative studies are conflicting regarding the mechanism of action of this novel sequence.

Clinical Implications of Rabphillin-3A-Like Gene Alterations in Breast Cancer.

For the rabphillin-3A-like (RPH3AL) gene, a putative tumor suppressor, the clinical significance of genetic alterations in breast cancers was evaluated. DNA and RNA were extracted from formalin-fixed, paraffin-embedded (FFPE) cancers and matching normal tissues. DNA samples were assessed for loss of heterozygosity (LOH) at the 17p13.3 locus of RPH3AL and the 17p13.1 locus of the tumor suppressor, TP53. RPH3AL was sequenced, and single nucleotide polymorphisms (SNPs) were genotyped. RNA samples were evaluated for expression of RPH3AL, and FFPE tissues were profiled for its phenotypic expression. Alterations in RPH3AL were correlated with clinicopathological features, LOH of TP53, and patient survival. Of 121 cancers, 80 had LOH at one of the RPH3AL locus. LOH of RHP3AL was associated with nodal metastasis, advanced stage, large tumor size, and poor survival. Although ~50% were positive for LOH at the RPH3AL and TP53 loci, 19 of 105 exhibited LOH only at the RPH3AL locus. Of these, 12 were non-Hispanic Caucasians (Whites), 15 had large tumors, and 12 were older (>50 years). Patients exhibiting LOH at both loci had shorter survival than those without LOH at these loci (log-rank, P = 0.014). LOH at the TP53 locus alone was not associated with survival. Analyses of RPH3AL identified missense point mutations in 19 of 125 cases, a SNP (C>A) in the 5'untranslated region at -25 (5'UTR-25) in 26 of 104, and a SNP (G>T) in the intronic region at 43 bp downstream to exon-6 (intron-6-43) in 79 of 118. Genotype C/A or A/A of the SNP at 5'UTR-25 and genotype T/T of a SNP at intron-6-43 were predominantly in Whites. Low levels of RNA and protein expression of RPH3AL were present in cancers relative to normal tissues. Thus, genetic alterations in RPH3AL are associated with aggressive behavior of breast cancers and with short survival of patients.