The absolute lymphocyte count can predict the overall survival of patients with non-small cell lung cancer on nivolumab: a clinical study.

INTRODUCTION: The neutrophil-to-lymphocyte (ANC/ALC) ratio is associated with worse prognosis in patients with NSCLC on immunotherapies, but the role of ALC remains unclear. The previous radiation therapy causes lymphopenia, and given approaches of combining radiation with immunotherapies, it is critical to better understand the impact of peripheral lymphocytes. PATIENTS AND METHODS: We evaluated retrospectively 22 patients with advanced NSCLC treated with nivolumab at Boston Medical Center from January 2014 to September 2016 and correlated the peripheral blood counts with the overall survival (OS) and overall time on treatment. We assessed the effect of the previous radiation on peripheral blood counts and clinical outcomes. RESULTS: Baseline ALC and ANC/ALC ratios are positively and negatively correlated, respectively, with the OS on nivolumab. The ALC and ALC/WBC ratios at 6 weeks on treatment are positively associated with the OS. Kaplan-Meier analysis at baseline and at 6 weeks showed significantly increased OS in the group of patients with the highest ALC. The previous radiation therapy was positively correlated with the ANC and negatively correlated with the ALC/WBC ratio at 8 weeks after the initiation of nivolumab. CONCLUSION: Our finding that ALC at baseline and at 6 weeks on treatment is positively correlated with the OS provides an easily obtained predictive marker. Our result that the previous radiation is associated with higher ANC and lower ALC during treatment supports that the combination of radiation therapy with immunotherapy should be carefully applied and potentially peripheral blood counts can be utilized to stratify patients for this approach.

Association of CD133 polymorphisms and response to bevacizumab in patients with metastatic colorectal cancer.

BACKGROUND: Bevacizumab, an angiogenesis inhibitor is used in regimens for metastatic colorectal cancer (CRC). A minority of cancer cells with characteristics of cancer stem cells (CSC) may be responsible for progression and development of chemotherapy resistance in this disease. CD133 is a well-known CSC marker and is associated with angiogenesis, poor prognosis and resistance to chemotherapy. OBJECTIVE: The purpose of our study was to evaluate the association between the rs3130 and rs2286455 polymorphisms of the CD133 gene and the response, toxicity, and overall survival of patients with CRC on bevacizumab-based treatment. METHODS: Forty-three patients receiving bevacizumab, irinotecan and capecitabine and 15 patients receiving bevacizumab, irinotecan and 5-FU were included. Efficacy and toxicity were evaluated. KRAS mutation analysis and rs3130 and rs2286455 polymorphisms genotyping in the tumors and peripheral blood respectively were performed with PCR-RFLP. RESULTS: No association between KRAS mutated alleles and response was found. The rs3130 CC genotype was associated with reduced toxicity of treatments (p= 0.0017), and with lower overall survival on bevacizumab (p= 0.002). CONCLUSIONS: The CC genotype of rs3130 polymorphism in the CD133 gene can predict poorer overall survival in patients with metastatic CRC on bevacizumab which cannot be attributed to increased treatment toxicity.

DNA damage response and prostate cancer: defects, regulation and therapeutic implications.

DNA damage response (DDR) includes the activation of numerous cellular activities that prevent duplication of DNA lesions and maintain genomic integrity, which is critical for the survival of normal and cancer cells. Specific genes involved in the DDR such as BRCA1/2 and P53 are mutated during prostate cancer progression, while various oncogenic signaling such as Akt and c-Myc are activated, enhancing the replication stress and increasing the genomic instability of cancer cells. These events may render prostate cancer cells particularly sensitive to inhibition of specific DDR pathways, such as PARP in homologous recombination DNA repair and Chk1 in cell cycle checkpoint and DNA repair, creating opportunities for synthetic lethality or synergistic cytotoxicity. Recent reports highlight the critical role of androgen receptor (AR) as a regulator of DDR genes, providing a rationale for combining DNA-damaging agents or targeted DDR inhibitors with hormonal manipulation or AR inhibition as treatment for aggressive disease. The aims of this review are to discuss specific DDR defects in prostate cancer that occur during disease progression, to summarize recent advances in understanding the regulation of DDR in prostate cancer, and to present potential therapeutic opportunities through combinational targeting of the intact components of DDR signaling pathways.

Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches.

Prostate cancer is the second-leading cause of cancer-related mortality in men in Western societies. Androgen receptor (AR) signaling is a critical survival pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally advanced and metastatic disease. Although a majority of patients initially respond to ADT, most will eventually develop castrate resistance, defined as disease progression despite serum testosterone levels of <20 ng/dl. The recent discovery that AR signaling persists during systemic castration via intratumoral production of androgens led to the development of novel anti-androgen therapies including abiraterone acetate and enzalutamide. Although these agents effectively palliate symptoms and prolong life, metastatic castration-resistant prostate cancer remains incurable. An increased understanding of the mechanisms that underlie the pathogenesis of castrate resistance is therefore needed to develop novel therapeutic approaches for this disease. The aim of this review is to summarize the current literature on the biology and treatment of castrate-resistant prostate cancer.

Post-colectomy assessment of gastrointestinal function: a prospective study on colorectal cancer patients.

BACKGROUND: Anatomical changes after intestinal resection and the effects of adjuvant treatment for colorectal cancer may lead to gastrointestinal disturbances. The aim of our study was to assess gastrointestinal function using validated health-related quality of life (HRQoL) questionnaires that are able to reliably quantify patients' symptoms. METHODS: Two hundred and eighty-nine colorectal cancer patients underwent HRQoL assessment preoperatively and at 3,6 and 12 months postoperatively. They were evaluated with the Gastrointestinal Quality of Life Index (GIQLI) ["global" and "symptoms" scales and questions 3 ("bloating"), 4 ("excessive gas"), 6 ("gurgling noises"), 7 ("frequent bowel movements (BMs)"), 30 ("urgent BMs"), 31 ("diarrhea"), 32 ("constipation"), 36 ("uncontrolled stools")] and the European Organization for Research and Treatment of Cancer (EORTC) modules QLQ-C30 (symptom scales: "constipation" and "diarrhea") and QLQ-CR29 (symptom scales: "defecation problems," "incontinence," and "bloating"). RESULTS: GIQLI "global" and "symptom" indices and the majority of single-item scores and the EORTC QLQ-C30 "constipation" and "diarrhea" subscales showed significant postoperative improvement (p < 0.05). Females and younger age (<70 years) patients appeared to have worse postoperative gastrointestinal function. Rectal cancer patients had more "urgent BMs," "uncontrolled stools" and worse "global" and "symptom" scores at 3 months and more "diarrhea" at 3 and 6 months than colon cancer patients (p < 0.03). Right colectomy patients had less "excessive passage of gas," "constipation," and "uncontrolled stools" than left colectomy patients (3 months, p < 0.01). Anterior resection patients faced more gastrointestinal difficulties, especially in the first 6 months after surgery. Adverse effects related to stage and adjuvant treatment were predominant only at baseline (p < 0.05). GIQLI "diarrhea" and "constipation" scores were correlated with the respective EORTC QLQ-C30 domains (p = 0.0001). CONCLUSIONS: Overall, gastrointestinal function is improved after colorectal cancer surgery. However, women and younger patients are at higher risk of postoperative gastrointestinal dysfunction.

Prospective evaluation of health-related quality of life after laparoscopic colectomy for cancer.

BACKGROUND: The aim of the present study was to prospectively determine health-related quality of life (HRQoL) changes and affecting factors after elective laparoscopic colectomy for cancer. METHODS: The SF-36, EORTC QLQ-C30 and QLQ-CR29, and Gastrointestinal Quality of life Index (GIQLI) were used to assess 85 patients preoperatively and at 1, 3, 6, and 12 months. RESULTS: An initial drop form baseline values was observed in 3 of 8 SF-36 domains, 3 of 5 QLQ-C30 functional scales and 1 of 5 GIQLI subscales. Emotional functioning (EF) was better postoperatively even from the first month (p = 0.03). Most functional domains were improved compared to baseline. The statistically significant changes (p < 0.05) were in the SF-36: general health (GH) (3 months), physical function (PF) (12 months) and role limitations due to emotional problems (12 months); in the QLQ-C30: EF (12 months); in the GIQLI: the global score and PF at 12 months and EF (3, 6, 12 months). From the first month after surgery, most QLQ-C30 "symptom" items were better than baseline. QLQ-CR29 "anxiety" and the "defecation problems" scales were significantly better than baseline at 1, 12 and at 6, 12 months (p < 0.05). Advanced stage (III) and chemotherapy were linked to worse EF, social function (SF), GH and global quality of life (QOL) at 3 and 6 months (p < 0.01). Males appeared to have a worse HRQoL than females at 3 and 6 months, and in 5 of 8 SF-36 domains and 3 of 5 GIQLI subscales at 12 months (p < 0.05). According to the QLQ-CR29, rectal surgery was associated more often with "impotence," "stoma problems" and "incontinence" up to 6 months, and ostomies with "embarrassment" and "stoma problems" (p < 0.05). CONCLUSIONS: HRQoL generally improved over the first year after laparoscopic colectomy reaching even better levels than before surgery. There was an early postoperative improvement in patients' emotional status. The main factors affecting HRQoL seem to be tumor stage, chemotherapy and male sex.

Serotonin transporter and G protein beta 3 subunit gene polymorphisms in Greeks with irritable bowel syndrome.

BACKGROUND: Polymorphisms in the serotonin transporter (SERT) and G protein ß3 subunit (GNB3) genes might contribute to the pathophysiology of irritable bowel syndrome (IBS). Association studies of SERT and GNB3 polymorphisms and IBS have shown diverse results among different populations, which might be due to subject composition differences. AIMS: The aim of the study was to assess the potential association between SERT and GNB3 polymorphisms and IBS in Greeks. METHODS: A total of 124 patients with IBS diagnosed according to the Rome III criteria and 238 healthy individuals were included in the study. SERT and GNB3 gene polymorphisms were genotyped using polymerase chain reaction-based methods. RESULTS: It was shown that the frequencies of the SS genotype and S allele of the serotonin transporter polymorphism were significantly associated with IBS (P = 0.0314 and P = 0.019, respectively). TT genotype and T allele frequencies of G protein ß3 subunit showed also significant difference between the IBS patients and healthy controls IBS (P = 0.0163 and P = 0.0001, respectively). None of the clinical symptoms analyzed was significantly associated with the polymorphisms tested. CONCLUSIONS: The results suggest that SERT and GNB3 gene polymorphisms might be associated with irritable bowel syndrome predisposition in Greeks.