Lineage-specific mechanisms and drivers of breast cancer chemoresistance revealed by 3D biomimetic culture.

To improve the success rate of current preclinical drug trials, there is a growing need for more complex and relevant models that can help predict clinical resistance to anticancer agents. Here, we present a three-dimensional (3D) technology, based on biomimetic collagen scaffolds, that enables the modeling of the tumor hypoxic state and the prediction of in vivo chemotherapy responses in terms of efficacy, molecular alterations, and emergence of resistance mechanisms. The human breast cancer cell lines MDA-MB-231 (triple negative) and MCF-7 (luminal A) were treated with scaling doses of doxorubicin in monolayer cultures, 3D collagen scaffolds, or orthotopically transplanted murine models. Lineage-specific resistance mechanisms were revealed by the 3D tumor model. Reduced drug uptake, increased drug efflux, and drug lysosomal confinement were observed in triple-negative MDA-MB-231 cells. In luminal A MCF-7 cells, the selection of a drug-resistant subline from parental cells with deregulation of p53 pathways occurred. These cells were demonstrated to be insensitive to DNA damage. Transcriptome analysis was carried out to identify differentially expressed genes (DEGs) in treated cells. DEG evaluation in breast cancer patients demonstrated their potential role as predictive biomarkers. High expression of the transporter associated with antigen processing 1 (TAP1) and the tumor protein p53-inducible protein 3 (TP53I3) was associated with shorter relapse in patients affected by ER+ breast tumor. Likewise, the same clinical outcome was associated with high expression of the lysosomal-associated membrane protein 1 LAMP1 in triple-negative breast cancer. Hypoxia inhibition by resveratrol treatment was found to partially re-sensitize cells to doxorubicin treatment. Our model might improve preclinical in vitro analysis for the translation of anticancer compounds as it provides: (a) more accurate data on drug efficacy and (b) enhanced understanding of resistance mechanisms and molecular drivers.

Setting Up a Medical Oncology Educational Program in Sub-Saharan Africa.

One of the major problems facing healthcare systems in countries with poor socio-economic conditions is the need to strengthen the system through the training of physicians, nurses and other healthcare operators. Partnering with more affluent countries is the key for hospitals in these areas, but such alliances are often based on limited educational exchanges. We present a retrospective study of our experience in building a collaborative relationship between our cancer institute in Italy and a Medical Center in sub-Saharan Africa (Tanzania). The main purpose is to see the changes in the clinical practice after educational interventions on health personnel in a Tanzanian cancer center.

Phase II study of liposomal doxorubicin, docetaxel and trastuzumab in combination with metformin as neoadjuvant therapy for HER2-positive breast cancer.

BACKGROUND: The aim of this study was to improve activity over single human epidermal growth factor receptor 2 (HER2)-blockade sequential neaodjuvant regimens for HER2-positive breast cancer, by exploiting the concomitant administration of trastuzumab, taxane and anthracycline, while restraining cardiac toxicity with use of liposomal doxorubicin, and by adding metformin, based on preliminary evidence of antitumor activity. PATIENTS AND METHODS: This multi-center, single-arm, two-stage phase II trial, assessed the safety and the activity of a new treatment regimen for HER2-positive, early or locally advanced breast cancer. Patients received six 21-day cycles of non-pegylated liposomal doxorubicin, 50 mg/m2 intravenously (i.v.) on day 1, docetaxel, 30 mg/m2 i.v. on days 2 and 9, trastuzumab, 2 mg/kg/week i.v. on days 2, 9, and 16 (with 4 mg/kg loading dose), in association with metformin 1000 mg orally twice daily. The primary endpoint was the rate of pathological complete response (pCR) in the breast and axilla (ypT0/is ypN0). A subgroup of patients performed a 3-deoxy-3-18F-fluorothymidine positron emission tomography (FLT-PET) at baseline and after one cycle. RESULTS: Among 47 evaluable patients, there were 18 pCR [38.3%, 95% confidence interval (CI) 24.5-53.6%]. A negative estrogen-receptor status, high Ki67, and histological grade 3 were related with pCR, although only grade reached statistical significance. FLT-PET maximum standardized uptake value after one cycle was inversely related to pCR in the breast (odds ratio 0.29, 95% CI 0.06-1.30, p = 0.11). Toxicity included grade 3-4 neutropenia in 70% and febrile neutropenia in 4% of patients, grade 1-2 nausea/vomiting in 60%/38%, and grade 3 in 4%/2%, respectively, grade 1-2 diarrhea in 72%, and grade 3 in 6%. There were two cases of reversible grade 2 left-ventricular ejection-fraction decrease, and one case of sharp troponin-T increase. CONCLUSIONS: The concomitant administration of trastuzumab, liposomal doxorubicin, docetaxel, and metformin is safe and shows good activity, but does not appear to improve activity over conventional sequential regimens.

An initiative to assess the quality of Tanzanian cervical cancer specimens for HPV and telomerase detection.

The aim of our study was to assess the quality of Tanzanian cervical cancer specimens, evaluating telomerase alterations and human papilloma virus (HPV) infection in relation to histopathological characteristics since these biomarkers are not routinely analyzed. Thirty-two Tanzanian women with invasive cervical cancer were included in the study. Histopathological classification and all the analyses on tissue, including TERT immunohistochemistry, were performed at IRST IRCCS (Meldola, Italy). HPV typization was performed by pyrosequencing. FHACT™ was used to identify chromosomal aberrations. Nonparametric ranking statistics were used. The majority (75 %) of the cases analyzed were squamous carcinoma, while 12.5 % were adenocarcinoma. The presence of HPV infection was confirmed in 26/27 (96.3 %) cases. A high percentage of patients (88 %) were infected with HPV16 of whom 12 (44.4 %) with African type 1, and 4 (14.8 %) with African type 2. TERT expression evaluated in the entire case series showed a median H-score of 130 (range 3-270), with only one negative case. 88 % of the FISH-evaluable samples showed an amplification of the chromosomal region 3q26 (TERC) and/or 5p15, and 20q13, associated with a higher median expression of TERT (P = 0.0226). Despite pre-analytical problems in terms of sample fixation, we showed that the search for biomarkers such as HPV and telomerase is feasible in Tanzanian tissue. These markers could be important risk-stratification tools in this population.

Preoperative or Perioperative Docetaxel, Oxaliplatin, and Capecitabine (GASTRODOC Regimen) in Patients with Locally-Advanced Resectable Gastric Cancer: A Randomized Phase-II Trial.

Docetaxel associated with oxaliplatin and 5-fluorouracil (FLOT) has been reported as the best perioperative treatment for gastric cancer. However, there is still some debate about the most appropriate number and timing of chemotherapy cycles. In this randomized multicenter phase II study, patients with resectable gastric cancer were staged through laparoscopy and peritoneal lavage cytology, and randomly assigned (1:1) to either four cycles of neoadjuvant chemotherapy (arm A) or two preoperative + two postoperative cycles of docetaxel, oxaliplatin, and capecitabine (DOC) chemotherapy (arm B). The primary endpoint was to assess the percentage of patients receiving all the planned preoperative or perioperative chemotherapeutic cycles. Ninety-one patients were enrolled between September 2010 and August 2016. The treatment was well tolerated in both arms. Thirty-three (71.7%) and 24 (53.3%) patients completed the planned cycles in arms A and B, respectively (p = 0.066), reporting an odds ratio for early interruption of treatment of 0.45 (95% confidence interval (CI): 0.18-1.07). Resection was curative in 39 (88.6%) arm A patients and 35 (83.3%) arm B patients. Five-year progression-free survival (PFS) was 51.2% (95% CI: 34.2-65.8) in arm A and 40.3% (95% CI: 28.9-55.2) in arm B (p = 0.300). Five-year survival was 58.5% (95% CI: 41.3-72.2) and 53.9% (95% CI: 35.5-69.3) (p = 0.883) in arms A and B, respectively. The planned treatment was more frequently completed and was more active, albeit not significantly, in the neoadjuvant arm than in the perioperative group.

Effectiveness of bevacizumab in first- and second-line treatment for metastatic colorectal cancer: ITACa randomized trial.

BACKGROUND: Cancer trials involving multiple treatment lines substantially increase our understanding of therapeutic strategies. However, even when the primary end-point of these studies is progression-free survival (PFS), their statistical analysis usually focuses on each line separately, or does not consider repeated events, thus missing potentially relevant information. Consequently, the evaluation of the effectiveness of treatment strategies is highly impaired. METHODS: We evaluated the potentially different effect of bevacizumab (B) administered for the first- or second-line treatment of metastatic colorectal cancer (mCRC) in the ITACa (Italian Trial in Advanced Colorectal Cancer) randomized trial. The ITACa trial consisted of two arms: first-line chemotherapy (CT)+B followed by second-line CT alone versus first-line CT alone followed by second-line CT+B or CT+B+cetuximab according to KRAS status. Cox models for repeated disease progression were performed, and potential selection bias was adjusted using the inverse probability of censoring weighting method. Hazard ratios (HR) [95% confidence interval (CI)] for PFS (primary endpoint) were reported. RESULTS: The overall effect of B across the two lines resulted in a HR = 0.80 (95% CI 0.68-0.95, p = 0.008). Evaluating the differential effect of B in first- and second-line, the addition of B to first-line chemotherapy (CT) produced a 10% risk reduction (HR = 0.90, 95% CI 0.72-1.12, p = 0.340) versus CT alone; B added to second-line CT produced a 36% risk reduction (HR = 0.64, 95% CI 0.49-0.84, p = 0.0011) versus CT alone. CONCLUSION: Our results seem to suggest that B confers a PFS advantage when administered in combination with second-line chemotherapy, which could help to improve current international guidelines on optimal sequential treatment strategies.

The impact of progesterone receptor expression on prognosis of patients with rapidly proliferating, hormone receptor-positive early breast cancer: a post hoc analysis of the IBIS 3 trial.

BACKGROUND: In the Italian Breast Cancer Intergroup Studies (IBIS) 3 phase III trial, we compared cyclophosphamide, methotrexate, 5-fluorouracil (CMF) alone to sequential epirubicin/CMF regimens in patients with rapidly proliferating early breast cancer (RPEBC). We performed a post hoc analysis in the subgroup of patients with hormone-receptor-positive RPEBC on the prognostic role of progesterone receptor (PgR) status. METHODS: RPEBC was defined by thymidine labeling index (TLI) >3% or grade 3 or S-phase >10% or Ki67 >20%. We analyzed 466 patients with hormone-receptor-positive RPEBC receiving sequential epirubicin/CMF regimens followed by tamoxifen, and for whom the status of ER and PgR was available. RESULTS: Considering both cut-off values of 10% and 20%, PgR expression was significantly associated with age, menopausal status, and ER expression; HER2 status was associated with PgR status only at a cutoff value of 20% PgR. Upon univariate analysis, tumor size, nodal status, and PgR were significantly associated with disease-free survival (DFS) and overall survival (OS), while age class and local treatment type were associated only with DFS. Patients with PgR <20% showed lower 5- and 10-year DFS [hazard ratio (HR) = 1.48; 95%CI: 1.01-2.18; p = 0.044] and OS (HR = 1.85; 95%CI: 1.08-3.19, p = 0.025) rates compared with patients with PgR ⩾20%. Upon multivariate analysis, only tumor size, nodal status, and PgR were independent prognostic factors. CONCLUSIONS: Our results highlight the independent prognostic relevance of PgR expression in patients with hormone-receptor-positive RPEBC treated with adjuvant chemotherapy and endocrine therapy, where the definition of prognostic subgroups is still a major need.

Insulin-like growth factor-1 receptor (IGF-1R) expression on circulating tumor cells (CTCs) and metastatic breast cancer outcome: results from the TransMYME trial.

PURPOSE: To evaluate the prognostic value of IGF-1R expression on circulating tumor cells (CTCs) in a prospective randomized clinical trial comparing chemotherapy plus metformin with chemotherapy alone in metastatic breast cancer (MBC) patients. METHODS: CTCs were collected at baseline and at the end of chemotherapy. An automated sample preparation and analysis system (CellSearch) were customized for detecting IGF-1R expression. The prognostic role of CTC count and IGF-1R was assessed for PFS and OS by univariate and multivariate analyses. RESULTS: Seventy-two out of 126 randomized patients were evaluated: 57% had ≥ 1 IGF-1R positive CTC and 37.5% ≥ 4 IGF-1R negative cells; 42% had CTC count ≥ 5/7.5 ml. At univariate analysis, the number of IGF-1R negative CTCs was strongly associated with risk of progression and death: HR 1.93 (P = 0.013) and 3.65 (P = 0.001), respectively; no association was detected between number of IGF-1R positive CTCs and PFS or OS (P = 0.322 and P = 0.840). The prognostic role of CTC count was confirmed: HR 1.69, P = 0.042 for PFS and HR 2.80 for OS, P = 0.002. By multivariate analysis, the prognostic role of the number of IGF-1R negative CTCs was maintained, while no residual prognostic role of CTC count or number of IGF-1R positive cells was found. CONCLUSION: Loss of IGF-1R in CTCs is associated with a significantly worse outcome in MBC patients. This finding supports further evaluation for the role of IGF-1R on CTCs to improve patient stratification and to implement new targeted strategies. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov (NCT01885013); European Clinical Trials Database (EudraCT No.2009-014,662-26).

Evaluating the appropriateness of chemotherapy in a low-resource cancer centre in sub-Saharan Africa.

BACKGROUND: To evaluate the appropriateness of chemotherapy use at the Oncology Department of the Bugando Medical Centre of Mwanza, Tanzania. METHODS: The study was an observational prevalence-based study designed to evaluate a single-chemotherapy cycle during a defined time period for a cross-section of patients at varying stages of their clinical history. The sample included 103 consecutive subjects who were treated during January-March 2017 and had at least one previous cycle. Chemotherapy treatment omissions, cycle delays, and dose reductions and their causes were recorded using a standard form that included demographic, anthropometric, and clinical items. The data were analyzed descriptively. RESULTS: There were 59 males (57.3%) and 44 females (42.7%). Ninety-four patients were aged ≥18 years. Considering cancer type/site, there were 23 distinct groups of patients. The recorded number of drugs in the chemotherapy regimens varied between one and five. The median cycle number was three (range: 2-11). Sixty-eight (66.0%) patients were treated in a standard fashion. For the remaining, cycle delay and dose reduction were the most common cause for nonstandard treatment. Hematologic toxicity was responsible for the greater part of cycle delays, whereas dose reductions were accounted for by a larger spectrum of causes. Overall, toxicity explained 21/35 (60.0%) patients receiving nonstandard treatment. The distribution of toxic events was skewed toward grade 1 and grade 2. CONCLUSIONS: The observed level of appropriateness of chemotherapy was encouraging. The proportion of patients experiencing severe toxic effects was lower than expected.

Multigene Panel Testing Increases the Number of Loci Associated with Gastric Cancer Predisposition.

The main gene involved in gastric cancer (GC) predisposition is CDH1, the pathogenic variants of which are associated with diffuse-type gastric cancer (DGC) and lobular breast cancer (LBC). CDH1 only explains a fraction (10-50%) of patients suspected of DGC/LBC genetic predisposition. To identify novel susceptibility genes, thus improving the management of families at risk, we performed a multigene panel testing on selected patients. We searched for germline pathogenic variants in 94 cancer-related genes in 96 GC or LBC Italian patients with early-onset and/or family history of GC. We found CDH1 pathogenic variants in 10.4% of patients. In 11.5% of cases, we identified loss-of-function variants in BRCA1, BRCA2, PALB2, and ATM breast/ovarian cancer susceptibility genes, as well as in MSH2, PMS2, BMPR1A, PRF1, and BLM genes. In 78.1% of patients, we did not find any variants with clear-cut clinical significance; however, 37.3% of these cases harbored rare missense variants predicted to be damaging by bioinformatics tools. Multigene panel testing decreased the number of patients that would have otherwise remained genetically unexplained. Besides CDH1, our results demonstrated that GC pathogenic variants are distributed across a number of susceptibility genes and reinforced the emerging link between gastric and breast cancer predisposition.

A biomimetic 3D model of hypoxia-driven cancer progression.

The fate of tumors depends both on the cancer cells' intrinsic characteristics and on the environmental conditions where the tumors reside and grow. Engineered in vitro models have led to significant advances in cancer research, allowing the investigation of cells in physiological environments and the study of disease mechanisms and processes with enhanced relevance. Here we present a biomimetic cancer model based on a collagen matrix synthesized through a biologically inspired process. We compared in this environment the responses of two breast tumor lineages characterized by different molecular patterns and opposite clinical behaviors: MCF-7 that belong to the luminal A subtype connected to an indolent course, and basal-like MDA-MB-231 connected to high-grade and aggressive disease. Cancer cells in the biomimetic matrix recreate a hypoxic environment that affects their growth dynamics and phenotypic features. Hypoxia induces apoptosis and the selection of aggressive cells that acquire expression signatures associated with glycolysis, angiogenesis, cell-matrix interaction, epithelial to mesenchymal transition and metastatic ability. In response to hypoxia MDA-MB-231 migrate on the collagen fibrils and undergo cellular senescence, while MCF-7 do not exhibit these behaviors. Our biomimetic model mimics the evolution of tumors with different grade of aggressiveness fostered by a hypoxic niche and provides a relevant technology to dissect the events involved in cancer progression.

Female breast cancers (T1-2, N0, M0, HR+, HER2-) with an intermediate genetic-based recurrence risk: a real-world estimate in Italy.

OBJECTIVES: Prognostic definition and treatment of breast cancer are supported by multigene testing. A recent trial (TAILORx) provided evidence against the use of adjuvant chemotherapy in early breast cancer (HR+ HER2-) with an intermediate result (11-25) in a multigene test (Oncotype DX). These results consequently fueled great discussion among oncologists. We aimed to estimate the burden of Italian incident breast cancer patients who, each year, may be involved in such decision-making. METHODS: We used the data collected in the Romagna Cancer Registry to estimate the number of cases with the inclusion criteria of the TAILORx trial. Adjustments based on geographical variability in breast cancer incidence in Italy were applied to national estimates. Cases were estimated by Oncotype DX recurrence risk groups: ⩽10, 11-25, ⩾26. We also estimated the proportion of grade 1, 2, or 3 disease among breast cancer cases. RESULTS: An overall 52,300 breast cancer cases were estimated to be diagnosed in Italy in 2018. Of these, 18,225 fit the TAILORx inclusion criteria: 3,025 were expected to have a low risk of recurrence (⩽10), 11,536 (63.3% of all cases) an intermediate risk (11-25), and 3,664 a high risk (⩾26). Among the group at intermediate risk, who may benefit from less aggressive therapy, 2,414 were estimated to have grade 1 disease, 7,618 grade 2, and 1,983 grade 3. CONCLUSIONS: This article provides reliable estimates on the burden of Italian women with breast cancer who, once tested with multigene testing, could potentially have their treatment changed to hormone therapy only.

Stemness underpinning all steps of human colorectal cancer defines the core of effective therapeutic strategies.

BACKGROUND: Despite their lethality and ensuing clinical and therapeutic relevance, circulating tumor cells (CTCs) from colorectal carcinoma (CRC) remain elusive, poorly characterized biological entities. METHODS AND FINDINGS: We perfected a cell system of stable, primary lines from human CRC showing that they possess the full complement of ex- and in-vivo, in xenogeneic models, characteristics of CRC stem cells (CCSCs). Here we show how tumor-initiating, CCSCs cells can establish faithful orthotopic phenocopies of the original disease, which contain cells that spread into the circulatory system. While in the vascular bed, these cells retain stemness, thus qualifying as circulating CCSCs (cCCSCs). This is followed by the establishment of lesions in distant organs, which also contain resident metastatic CCSCs (mCCSCs). INTERPRETATION: Our results support the concept that throughout all the stages of CRC, stemness is retained as a continuous property by some of their tumor cells. Importantly, we describe a useful standardized model that can enable isolation and stable perpetuation of human CRC's CCSCs, cCCSCs and mCCSCs, providing a useful platform for studies of CRC initiation and progression that is suitable for the discovery of reliable stage-specific biomarkers and the refinement of new patient-tailored therapies. FUND: This work was financially supported by grants from "Ministero della Salute Italiano"(GR-2011-02351534, RC1703IC36 and RC1803IC35) to Elena Binda and from "Associazione Italiana Cancro" (IG-14368) Angelo L. Vescovi. None of the above funders have any role in study design, data collection, data analysis, interpretation, writing the project.

Ten-year experience of the multidisciplinary Osteoncology Center.

PURPOSE: Bone metastases (BMs) are responsible for high morbidity in patients. A multidisciplinary approach involving a team of specialists offers an effective therapeutic strategy based on disease characteristics, medical history, and performance status. We evaluated the impact of our 10-year multidisciplinary experience on the management of patients with BM. METHODS: We retrospectively analyzed 2194 medical reports of 1628 patients referred to our Osteoncology Center from 2005 to 2015. Cases were discussed weekly by a multidisciplinary team. RESULTS: Eight hundred thirty-eight (38.2%) of the 2194 visits were requested because of a risk of complications from BM. Antiblastic treatment and bone-targeted therapy were modified in 709 (66.3%) and 309 (31%) of cases, respectively. Radiotherapy was scheduled in 220 (20%) of the 1099 patients for whom information was recorded. Patients completed the Brief Pain Inventory (BPI) during their first visit, 1296 (59.1%) reporting pain (median intensity 4), and 537 (41.4%) experiencing a level that interfered substantially with daily activities. New ortheses and/or antalgic therapy was prescribed accordingly. After 7 days, 208 (16%) patients were re-evaluated and a new BPI administered. A significant improvement in the worst (p < 0.0001) and current pain (p = 0.03) was seen, together with a favorable impact on daily activities (p = 0.02). Two thousand fifty-one patients completed an anonymous questionnaire on the quality of the service, the majority (69.4%) expressing high satisfaction. CONCLUSIONS: Our 10-year osteoncology experience confirms the importance of a multidisciplinary approach to optimize BM management. Further evaluations are needed in relation to quality of life, outcome, and costs.

Phase II Study of Dehydroepiandrosterone in Androgen Receptor-Positive Metastatic Breast Cancer.

LESSONS LEARNED: The androgen receptor (AR) is present in most breast cancers (BC), but its exploitation as a therapeutic target has been limited.This study explored the activity of dehydroepiandrosterone (DHEA), a precursor being transformed into androgens within BC cells, in combination with an aromatase inhibitor (to block DHEA conversion into estrogens), in a two-stage phase II study in patients with AR-positive/estrogen receptor-positive/human epidermal growth receptor 2-negative metastatic BC.Although well tolerated, only 1 of 12 patients obtained a prolonged clinical benefit, and the study was closed after its first stage for poor activity. BACKGROUND: Androgen receptors (AR) are expressed in most breast cancers, and AR-agonists have some activity in these neoplasms. We investigated the safety and activity of the androgen precursor dehydroepiandrosterone (DHEA) in combination with an aromatase inhibitor (AI) in patients with AR-positive metastatic breast cancer (MBC). METHODS: A two-stage phase II study was conducted in two patient cohorts, one with estrogen receptor (ER)-positive (resistant to AIs) and the other with triple-negative MBC. DHEA 100 mg/day was administered orally. The combination with an AI aimed to prevent the conversion of DHEA into estrogens. The main endpoint was the clinical benefit rate. The triple-negative cohort was closed early. RESULTS: Twelve patients with ER-positive MBC were enrolled. DHEA-related adverse events, reported in four patients, included grade 2 fatigue, erythema, and transaminitis, and grade 1 drowsiness and musculoskeletal pain. Clinical benefit was observed in one patient with ER-positive disease whose tumor had AR gene amplification. There was wide inter- and intra-patient variation in serum levels of DHEA and its metabolites. CONCLUSION: DHEA showed excellent safety but poor activity in MBC. Although dose and patient selection could be improved, high serum level variability may hamper further DHEA development in this setting.

Oxaliplatin plus leucovorin and 5-fluorouracil (FOLFOX-4) as a salvage chemotherapy in heavily-pretreated platinum-resistant ovarian cancer.

BACKGROUND: The purpose of this study was to evaluate the clinical impact of oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX-4) chemotherapy in terms of the response rate, progression-free/overall survival (PFS/OS) and safety profile in patients with heavily pretreated recurrent epithelial ovarian cancer. METHODS: Clinical data were reviewed in 29 patients who received FOLFOX-4 as more than third-line chemotherapy, consisting of 85 mg/m2 of oxaliplatin, 200 mg/m2 of leucovorin, and bolus 400 mg/m2 on day 1 of 5-fluorouracil, followed by a 22-h infusion of 600 mg/m2 of 5-fluorouracil for 2 consecutive days every 3 weeks. We also compared the efficacy and toxicity of FOLFOX-4 with that of topotecan, a standard treatment, given at a dosage of 1.5 mg/m2 every three weeks in 26 patients. RESULTS: The median age of enrolled patients was 60 years (range 33 to 85). A median of 4 cycles (range 1-17) of FOLFOX-4 were administered. Complete response and partial response were observed in one (3.5%) and 5 (17.2.2%) patients, respectively, while stable disease was reported in 8 (27.6%) patients. Among all patients, grade 3-4 anemia, neutropenia, and thrombocytopenia were observed in 0 (0%), 5 (17.2%), and 3 (10.3%) cases, respectively. Grade 3-4 fatigue was recorded in one (3.4%) patient and diarrhea in 2 (6.9%). Median PFS and OS were 2.8 months [95% confidence interval (CI) 1.7-4.9] and 6.2 months (95% CI 2.4-14.6), respectively. No significant differences in terms of efficacy and toxicity were observed between patients receiving FOLFOX-4 and those treated with topotecan. CONCLUSIONS: The FOLFOX-4 regimen would seem to obtain similar survival rates to those of standard therapy with topotecan in platinum-resistant ovarian cancer. Further randomized trials are warranted to confirm our findings.

Metastatic neuroendocrine neoplasia treatments in patients over 70 years of age.

The incidence of neuroendocrine neoplasia (NEN) is higher in individuals ≥70 years of age (elderly) who are underrepresented in clinical trials because of comorbidities and low performance status. We retrospectively analyzed the outcome of elderly patients with metastatic NEN (mNEN). Comorbidities were summarized by Charlson Comorbidity Index (CCI), Kaplan-Meier method was applied to estimate overall survival (OS) and Cox's proportional hazard model was used to assess the impact of known prognostic factors. We retrieved data on 145 mNEN patients aged ≥70 years seen at our center from June 2007 to March 2016. Fifty-six (38.6%) were aged ≥75 years. ECOG PS was 0 in 45.7% of cases and CCI was 0 in 41.0% and 1 in 37.4%. A total of 75.4% of patients had grade (G)1/G2 NEN and 24.6%, G3. Octreoscan/Gallium PET/CT and FDG-PET/CT were positive in 94.2% and 70.3% of cases, respectively. Median follow-up was 72.3 (53.2-85.1) months. Seventy-nine patients received first-line somatostatin analogs (SSA), 23 peptide receptor radionuclide therapy (PRRT) and 36 chemotherapy (CHT). Seven did not undergo first-line therapy and 102 received more than one line. Median overall survival (mOS) was 5.1 years (95% CI: 3.4-6.6). No differences in mOS were seen according to CCI. First-line PRRT patients had a mOS of 6.5 years (95% CI: 3.3-not reached (NR)), SSA 5.7 years (95% CI: 4.2-7) and CHT 5.9 years (95% CI: 0.4-NR). mOS in CHT-treated G3 patients was 1.5 years (1.0-2.5). ECOG PS and FDG PET/CT were identified as independent prognostic factors. Results suggest that the above treatments positively impacted OS in elderly mNEN patients, including those aged ≥75 years.

IL-8 and thrombospondin-1 as prognostic markers in patients with metastatic colorectal cancer receiving bevacizumab.

Purpose: Bevacizumab (B) plus chemotherapy (CT) is a common choice for first-line treatment of metastatic colorectal cancer. Molecular predictors of B efficacy have still not been identified. We analyzed the role of 22 angiogenesis-associated proteins in patient outcome. Patients and methods: Serum samples collected at baseline and at the first clinical evaluation were available for 58 patients enrolled in the randomized multicenter ITACa trial and who received CT+ B. Serum protein levels were determined using multiplex ELISA. Results: Patients with baseline ≥145 pg/mL IL-8 showed shorter median progression-free survival and overall survival (OS) than those with lower levels (6.5 vs 6. 12.6 months; HR 7.39, P<0.0001 and 8.7 vs 28.8 months, HR 7.68, P<0.001, respectively). Moreover, patients with baseline thrombospondin-1 levels ≥12,000 ng/mL had a better median OS than those with lower levels (34.5 vs 13.1 months, HR 0.43, P=0.007). Patients with a ≥20% reduction in IL-8 levels from baseline to first clinical evaluation showed a better progression-free survival and OS than the others (HR 0.41, P=0.005 and HR 0.43, P=0.007, respectively). Conclusion: Baseline IL-8 and thrombospondin-1 levels and reduced IL-8 during B treatment could represent potential prognostic markers in metastatic colorectal cancer.

Prognostic role of aspartate aminotransferase-lymphocyte ratio index in patients with metastatic colorectal cancer: results from the randomized ITACa trial.

BACKGROUND: The aim of this study was to investigate the role of pre-treatment aspartate aminotransferase-lynphocyte ratio (ALRI) as a predictor of prognosis and treatment efficacy in patients with metastatic colorectal cancer (mCRC) enrolled in the prospective multicenter randomized ITACa (Italian Trial in Advanced Colorectal Cancer) trial to receive first-line chemotherapy (CT) + bevacizumab (B) or CT alone. PATIENTS AND METHODS: Patients randomly received CT+B or CT alone as first-line therapy. CT consisted of either FOLFOX4 or FOLFIRI at the clinician's discretion. RESULTS: Out of the 284 patients enrolled, increased ALRI levels were associated with shorter PFS and OS (p<0.0001). At baseline, median PFS was 10.3 months (95% CI 9.4-12.0) and 8.0 months (95 % CI 6.8-8.9), and median OS was 25.2 months (95 % CI 21.3-30.2) and 18.8 months (95 % CI 16.6-21.7) for patients with low (<14) and high (≥14) ALRI levels, respectively (HR 1.43, 95% CI 1.12-1.82, p=0.004; HR=1.51, 95% CI 1.17-1.96, p<0.001). Interaction tests on ALRI levels and treatment efficacy in the CT+B and the CT groups were statistically significant for PFS (p=0.0003), but not for OS (p=0.228). CONCLUSION: Our results indicate that ALRI is a good prognostic and predictive marker for mCRC patients candidate for CT+B.