Role of Diet in the Management of Carcinoid Syndrome: Clinical Recommendations for Nutrition in Patients with Neuroendocrine Tumors.

Nutrition and metabolism are altered in patients with gastroenteropancreatic neuroendocrine tumors, which is related to excessive production of gastrointestinal hormones, peptides, and amines that can cause maldigestion, diarrhea, steatorrhea, and altered gastrointestinal motility. Patients with carcinoid syndrome are at risk of malnutrition due to tryptophan depletion, reduced intake of food, and loss of appetite because of diarrhea and/or flushing. To date, there is limited information on the nutritional issues faced by patients with neuroendocrine tumors, and on what specific recommendations should be made to patients concerning nutrition at various stages of the disease process. Dietary planning should therefore be an integral part of multidisciplinary management for patients with neuroendocrine tumors. Herein, we review current guidance for nutrition in patients with neuroendocrine tumors, focusing on intake of amines and foods to avoid, as well as concurrent medications. We also propose a new and practical food pyramid based on the principles of Mediterranean diet 4.0 that can be easily adapted according to the unmet needs of patients with neuroendocrine tumors at all stages of disease. The overarching goal of the present review is to create greater awareness of nutritional care and considerations that should be given to patients with neuroendocrine tumors.

Nilotinib-induced bone marrow CD34+/lin-Ph+ cells early clearance in newly diagnosed CP-Chronic Myeloid Leukemia: Final report of the PhilosoPhi34 study.

Chronic Myeloid Leukemia is a clonal disorder characterized by the presence of the Ph-chromosome and the BCR-ABL tyrosine-kinase (TK). Target-therapy with Imatinib has greatly improved its outcome. Deeper and faster responses are reported with the second-generation TKI Nilotinib. Sustained responses may enable TKI discontinuation. However, even in a complete molecular response, some patients experience disease recurrence possibly due to persistence of quiescent leukemic CD34+/lin-Ph+ stem cells (LSCs). Degree and mechanisms of LSCs clearance during TKI treatment are not clearly established. The PhilosoPhi34 study was designed to verify the in-vivo activity and timecourse of first-line Nilotinib therapy on BM CD34+/lin-Ph+ cells clearance. Eighty-seven CP-CML patients were enrolled. BM cells were collected and tested for Ph+ residual cells, at diagnosis, 3, 6 and 12 months of treatment. FISH analysis of unstimulated CD34+/lin- cells in CCyR patients were positive in 8/65 (12.3%), 5/71 (7%), 0/69 (0%) evaluable tests, respectively. Per-Protocol analysis response rates were as follows: CCyR 95% at 12 months, MR4.5 31% and 46% at 12 and 36 months, respectively. An exploratory Gene Expression Profiling (GEP) study of CD34+/lin- cells was performed on 30 patients at diagnosis and after, on 79 patients at diagnosis vs 12 months of nilotinib treatment vs 10 healthy subjects. Data demonstrated some genes significantly different expressed: NFKBIA, many cell cycle genes, ABC transporters, JAK-STAT signaling pathway (JAK2). In addition, a correlation between different expression of some genes (JAK2, OLFM4, ICAM1, NFKBIA) among patients at diagnosis and their achievement of an early and deeper MR was observed.

Young-onset colorectal cancer: treatment-related nausea, vomiting and diarrhoea.

OBJECTIVES: Early-onset colorectal cancer (EO-CRC) incidence is increasing, raising a clinical challenge. Clinicians tend to treat EO-CRC patients with more intensive regimens despite the lack of survival benefits, based on an age-related bias. Limited evidence is available regarding treatment-related toxicities in this peculiar subset of patients. METHODS: We performed a literature search in MEDLINE/PubMed, EMBASE and Scopus, looking for reporting of nausea, vomiting and diarrhoea occurring in patients with EO-CRC, defined by age lower than 50 years old at initial diagnosis, while receiving anticancer treatment. RESULTS: 2318 records were screened and 9 full-text articles were considered eligible for inclusion for a total of 59 783 patients (of whom 8681 EO-CRC patients). We found nausea and vomiting occurring at higher incidence among EO-CRC compared with older patients, while no difference was reported as for diarrhoea. Peritoneal involvement, age younger than 40, female gender, suboptimal adherence to guidelines and oxaliplatin might represent potential risk factors for increased nausea and vomiting in patients with EO-CRC. CONCLUSION: EO-CRC patients experience more nausea and vomiting but equal or less diarrhoea compared with older patients. Adherence to clinical guidelines is recommended, and more data are warranted to assess if an enhanced antiemetic approach might be required, particularly in case of specific risk factors.

Panitumumab in combination with infusional oxaliplatin and oral capecitabine for conversion therapy in patients with colon cancer and advanced liver metastases. The MetaPan study.

BACKGROUND: Preoperative chemotherapy improves the outcome in patients with colorectal cancer with liver metastases. In the current study, the authors evaluated the activity of a conversion treatment with the combination of capecitabine plus oxaliplatin (XELOX) used in association with panitumumab in patients with unresectable, liver-only, metastatic colon cancer. METHODS: Chemotherapy-naive patients with unresectable liver metastases from colon cancer with no other metastatic disease sites were enrolled. All patients received upfront therapy with XELOX plus panitumumab (P-XELOX) and were reevaluated for resectability every 4 cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints were overall survival (OS), progression-free survival, the percentage of patients whose disease became radically resectable, and the safety of the P-XELOX combination. RESULTS: A total of 49 patients were recruited, 35 of whom had wild-type KRAS (wtKRAS) and 14 of whom (who were enrolled before study amendment) had unknown (9 patients) or mutated (5 patients) KRAS mutational status. Forty-six patients were evaluable for response. After conversion P-XELOX therapy, the ORR in the general population was 54%, with 2 complete responses, 23 partial responses, and 14 cases of stable disease. In patients with wtKRAS, the ORR of the patients reached 65% (2 CRs and 19 PRs), which allowed 15 patients with initial unresectable liver metastasis to be reclassified as having resectable disease. Survival analysis demonstrated a median progression-free survival of 8.5 months and a median OS of 21.9 months. Patients who underwent surgery were found to have a significantly better OS when compared with those who did not undergo surgery (P < .001). Overall, toxicities were found to be predictable and manageable, with the most common being cutaneous, gastrointestinal, and neurologic toxicities. CONCLUSIONS: Conversion P-XELOX therapy yields high response and resectability rates for patients with metastatic colon cancer with extensive liver involvement.

Tas-102 for Refractory Metastatic Colorectal Cancer: A Multicenter Retrospective Cohort Study.

Trifluridine/tipiracil (TAS-102) is an oral chemotherapy approved for the treatment of metastatic colorectal cancer. The efficacy and tolerability of TAS-102 were shown in phase II-III clinical trials and in several real-life studies. The elderly and other special subgroups are underrepresented in published literature. We conducted a retrospective multicenter study to assess the effectiveness and safety of TAS-102 in consecutive patients with pretreated mCRC. In particular, we estimated the effectiveness and safety of TAS-102 in elderly patients (aged ≥70, ≥75 and ≥80 years) and in special subgroups, e.g., patients with concomitant heart disease. One hundred and sixty patients were enrolled. In particular, 71 patients (44%) were 70 years of age or older, 50 (31%) were 75 years of age or older, and 23 (14%) were 80 years of age or older. 19 patients (12%) had a concomitant chronic heart disease, three (2%) patients were HIV positive, and one (<1%) patient had a DPYD gene polymorphism. In 115 (72%) cases TAS-102 was administered as a third-line treatment. The median overall survival (OS) in the overall population was 8 months (95% confidence interval [CI], 6-9), while the median progression-free survival (PFS) was 3 months (95% CI, 3-4). No significant age-related reduction in effectiveness was observed in the subpopulations of elderly patients included. The toxicity profile was acceptable in both the whole and subgroups' population. Our study confirms the effectiveness and safety of TAS-102 in patients with pretreated mCRC, suggesting a similar risk-benefit profile in the elderly.

Adjuvant capecitabine in triple negative breast cancer patients with residual disease after neoadjuvant treatment: real-world evidence from CaRe, a multicentric, observational study.

Background: In triple negative breast cancer patients treated with neoadjuvant chemotherapy, residual disease at surgery is the most relevant unfavorable prognostic factor. Current guidelines consider the use of adjuvant capecitabine, based on the results of the randomized CREATE-X study, carried out in Asian patients and including a small subset of triple negative tumors. Thus far, evidence on Caucasian patients is limited, and no real-world data are available. Methods: We carried out a multicenter, observational study, involving 44 oncologic centres. Triple negative breast cancer patients with residual disease, treated with adjuvant capecitabine from January 2017 through June 2021, were recruited. We primarily focused on treatment tolerability, with toxicity being reported as potential cause of treatment discontinuation. Secondarily, we assessed effectiveness in the overall study population and in a subset having a minimum follow-up of 2 years. Results: Overall, 270 patients were retrospectively identified. The 50.4% of the patients had residual node positive disease, 7.8% and 81.9% had large or G3 residual tumor, respectively, and 80.4% a Ki-67 >20%. Toxicity-related treatment discontinuation was observed only in 10.4% of the patients. In the whole population, at a median follow-up of 15 months, 2-year disease-free survival was 62%, 2 and 3-year overall survival 84.0% and 76.2%, respectively. In 129 patients with a median follow-up of 25 months, 2-year disease-free survival was 43.4%, 2 and 3-year overall survival 78.0% and 70.8%, respectively. Six or more cycles of capecitabine were associated with more favourable outcomes compared with less than six cycles. Conclusion: The CaRe study shows an unexpectedly good tolerance of adjuvant capecitabine in a real-world setting, although effectiveness appears to be lower than that observed in the CREATE-X study. Methodological differences between the two studies impose significant limits to comparability concerning effectiveness, and strongly invite further research.

Positive Effects of α-Lactalbumin in the Management of Symptoms of Polycystic Ovary Syndrome.

To date, the involvement of α-Lactalbumin (α-LA) in the management of polycystic ovary syndrome (PCOS) refers to its ability to improve intestinal absorption of natural molecules like inositols, overcoming the inositol resistance. However, due to its own aminoacidic building blocks, α-LA is involved in various biological processes that can open new additional applications. A great portion of women with PCOS exhibit gastrointestinal dysbiosis, which is in turn one of the triggering mechanisms of the syndrome. Due to its prebiotic effect, α-LA can recover dysbiosis, also improving the insulin resistance, obesity and intestinal inflammation frequently associated with PCOS. Further observations suggest that altered gut microbiota negatively influence mental wellbeing. Depressive mood and low serotonin levels are indeed common features of women with PCOS. Thanks to its content of tryptophan, which is the precursor of serotonin, and considering the strict link between gut and brain, using α-LA contributes to preserving mental well-being by maintaining high levels of serotonin. In addition, considering women with PCOS seeking pregnancy, both altered microbiota and serotonin levels can induce later consequences in the offspring. Therefore, a deeper knowledge of potential applications of α-LA is required to transition to preclinical and clinical studies extending its therapeutic advantages in PCOS.

A Nutritional Approach for the Management of Chemotherapy-Induced Diarrhea in Patients with Colorectal Cancer.

This study aimed to determine if dietary modifications using a nutritional regimen could prevent or reduce the incidence of cancer therapy-induced diarrhea in patients with metastatic colorectal cancer and to evaluate the relationship of Vitamin D blood levels with diarrhea severity. Patients with metastatic colorectal cancer were enrolled. A Mediterranean diet, containing some special limitations aiming to reduce the risk of diarrhea, was administered before and during the entire chemotherapy program. Enrolled patients numbering 60/137 (44%) had diarrhea during chemotherapy. Adherence to the diet was high in 36 (26.3%) patients, medium in 94 (68.6%), and low in 7 (5.1%). Mean adherence to the diet was significantly lower in patients who experienced diarrhea with maximum grade 2−3 compared to those who had no diarrhea or grade 1 diarrhea (score = 5.4 ± 1.9 vs. 7.1 ± 1.5, p < 0.001). Patients with higher adherence to the diet had a lower risk of grade 2−3 diarrhea (odds ratio: 0.5 (95% CI: 0.3−0.7, p < 0.001)). In addition, patients who completed a higher number of chemotherapy cycles had an increased risk of grade 2−3 diarrhea (odds ratio: 1.2 (95% CI: 1.0−1.5, p = 0.02)). Of note, a lower level of Vitamin D correlated with an increased risk of G2-G3 diarrhea (p = 0.03). A diet based on vegetables with a controlled fiber content, Mediterranean Modified Healthy Diet (MMHD), is useful to control the incidence of cancer therapy-induced diarrhea.

Prognostic role of hematologic parameters of metastatic renal cell carcinoma treated with sunitinib.

BACKGROUND: Hemochrome parameters at the diagnosis of metastatic renal cell carcinoma (mRCC) and the development of macrocytosis during sunitinib therapy are considered prognostic. OBJECTIVE: To evaluate the prognostic role of hematologic parameters and macrocytosis in mRCC treated with sunitinib. METHODS: We analyzed clinical data of 100 patients with mRCC treated with sunitinib as first-line therapy in a retrospective multicenter study. We calculated neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) at baseline and erythrocyte mean corpuscular volume (MCV) during therapy. We considered the following cutoffs: NLR >3, PLR >150, LMR <3, and MCV >100 fl. Clinical data histology, prior nephrectomy, Fuhrman grading, metastatic sites, Memorial Sloan-Kettering Cancer Center score, and Heng score were collected. Overall survival (OS) and progression-free survival (PFS) were calculated. Univariate and multivariate analysis using Cox regression model with time-dependent (macrocytosis) covariate were applied. RESULTS: At the univariate analysis, low LMR was associated with shorter PFS and OS (p = 0.02 and p = 0.06, respectively). High PLR was associated with worse PFS (p = 0.005); median OS was 23 vs 28 months (p = 0.13). At the multivariate analysis, poor risk (Heng score), low LMR, and high PLR were associated with shorter PFS (hazard ratio 7.1, 1.5, and 2, respectively); poor PS and poor risk (Heng score) were related to worst OS. Macrocytosis was observed in 26 patients and was not prognostic of survival. CONCLUSIONS: In our cohort of patients with mRCC treated with sunitinib, low LMR (>3) and high PLR (>150) were associated with shorter PFS. Macrocytosis was not prognostic.

On-target Toxicities Predictive of Survival in Metastatic Renal Cell Carcinoma (mRCC) Treated With Sunitinib: A Multicenter Retrospective Study.

BACKGROUND: Preliminary studies suggested that selected drug-related toxicities of sunitinib may correlate with a better prognosis. PATIENTS AND METHODS: From January 2006 through December 2015, we retrospectively analyzed data of 145 patients with metastatic renal cell carcinoma treated with sunitinib as a first-line therapy in 7 different Italian oncology departments. Hypertension, hypothyroidism, thrombocytopenia, neutropenia, and anemia were evaluated. Overall survival (OS) and progression-free survival (PFS) were calculated. OS and PFS were compared in patients who developed and who did not develop a drug-related toxicity. A multivariate analysis using the Cox regression model was performed. RESULTS: We evaluated 145 patients (92 males; median age, 70 years); 105 (62.4%) patients experienced at least 1 toxicity: 66 (45.5%) patients developed hypothyroidism, 41 (28.3%) thrombocytopenia, 39 (26.9%) hypertension that required medical therapy, 22 (15.2%) anemia, and 11 (7.6%) neutropenia. The median PFS of patients who developed hypertension was 12 months (95% confidence interval [CI], 9-21 months) versus 9 months (95% CI, 7-12 months) in patients who did not develop toxicity; the median OS was 36 months (95% CI, 22 months to not reached) versus 26 months (95% CI, 18-34 months). For neutropenia, the median PFS was 17.5 months (95% CI, 9-65 months) versus 10 months (95% CI, 8-12 months); the median OS was 23 months (95% CI, 13 months to not reached) versus 28 months (95% CI, 22-35 months). At univariate and multivariate analysis, we observed a protective effect of hypertension and neutropenia on tumor progression (hazard ratio, 0.47; 95% CI, 0.28-0.78 and hazard ratio, 0.26; 95% CI, 0.09-0.76, respectively). CONCLUSIONS: Many patients developed toxicities during treatment with sunitinib; hypertension and neutropenia were related to longer PFS in our cohort.

Is There Still a Role for Endocrine Therapy Alone in HR+/HER2- Advanced Breast Cancer Patients? Results from the Analysis of Two Data Sets of Patients Treated with High-Dose Fulvestrant as First-Line Therapy in the Real-World Setting: The EVA and GIM-13 AMBRA Studies.

BACKGROUND: Different studies suggest that fulvestrant 500 mg every 28 days (HD-FUL) could be an active treatment in HR+ advanced breast cancer (ABC) patients even treated with aromatase inhibitors in the adjuvant setting. The aim of this analysis is to describe the outcome of ABC patients treated with HD-FUL as first-line treatment in terms of median duration of treatment and the overall response rate in a real-world setting. METHODS: For the purpose of the present analysis, we considered two data sets of HR+ ABC patients collected in Italy between 2012 and 2015 (EVA and GIM-13 AMBRA studies). RESULTS: Eighty-one and 91 patients have been identified from the two data sets. The median age was 63 years (range 35-82) for the EVA and 57.8 years (range 35.0-82.3) for the AMBRA patients. ORRs were 23.5 and 24.3% in the whole population, 26.9% in the patients with bone only, and 21.8 and 21.4% in those with visceral metastases. The median duration of HD-FUL was 11.6 months (range 1-48) and 12.4 months (range 2.9-70.0) in the two data sets, respectively. CONCLUSION: These data suggest that HD-FUL should still continue to play a significant role as first-line therapy in HR+ ABC patients.

Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial.

BACKGROUND: Preclinical data have suggested a synergistic effect of cetuximab combined with gemcitabine and cisplatin and clinical data have shown a substantial improvement in response and survival when gemcitabine is combined with a platinum analogue compared with gemcitabine alone. The aim of this study was to assess the activity and feasibility of a combination of cetuximab with gemcitabine and cisplatin compared with use of gemcitabine and cisplatin alone for the treatment of advanced pancreatic cancer. METHODS: In a multicentre, randomised phase II trial, 84 patients with advanced pancreatic cancer were randomly assigned to either 250 mg/m2 cetuximab weekly, after a loading dose of 400 mg/m2, plus 1000 mg/m2 gemcitabine and 35 mg/m2 cisplatin on days 1 and 8 of a 21-day cycle or to the same chemotherapeutic regimen without cetuximab. The primary endpoint was objective response (defined as the proportion of patients whose best response was either partial response or complete response). Secondary endpoints included disease control (defined as the proportion of patients whose best response was either partial response, complete response, or stable disease), progression-free survival, and overall survival. All assessments of response at each site were done blindly by a local experienced radiologist who was not directly involved in the trial. Responses were measured according to an intention-to-treat analysis. This trial is registered with the Clinical Trial registry, number NCT00536614. FINDINGS: 29 men and 13 women were randomly assigned to cetuximab plus gemcitabine and cisplatin (median age 61 years [range 38-78]) and 22 men and 20 women were randomly assigned to gemcitabine and cisplatin (median age 64 years [range 40-76]). Seven of 40 (17.5%) patients had an objective response in the cetuximab group (95% CI 7.3-32.8) and five of 41 (12.2%) patients had an objective response in the non-cetuximab group (95% CI 4.1-26.2). No significant difference was noted between the groups both for objective response (5.3% higher in the cetuximab group [95% CI -16.5 to 27.1]; chi2 test=0.360; p=0.549) or for disease control (3.5% higher in the non-cetuximab group [-34.0% to 27.0%]; 0.446; p=0.504). Overall median follow-up was 11.8 months (range 2.5-18.5). No significant differences between the groups were noted in median progression-free survival (hazard ratio 0.96, 95% CI 0.60-1.52, p=0.847) or in median overall survival (0.91, 0.54-1.55, p=0.739): median progression-free survival was 3.4 months (95% CI 2.4-5.1) in the cetuximab group and 4.2 months (2.6-5.4) in the non-cetuximab group; median overall survival was 7.5 months (5.1-8.8) and 7.8 months (5.3-15.0), respectively. 33 patients from both groups had at least one grade 3-4 toxic effect. INTERPRETATION: The addition of cetuximab to a combination of gemcitabine and cisplatin does not increase response or survival for patients with advanced pancreatic cancer. Although toxic effects were not increased by cetuximab, this combination should not be further assessed in phase III trials.

Neuroendocrine Differentiation, Microsatellite Instability, and Tumor-infiltrating Lymphocytes in Advanced Colorectal Cancer With BRAF Mutation.

BACKGROUND: Approximately 10% of metastatic colorectal cancer (mCRC) cases will harbor the BRAF p.V600E mutation (BRAF-mCRC) and have been associated with a poor prognosis. Although they are usually considered a unique clinical entity, biologic heterogeneity has been described. We performed an extensive clinicopathologic study of a multicenter series of BRAF-mCRC to highlight differences between tumors with microsatellite instability (MSI) and microsatellite stable tumors, focusing on both inflammatory profiles and neuroendocrine differentiation. METHODS: We included 59 BRAF-mCRC cases and collected the clinical data (ie, surgery, treatment, and follow-up). We evaluated MSI status, budding, lympho-angioinvasion, neuroinvasion, extent of active stroma, CD3+ and CD8+ intratumoral and peritumoral lymphocytes, programmed cell death ligand 1, p53, Ki-67, synaptophysin, and CDX2 expression. RESULTS: The 22 MSI BRAF-mCRC cases were associated with the right side (P < .0001), an expansive grown pattern (P < .01), programmed cell death ligand 1 expression (P < .0001), high CD8 T-cell content (P = .0001), and lymph node metastases (P < .029). The 37 MSS BRAF-mCRC cases were characterized by a greater stromal component (P = .0002), pulmonary metastases (P = .095), and p53 and synaptophysin immunoreactivity (P = .004 and P = .001, respectively). Univariate analysis demonstrated that MSI and a high CD8 T-cell content were associated with a 34% (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.34-1.28; P = .2) and 33% (HR, 0.67; 95% CI, 0.45-0.99; P = .04) reduction in the risk of death, respectively. The combined presence of MSI and CD8 T-cell content decreased the hazard of mortality ≤ 63% (HR, 0.37; 95% CI, 0.14-0.97; P = .2), which was slightly reduced after multivariate analysis. CONCLUSION: A simultaneous evaluation of MSI, CD8 T-cell content, and neuroendocrine markers could allow for the identification of subsets of BRAF-mCRC with a different prognosis and potential eligibility for specific treatments.

Nilotinib interferes with cell cycle, ABC transporters and JAK-STAT signaling pathway in CD34+/lin- cells of patients with chronic phase chronic myeloid leukemia after 12 months of treatment.

Chronic myeloid leukemia (CML) is characterized by the constitutive tyrosine kinase activity of the oncoprotein BCR-ABL1 in myeloid progenitor cells that activates multiple signal transduction pathways leading to the leukemic phenotype. The tyrosine-kinase inhibitor (TKI) nilotinib inhibits the tyrosine kinase activity of BCR-ABL1 in CML patients. Despite the success of nilotinib treatment in patients with chronic-phase (CP) CML, a population of Philadelphia-positive (Ph+) quiescent stem cells escapes the drug activity and can lead to drug resistance. The molecular mechanism by which these quiescent cells remain insensitive is poorly understood. The aim of this study was to compare the gene expression profiling (GEP) of bone marrow (BM) CD34+/lin- cells from CP-CML patients at diagnosis and after 12 months of nilotinib treatment by microarray, in order to identify gene expression changes and the dysregulation of pathways due to nilotinib action. We selected BM CD34+/lin- cells from 78 CP-CML patients at diagnosis and after 12 months of first-line nilotinib therapy and microarray analysis was performed. GEP bioinformatic analyses identified 2,959 differently expressed probes and functional clustering determined some significantly enriched pathways between diagnosis and 12 months of nilotinib treatment. Among these pathways, we observed the under expression of 26 genes encoding proteins belonging to the cell cycle after 12 months of nilotinib treatment which led to the up-regulation of chromosome replication, cell proliferation, DNA replication, and DNA damage checkpoint at diagnosis. We demonstrated the under expression of the ATP-binding cassette (ABC) transporters ABCC4, ABCC5, and ABCD3 encoding proteins which pumped drugs out of the cells after 12 months of nilotinib. Moreover, GEP data demonstrated the deregulation of genes involved in the JAK-STAT signaling pathway. The down-regulation of JAK2, IL7, STAM, PIK3CA, PTPN11, RAF1, and SOS1 key genes after 12 months of nilotinib could demonstrate the up-regulation of cell cycle, proliferation and differentiation via MAPK and PI3K-AKT signaling pathways at diagnosis.

Impressive Response to Tandem Treatment With [90Y]DOTATOC and [177Lu]DOTATOC in Grade 3 Pancreatic Neuroendocrine Carcinoma.

Peptide receptor radionuclide therapy is an effective, well-tolerated, treatment for well-differentiated neuroendocrine tumors, resulting in a significant survival benefit and improvement of quality of life. Very few data are available on peptide receptor radionuclide therapy effectiveness in grade 3 neuroendocrine carcinomas with high somatostatin receptor expression. We report the case of a 70-year-old woman with metastatic pancreatic grade 3 neuroendocrine carcinoma who underwent 6 cycles of tandem treatment with investigational radiopharmaceuticals Y-DOTATOC and Lu-DOTATOC achieving an impressive response.

Statin use and survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone or enzalutamide after docetaxel failure: the international retrospective observational STABEN study.

BACKGROUND: Statins may potentiate the effects of anti-hormonal agents for metastatic castration-resistant prostate cancer (mCRPC) through further disruption of essential steroidogenic processes. We investigated the effects of statin use on clinical outcomes in patients with mCRPC receiving abiraterone or enzalutamide. MATERIALS AND METHODS: This was a retrospective multicenter study including patients that received abiraterone or enzalutamide for mCRPC. The effect of concurrent statin use on outcomes was evaluated. The associations of statins with early (≤12 weeks) prostate-specific antigen (PSA) declines (> 30%), cancer-specific survival and overall survival (OS) were evaluated after controlling for known prognostic factors. RESULTS: Five hundred and ninety-eight patients treated with second-line abiraterone or enzalutamide after docetaxel for mCRPC were included. A total of 199 men (33.3%) received statins during abiraterone/enzalutamide treatment. Median OS was 20.8 months (95% CI = 18.3-23.2) for patients who received statins, versus 12.9 months (95% CI = 11.4-14.6) for patients who did not receive statins (P < 0.001). After adjusting for age, alkaline phosphatase, PSA, neutrophil-to-lymphocytes ratio, Charlson comorbidity score, Gleason score, visceral disease, hemoglobin, opiate use and abiraterone versus enzalutamide treatment, the use of statin therapy was associated with a 53% reduction in the overall risk of death (hazard ratio [HR] = 0.47; 95% CI = 0.35-0.63; P < 0.001). Statin use was also associated with a 63% increased odds of a > 30% PSA decline within the first 12 weeks of treatment (OR = 1.63; 95% CI = 1.03-2.60; P = 0.039). CONCLUSIONS: In this retrospective cohort, statin use was significantly associated with both prolonged OS and cancer-specific survival and increased early > 30% PSA declines. Prospective validation is warranted.

Correction 2: Everolimus (EVE) and exemestane (EXE) in patients with advanced breast cancer aged ≥ 65 years: new lessons for clinical practice from the EVA study.

[This corrects the article DOI: 10.18632/oncotarget.25874.].

Everolimus (EVE) and exemestane (EXE) in patients with advanced breast cancer aged ≥ 65 years: new lessons for clinical practice from the EVA study.

BACKGROUND: The present analysis focuses on real-world data of Everolimus-Exemestane in advanced HR+ve, HER2-ve elderly breast cancer patients (aged 65 years) included in the EVA study, with unique findings in those aged 70 years. METHODS: Data are collected from clinical records and analysed according to age cut-off (< 65 years; 65 - 69 years and {greater than or equal to} 70 years). Relationship of analyzed variables with response were tested by mean of a Mantel-Haenszel chi square test. Time to event analysis was described by Kaplan Meier approach and association with baseline characteristics was analysed by stratified log-rank test and proportional hazard model. RESULTS: From July 2013 to December 2015, the EVA study enrolled overall 404 pts. 154 patients out of 404 (38,1%) were aged {greater than or equal to} 65 years, of whom 87 were {greater than or equal to} 70 years. Median duration of EVE treatment was 28.5 weeks (95% CI 19.0 - 33.8) in patients aged 65-69 years and 24,4 weeks (95% CI 19,2 - 33,2) in those aged {greater than or equal to} 70 years. Fewer patients aged 65 years received the highest EVE Dose-Intensity (>7.5 mg/day) in comparison to younger patients (49,6% vs. 66,8%). Grade 3-4 toxicities occurred to 55 patients (35,7%), mainly stomatitis (10,9%), rash (5,8%) and non-infectious pneumonitis (NIP) (3,6%). Some toxicities, such as weight loss and anaemia were peculiarly observed in patients aged {greater than or equal to} 70 years. Five treatment-related deaths were collected (3,2%). CONCLUSIONS: EVE-EXE combination remains one of the potential treatments in HR+ patients also for elderly ones.

Correction: Everolimus (EVE) and exemestane (EXE) in patients with advanced breast cancer aged ≥ 65 years: new lessons for clinical practice from the EVA study.

[This corrects the article DOI: 10.18632/oncotarget.25874.].