Federica Mazzuca

Predictors of existential and religious well-being among cancer patients

Well-being and mental health are not only direct functions of amount of stress, but also depend on how people appraise and face critical situations. Spiritual well-being seems to be a central component of psychological health in physically healthy individuals and it offers some protection against end-of-life despair in those with chronic diseases. In this study, 250 out and in-patients with a cancer diagnosis were interviewed with standardised instruments to measure two aspects of spirituality, existential and religious well-being, coping strategies, psychological state, and quality of life (QoL). Using multivariate logistic regression models we found that coping strategies characterized by acceptance and positive reinterpretation of the stressor, and the absence of anxiety disorder, independently increased the likelihood of the existential well-being (Odds Ratio, OR, 7.7, and OR, 4.5, respectively), whereas religious well-being was not significantly associated with these variables. Our findings show that existential and religious well-being may be very different. A spirituality-based intervention could be differently utilized by patients with different beliefs, cognitive and behaviour characteristics. Measure of coping strategies and psychological state should be part of routine management of cancer patients.

The importance of lymph node retrieval and lymph node ratio following preoperative chemoradiation of rectal cancer

Preoperative chemoradiation (CRT) for rectal cancer decreases the number of examined lymph nodes (NELN) found in the resected specimen. However, the prognostic role of lymph node evaluation including overall numbers and the lymph node ratio (LNR) in patients having preoperative CRT have not yet been defined. The study has assessed the influence of CRT on the NELN and on lymph node number and LNR on the survival of patients with rectal cancer.

Cross-talk between microbiota and immune fitness to steer and control response to anti PD-1/PDL-1 treatment.

Immune Checkpoint Inhibitors (ICIs) are improving the survival of cancer patients, however only the 20-30% of treated patients present clinical benefits. Toxicity represents the major cause of reduced dosage, delayed drug administration and therapy discontinuation. Hence in the context of multiple treatment possibilities, the identification of predictive markers of response and toxicity is a challenging approach for drug selection in order to obtain the best clinical benefit while minimizing the side effects. The loss of the protective function of intestinal barriers that interacts with the environment measured as increased intestinal permeability and the changes occurring in the microbiota composition have been proposed as a mechanism potentially explaining the pathogenesis of immune related toxicity. In this review we discuss the new perspectives on the involvement of PD-1 and PDL-1 in the cross talk between gut microbiota and immune fitness and how gut microbiota impacts on the efficacy of anti-PD-1 and anti-PDL-1 treatments in cancer.

Being positive despite illness: The contribution of positivity to the quality of life of cancer patients.

Objective: The purpose of this study was to examine the longitudinal relationship between Positivity (POS), defined as a stable disposition to view at experience under a positive outlook, and physical and psychological functioning in a sample of cancer patients immediately after diagnosis and one year later. Methods: A total of 110 patients (40% males) with pulmonary, colorectal and breast cancer, aged 30–75 (M age = 59.62; SD = 10.33), have been prospectively enrolled between 2012 and 2013, at the S. Andrea Hospital in Rome. All patients were previously aware of their diagnosis. A follow-up one year after diagnosis was conducted. We used structural equation modeling in order to analyse the specific effects of POS on functioning impairment from diagnosis to follow up. Results: POS was associated with less functioning impairment both at diagnosis and follow-up assessments. Furthermore, POS level at diagnosis continued to be associated with less functioning impairment one year later, after controlling for its stability. Conclusions: Patients with higher level of POS tended to report less symptoms associated with negative affect such as anxiety and despondency and to preserve their habitual relationships and social roles. POS may act as a basic disposition that sustains patients’ efforts to deal efficaciously with severe illness, by complying with medical treatment and using cognitive strategies that enable individuals to cope with concurrent and prospective challenges of illness.

Pre-treatment evaluation of 5-fluorouracil degradation rate: association of poor and ultra-rapid metabolism with severe toxicity in a colorectal cancer patients cohort

Despite the wide use of 5-fluorouracil-based chemotherapy, development of severe toxicity that follow the treatment is not a rare event. The efforts to establish pretreatment tools for toxicity prediction, led to the development of various pharmacogenetic and biochemical assays, mainly targeted to assess the activity level of dihydropyrimidine dehydrogenase (DPD), the main metabolizing enzyme for 5-fluorouracil. Using peripheral blood mononuclear cells, we developed a biochemical assay, that is not limited to the evaluation of DPD activity, but determines the net result of all the enzymatic transformation of 5FU, in terms of the amount of drug consumed by the cells in a time unit. This parameter, named 5-fluorauracil degradation rate, presents a normal distribution inside the population and highlight the presence of an ultra-rapid metabolizers class of subjects, besides the expected poor metabolizers class. Here we will show that, in a colorectal cancer patient cohort, both poor and ultra-rapid metabolizers have significantly increased the risk of developing severe toxicity (grade3–4). Patient stratification depending on the individual 5-fluorouracil degradation rate allows to identify a 10% of the overall population at high risk of developing severe toxicity, compared to the 1.3% (as assessed in the Italian population) identified by the most commonly employed pharmacogenetic test, including the DPD polymorphism IVS14+1G>A.

The TYMS-TSER polymorphism is associated with toxicity of low-dose capecitabine in patients with advanced gastrointestinal cancer

Low doses of drugs delivered at close, regular intervals are increasingly being used to manage patients with different neoplasms. Despite the good tolerability, treatment-related adverse events still occur following metronomic protocols. The aim of this study was to retrospectively investigate whether polymorphisms of different genes involved in fluoropyrimidine metabolism and 5-fluorouracil (5-FU) degradation rate were associated with the outcome of a low-dose capecitabine schedule. Genotyping of DPYD IVS14+1 G>A, MTHFR C677T, and A1298C single-nucleotide polymorphisms was performed by pyrosequencing technology. A PCR technique was used for genotyping TYMS-TSER. Using peripheral blood mononuclear cells, we also evaluated the 5-FU degradation rate, which determines the net result of all the enzymatic transformation of 5-FU, in terms of the amount of drug consumed by the cells in a time unit. The association of these variables with clinical outcome was evaluated using multivariate logistic regression analysis. Eighty-four patients with metastatic gastrointestinal cancer, who had been treated with a low-dose fluoropyrimidine schedule, as a rescue therapy were included in the study. The TSER 2R/2R genotype was significantly associated with both hematologic (odds ratio=7.90, P=0.002) and gastrointestinal toxicity (odds ratio=3.24, P=0.009). Because DPYD IVS14 G>A single-nucleotide polymorphism was not observed in the cohort, it was excluded from the statistical analysis. No significant association was detected between clinical outcome and both MTHFR polymorphisms and the 5-FU degradation rate. In the advanced setting of cancer care, high attention should be paid toward avoiding toxicity and worsening of quality of life. Although metronomic chemotherapy is generally well tolerated, treatment toxicity nonetheless does occur. Our data suggest a possible role of the TSER 2R/2R polymorphism as a predictive marker of toxicity in patients treated with low-dose capecitabine.

The sexist behaviour of immune checkpoint inhibitors in cancer therapy

Background Immune checkpoint inhibitors, targeting the molecules CTLA-4, PD-1 and PD-L1, showed efficacy against several type of cancers and are currently used in clinical practice. An important biological variable that influences innate and adaptive immunity is the sex, acting through genetic, hormonal and environmental factors. The overall differences between sexes could be crucial to evaluate the response to ICIs. Materials and methods We performed a meta-analysis of Phase II-III Clinical Trials published up to June 2017 in which anti-CTLA-4, anti-PD-1 and anti-PD-L1 were studied. We extracted the OS and PFS HR differentiated by sex from subgroups analysis of each trial. We analyzed the three classes of drugs separately. Results We selected 36 Phase II-III Clinical Trials, 9 of which reported results for OS and 6 for PFS. We analyzed 2 Clinical Trials for OS with anti-CTLA-4, including 1178 patients, observing a benefit for males vs females (HR 0.65, 95% CI 0.55-0.77 vs HR 0.79, 95% CI 0.65-0.96, p 0.078). Not statistically significant results were observed with anti-PD-1 neither for OS (males vs females: HR 0.72, 95% CI 0.64-0.83 vs HR 0.81, 95% CI 0.70-0.94, p 0.285) neither for PFS (males vs females: HR 0.66, 95% CI 0.52-0.82 vs HR 0.85, 95% CI 0.66-1.09, p 0.158). We cannot perform a meta-analysis for anti-PD-L1 due to the lack of data. Conclusions Different mechanisms could be involved in sex differences with regard to immunotherapy. These differences could be relevant to identify immunological targets in order to draw studies exploring novel combinations of immunotherapy agents.

CYP19A1 Genetic Polymorphisms rs4646 and Osteoporosis in Patients Treated with Aromatase Inhibitor-Based Adjuvant Therapy.

OBJECTIVE Third-generation aromatase inhibitors (AI) are potent suppressors of aromatase activity. The aim of this study was to measure the incidence of adverse effects in breast cancer patients treated with AI-based adjuvant therapy and the relationship with the CYP19A1 genotypes. MATERIALS AND METHODS Forty-five postmenopausal breast cancer patients (46-85 yrs) in AI adjuvant treatment were genotyped for the rs4646 polymorphisms of CYP19A1 gene and three variations were identified. Toxicities were registered at each follow-up medical examination, and classified in accord with the Common Terminology Criteria for Adverse Events. RESULTS Twenty-four (53.3%) patients presented the GG genotype; 19 (42.2%) the GT, and 2 (4.4%) the TT. The AI treatment was Anastrazole for 35 patients (77.8%) and Letrozole for the others (n=10; 22.2%). Osteoporosis was significantly associated with the GG genotype (p=0.001). Treatment discontinuation (TD) was observed in 6 cases (13.3%). The only parameter able to predict TD was the appearance of severe arthralgia/myalgia (Odds Ratio, OR=23.75; p=0.009), when adjusted for age and AI treatment. CONCLUSION Our results suggest that CYP19A1 polymorphic variants may influence susceptibility to develop AI-related side effects. Further prospective studies are needed to confirm the role of the aromatase gene (CYP19A1) polymorphisms in predicting adverse effects to AI-based therapy.

A nomogram to predict 5-fluorouracil toxicity: when pharmacogenomics meets the patient

Fluoropyrimidines combined with other agents are commonly used for gastrointestinal cancer treatment. Considering that severe toxicities occur in 30% of patients, we aimed to structure a nomogram to predict toxicity, based on metabolic parameter and patients’ characteristics. We retrospectively enrolled patients affected by gastrointestinal tract cancers. Pretreatment 5-fluorouracil (5-FU) degradation rate and DPYD, TSER, MTHFR A1298T, and C677T gene polymorphisms were characterized. Data on toxicities were collected according to CTCAE v3.0. Multivariate logistic regression analysis was used to structure a nomogram. 642 patients were enrolled (384 men; 258 female; median age: 67 years, range: 27–87): 449 (69.9%) patients were affected by colorectal cancer; 118 (18.4%) by gastroesophageal cancer; 66 (10.3%) by pancreatic cancer; and nine (1.4%) by other cancers. Grade 3–4 toxicities were observed in 118 (18.4%) patients and were most frequently observed in patients with altered 5-FU degradation rate (43.5 and 26.7% of the patients in the poor metabolizer and in the ultrarapid metabolizer group respectively, vs. 17% in the normal metabolizer group) and in DPYD heterozygous mutated patients (83.3% of the patients). Age, DPYD status, the number of drugs administered, and 5-FU degradation rate value were associated to severe toxicities. On the basis of these findings, we structured a nomogram to assess a score to predict the risk of developing severe toxicity. Compared with the available pharmacogenetic tests, this approach can be applied to the whole population, predicting the risk for severe toxicity, with an easy, low-cost, and not invasive technique.

Standard versus limited colon resection for high risk T1 colon cancer. A matched case-control study

BACKGROUND AND AIMS The National Comprehensive Cancer Network (NCCN) recommends a colectomy in presence of high risk T1 colon polyps considering the risk of incomplete lymph node dissection or presence of residual disease. We evaluated the outcomes of segmental versus standard colon resection for high risk T1 colon cancers, in order to demonstrate if segmental colectomy (SegCR) allows same short-term and oncological results compared to standard radical colectomy (StaCR). METHODS. A matched case-control study on patients who had undergone segmental versus standard colon resection was performed. One-hundred and two patients with high risk T1 colon cancer after endoscopic polypectomy, divided in 2 homogeneous groups of 51 cases, were analyzed and intra-operative, post-operative and oncological data were compared. RESULTS. Segmental colectomy allowed less operative time and intra-operative blood loss compared to StaCR (p < 0.001). Hospital stay after SegCR was shorter compared to StaCR (p < 0.001). No differences were found in terms of overall morbidity and mortality rates. Five-year actuarial overall, disease-free and disease-specific survival after StaCR were similar to SegCR (87%, 96% and 95% vs. 88%, 97% and 94%, respectively, p = 0.51, p=0.33, p=0.78). CONCLUSIONS. According to our findings, SegCR can be a valid alternative to StaCR for high risk T1 colon polyps. Segmental colectomy allows better peri-operative outcomes compared to StaCR ensuring the same oncological long-term outcomes.