Machine learning to predict overall short-term mortality in cutaneous melanoma.

BACKGROUND: Cutaneous malignant melanoma (CMM) ranks among the ten most frequent malignancies, clinicopathological staging being of key importance to predict prognosis. Artificial intelligence (AI) has been recently applied to develop prognostically reliable staging systems for CMM. This study aims to provide a useful machine learning based tool to predict the overall CMM short-term survival. METHODS: CMM records as collected at the Veneto Cancer Registry (RTV) and at the Veneto regional health service were considered. A univariate Cox regression validated the strength and direction of each independent variable with overall mortality. A range of machine learning models (Logistic Regression classifier, Support-Vector Machine, Random Forest, Gradient Boosting, and k-Nearest Neighbors) and a Deep Neural Network were then trained to predict the 3-years mortality probability. Five-fold cross-validation and Grid Search were performed to test the best data preprocessing procedures, features selection, and to optimize models hyperparameters. A final evaluation was carried out on a separate test set in terms of balanced accuracy, precision, recall and F1 score. The best model was deployed as online tool. RESULTS: The univariate analysis confirmed the significant prognostic value of TNM staging. Adjunctive clinicopathological variables not included in the AJCC 8th melanoma staging system, i.e., sex, tumor site, histotype, growth phase, and age, were significantly linked to overall survival. Among the models, the Neural Network and the Random Forest models featured the best prognostic performance, achieving a balanced accuracy of 91% and 88%, respectively. According to the Gini importance score, age, T and M stages, mitotic count, and ulceration appeared to be the variables with the greatest impact on survival prediction. CONCLUSIONS: Using data from patients with CMM, we developed an AI algorithm with high staging reliability, on top of which a web tool was implemented ( unipd.link/melanomaprediction ). Being essentially based on routinely recorded clinicopathological variables, it can already be implemented with minimal effort and further tested in the current clinical practice, an essential phase for validating the model's accuracy beyond the original research context.

Isolated limb perfusion for the management limb threatening soft tissue sarcomas: The role of histological type on clinical outcomes.

BACKGROUND: Hyperthermic isolated limb perfusion (HILP) is an effective neoadjuvant treatment to avoid amputation in patients with locally advanced extremity soft tissue sarcomas (STS). We aimed to investigate whether STS histological type plays a role in predicting clinical outcomes. METHODS: This study reports a retrospective analysis of 125 patients with limb threatening STS (liposarcoma, n = 41; malignant peripheral nerve sheath tumor, n = 20; leiomyosarcoma, n = 20; miscellany, n = 44), who underwent HILP from 1990 through 2015 at our institution. The following endpoints were evaluated: tumor response (assessed by radiological imaging and histology), limb sparing rate, local progression-free survival (LPFS) and overall survival (OS). RESULTS: On average, overall (complete + partial) tumor response was significantly greater in patients affected with liposarcoma as compared to those with other histotypes (radiological response rate: 38/41, 92.7% vs 66/84, 78.6%, P-value: 0.048; mean histological necrosis: 83.6% vs 52.9%, P < 0.0001). Limb sparing rate was also higher among patients with liposarcoma as compared to other histotypes (39/41, 95.1% vs 62/84, 73.8%, P-value: 0.005). As regards survival, LPFS was similar across tumor types, whereas OS resulted significantly worse in patients with limb leiomyosarcoma (log-rank P-value: 0.009). CONCLUSIONS: HILP is a very effective treatment modality for limb threatening STS. In our series, liposarcoma appears to be the histological type most sensitive to HILP in terms of tumor response and thus limb sparing, which might help clinicians in the patient selection process.

Treatment efficacy with electrochemotherapy: A multi-institutional prospective observational study on 376 patients with superficial tumors.

BACKGROUND: Cutaneous metastases represent a therapeutic challenge. An increasing body of experience suggests that electrochemotherapy (ECT) provides effective tumor control, although its evidence basis should be strengthened. METHODS: This prospective, multicenter, observational study enrolled patients with superficial metastases, who underwent ECT at 10 centers between 2008 and 2013. Outcomes included adherence to European Standard Operating Procedures of ECT (ESOPE), tumor response, local progression-free survival (LPFS), toxicity and patient-reported outcomes (PROs, EORTC QLQ-C30 plus an 8-item questionnaire). RESULTS: We enrolled 376 eligible patients. Tumor histotype distribution was as follows: melanoma, 56%; squamous cell carcinoma, 11%; Kaposi sarcoma, 11%; breast carcinoma, 8%; basal cell carcinoma, 6%; soft tissue sarcomas, 3%; others, 5%. We registered 1304 target tumors (median size 1 cm). Treatment adhered to ESOPE in 88% of patients as to the route of drug administration, and in 70% as to electrode application. The procedure was mainly performed under sedation (64.6%) and by using intravenous chemotherapy (93.4%). Tumor response rate at 60 days was 88% (complete, 50%). Small tumor size predicted complete response achievement (OR 2.24, p = 0.003), higher LPFS (HR 0.68, p = 0.004) and improved PROs (Global Health Status, p < 0.001; wound bleeding, p < 0.001; healing, p = 0.002; and aesthetics, p < 0.001). Skin toxicity (grade ≥3, 7.8%) was lower in patients with tumors <2 cm (p≤0.001). One-year LPFS was 73.7% (95%CI 68.4-78.3). CONCLUSIONS: ECT represents a valuable skin-directed therapy across a range of malignancies. The most frequently applied treatment modality is intravenous chemotherapy under sedation. Small tumor size predicts durable tumor control, fewer side-effects and better PROs.

Differences in telomere length between sporadic and familial cutaneous melanoma.

BACKGROUND: Several pieces of evidence indicate that a complex relationship exists between constitutional telomere length (TL) and the risk of cutaneous melanoma. Although the general perception is that longer telomeres increase melanoma risk, some studies do not support this association. We hypothesize that discordant data are due to the characteristics of the studied populations. OBJECTIVES: To evaluate the association of TL with familial and sporadic melanoma. MATERIALS AND METHODS: TL was measured by multiplex quantitative polymerase chain reaction in leukocytes from 310 patients with melanoma according to familial/sporadic and single/multiple cancers and 216 age-matched controls. RESULTS: Patients with sporadic melanoma were found to have shorter telomeres compared with those with familial melanoma. In addition, shorter telomeres, while tending to reduce the risk of familial melanoma regardless of single or multiple tumours, nearly trebled the risk of single sporadic melanoma. CONCLUSIONS: This is the first time that TL has been correlated to opposite effects on melanoma risk according to the presence or absence of familial predisposition. Individual susceptibility to melanoma should be taken into account when assessing the role of TL as a risk factor.

Personalised medicine: Development and external validation of a prognostic model for metastatic melanoma patients treated with ipilimumab.

PURPOSE: The purpose of this study was to set up a prognostic model for the identification of survival predictors specific for melanoma patients treated with ipilimumab. EXPERIMENTAL DESIGN: The following prospectively collected data were utilised: patient and primary tumour characteristics, relapse-free-interval, site and number of metastases, previous therapies and level of serum biomarkers (lactic dehydrogenase (LDH), C-reactive protein, ß2-microglobulin, vascular endothelial growth factor (VEGF), IL2, IL6, S-100, alkaline phosphatase (ALP), transaminases, leucocyte count, lymphocytes subpopulations). A multivariate prognostic model was developed using the Cox regression model fitted to the data of 113 consecutive metastatic patients treated with ipilimumab (3 mg/kg, q3w) at Veneto Institute of Oncology (IOV). External validation was obtained using the data of 69 and 34 patients treated at European Oncology Institute (IEO) and University of Torino (UT), respectively. RESULTS: Median survival was 8.3, 4.9 and 7.1 months from first ipilimumab administration at IOV, IEO and UT, respectively. Both higher baseline levels of LDH (Hazard Ratio [HR] v=1.36, 95% Confidence Interval [CI] 1.16-1.58, P<.001) and neutrophils (HR=1.76, 95% CI 1.41-2.10, P<.001) were associated with worse prognosis. Model performance was satisfactory both upon internal validation (Dxy=0.42) and external validation (Dxy=0.40). Serum LDH and neutrophil count discriminated patients who lived more (low neutrophils and low LDH) or less (high LDH or neutrophils) than 24 months. CONCLUSION: Serum LDH and neutrophil count were significant independent prognostic factors. This externally validated prognostic nomogram, could help clinicians to identify the patients who would benefit most from ipilimumab and consequently to improve resource allocation. These easily available biomarkers deserve further validation.

Histopathological characteristics of subsequent melanomas in patients with multiple primary melanomas.

BACKGROUND: Multiple primary melanomas (MPM) occur in up to 20% of melanoma patients, and subsequent tumours seem to have a favourable histopathological pattern. OBJECTIVE: A prospectively collected cohort of 194 patients with MPM was retrospectively reviewed to investigate clinical and histopathological features of first and subsequent melanomas. METHODS: Patients with MPM who were diagnosed at our Department (1985-2011) and who attended at least a follow-up control yearly were identified. RESULTS: The number of nevi was <10, 10-50 and >50 in 8.7%, 41% and 50.3% of patients respectively. Histopathological dysplastic nevi have been diagnosed in 105 patients. During a median follow-up of 58 months, 159 (81.9%), 24 (12.3%), 7 (3.6%) and 4 (2%) patients developed 2, 3, 4 and ≥ 5 melanomas, respectively. The median time to second primary melanoma was 45 months. The second primary melanoma was diagnosed within 1-year and after 5-year from the first melanoma in 36.6% and 17.3% of patients respectively. First and second primary melanomas were in situ in 41 (21%) and 104 (54%) patients respectively (P < 0.001). Among patients with ≥ 2 invasive melanomas (N = 80), median tumour thickness and ulceration of first and second primaries were 0.91 and 0.44 mm (P <0.001), and 32% and 7.7% (P = 0.001) respectively. CONCLUSIONS: Subsequent melanomas occurred within 1-year from the appearance of the first melanoma in 36% of patients with MPM, while a late melanoma diagnosis was detected in 17% of cases. Second primary melanoma had favourable histopathological features. Our findings support long-term skin surveillance to detect subsequent melanomas at an early stage.

The number of excised lymph nodes is associated with survival of melanoma patients with lymph node metastasis.

BACKGROUND: Although the number of excised LNs has been associated with patient prognosis in many solid tumors, this association has not been widely investigated in cutaneous melanoma. This study aims to evaluate the association between the number of excised regional lymph nodes (LNs) and melanoma-specific survival. PATIENT AND METHODS: Clinico-pathological data from 2507 patients with LN metastasis treated at nine Italian centers were retrospectively collected. RESULTS: The number of excised LNs correlated with younger age (P < 0.001), male sex (P < 0.001), neck LN field (P < 0.001), LN micrometastasis (P < 0.001) and number of positive LNs (P < 0.001). The number of excised LNs was an independent prognostic factor (HR = 0.85; P = 0.002) after adjustment for other staging features. Upon subgroup analysis, the number of excised LNs had a significant prognostic value in patients bearing 1.01-2.00 mm (HR = 0.79; P = 0.032) and 2.01-4.00 mm (HR = 0.71; P < 0.001) thick melanomas, primary tumors showing ulceration (HR = 0.86; P = 0.033) and Clark level V of invasion (HR = 0.86; P = 0.010), LN micrometastasis (HR = 0.83; P = 0.014) and two to three positive LNs (HR = 0.71; P = 0.001). Finally, this study investigated the influence of the number of excised LNs on patient staging: only when ≥11 nodes were excised the AJCC N stage could stratify prognosis (P < 0.001). Considering the number of excised LNs for each lymphatic field, at least 14, 11, 10 and 12 LNs were needed to stage patients according to the AJCC N stage after a lymphadenectomy of the neck, axilla, inguinal and ilioinguinal LN fields, respectively. CONCLUSIONS: The number of excised LNs can be considered for risk stratification of patients with regional LN metastasis from cutaneous melanoma. We demonstrated that a minimum number of LNs is required for the correct staging of patients. Further research is needed to evaluate the effectiveness of the minimum number of LNs to be dissected.

Gastrointestinal carcinoid: epidemiological and survival evidence from a large population-based study (n = 25 531).

BACKGROUND: Owing to its rarity, the published evidence on gastrointestinal (GI) carcinoid is often based on small series of patients or population-based studies regarding all neuroendocrine tumors. Here, we present a comprehensive epidemiological and survival analysis of the largest cohort of patients with GI carcinoid ever reported. PATIENTS AND METHODS: Patients with histological diagnosis of GI carcinoid (n = 25 531) were identified from the Surveillance Epidemiology End Results (SEER) database (including 18 USA cancer registries and spanning the 1973-2009 time frame). Demographic and disease data were used for epidemiological and survival analyses. RESULTS: The incidence of GI carcinoid is steadily increasing over the past three decades at a rate higher than any other cancer [annual percentage change (APC) = 4.4, 95% confidence interval (CI) 4.0-4.8]. These patients have a higher risk of further primary tumor (standardized incidence ratio, SIR = 1.15, 95% CI 1.10-1.21), but also a reduced risk of skin melanoma (SIR = 0.64, 95% CI 0.41-0.95). Despite the overall favorable prognosis (5-year disease-specific and relative survival rate: 91.3% and 87.4%, respectively), the mortality rate is increasing over time (APC = 3.5, 95% CI 3.0-4.0) and the 5-year survival rate of patients dying of GI carcinoid (28.5%), though better than that reported for GI cancers in general (8.4%), cannot be considered satisfactory. Finally, a nomogram is provided to predict patient survival on the basis of clinico-pathological factors independently associated with prognosis at multivariate analysis. CONCLUSIONS: These findings can be clinically useful for the management of patients with GI carcinoid and eagerly prompt the continuous effort to develop more effective therapeutic strategies against this slow-growing but chemoresistant tumor.

Adherence to treatment guidelines for primary sarcomas affects patient survival: a side study of the European CONnective TIssue CAncer NETwork (CONTICANET).

BACKGROUND: The impact of adherence to clinical practice guidelines (CPGs) for loco-regional treatment (i.e. surgery and radiotherapy) and chemotherapy on local disease control and survival in sarcoma patients was investigated in a European study conducted in an Italian region (Veneto). PATIENTS AND METHODS: The completeness of the adherence to the Italian CPGs for sarcomas treatment was assessed by comparing the patient's charts and the CPGs. Propensity score-adjusted multivariate survival analysis was used to assess the impact of CPGs adherence on patient clinical outcomes. RESULTS: A total of 151 patients were included. Adherence to CPGs for loco-regional therapy and chemotherapy was observed in 106 out of 147 (70.2%) and 129 out of 139 (85.4%) patients, respectively. Non-adherence to CPGs for loco-regional treatment was independently associated with AJCC stage III disease [odds ratio (OR) 1.77, P = 0.011] and tumor-positive excision margin (OR 3.55, P = 0.003). Patients not treated according to the CPGs were at a higher risk of local recurrence [hazard ratio (HR) 5.4, P < 0.001] and had a shorter sarcoma-specific survival (HR 4.05, P < 0.001), independently of tumor stage. CONCLUSIONS: Incomplete adherence to CPGs for loco-regional treatment of sarcomas was associated with worse prognosis in patients with non-metastatic tumors.

Circumventing melanoma chemoresistance by targeting DNA repair.

Available evidence demonstrates that the DNA repair machinery is involved in melanoma resistance to chemotherapeutics. Furhtermore, preclinical findings suggest that interfering with DNA repair could increase chemosensitivity of melanoma cells. However, the clinical implementation of these principles is still in its infancy and no such strategy is currently proven to be effective in patients with advanced melanoma. Since the molecular mechanisms governing the relationship between chemoresistance and DNA repair are not fully elucidated, more basic and translational research is needed to understand the reasons for the failures and to identify novel targets. In this review we summarize the experimental and clinical findings that are fostering the research in this promising field of oncology.

Cancer resistance to type II topoisomerase inhibitors.

Type II topoisomerases (TOPO2) are ubiquitously expressed enzymes that overcome topological problems in genomic DNA, which can result from DNA replication, transcription and repair. The class of compounds targeting TOPO2 includes some of the most active chemotherapy agents currently available for the treatment of patients with different cancer types. Therefore, understanding of the molecular mechanisms underlying resistance to these drugs is of pivotal importance to improve their efficacy and ultimately increase the life expectancy of cancer patients. The first aim of this review is to summarize the molecular biology of TOPO2 inhibitors, which is the key to understand cancer resistance to them; the second part of this work is dedicated to overview and discuss the available evidence on the mechanisms of resistance to these drugs, with special attention to the strategies that might be useful to circumvent this phenomenon on the clinical ground.

Electrochemotherapy for disseminated superficial metastases from malignant melanoma.

BACKGROUND: The aim of the study was to determine predictive factors for effectiveness, toxicity and local disease control in patients with malignant melanoma treated with bleomycin-based electrochemotherapy (ECT). METHODS: Electrochemotherapy was offered to patients with superficially disseminated melanoma metastases unsuitable for resection and unresponsive to chemotherapy. RESULTS: Eighty-five patients were treated with up to six ECT cycles with minimal, mainly dermatological, toxicity. One month after the first ECT, an objective response was observed in 80 patients (94 per cent). After retreatment because of a partial response in 39 patients, a complete response was achieved in 19 patients. Among the 41 (48 per cent) complete responders at first ECT, 19 patients received a second cycle because of new lesions after a median of 6 (range 2-14) months. After a median follow-up of 26 months, six patients experienced local recurrence with a 2-year local progression-free survival rate of 87 per cent. In multivariable analysis, significant predictive factors for response were tumour size (odds ratio (OR) 0·23, 95 per cent confidence interval (c.i.) 0·19 to 0·86; P = 0·003) and number of lesions (OR 0·38, 0·28 to 0·88; P = 0·002). An increasing number of electrode applications (hazard ratio (HR) 2·18, 95 per cent c.i. 1·22 to 3·44; P = 0·041) and ECT cycles (HR 0·46, 0·22 to 0·95; P = 0·005) were predictors of local control. There were no predictors of toxicity. Melanoma thickness and lower limb location of metastases were prognostic for survival. CONCLUSION: The most suitable candidates for ECT were patients with few and small metastases on the lower limb treated with multiple electrode applications and ECT cycles.

Validation of the new AJCC TNM staging system for gastric cancer in a large cohort of patients (n = 2,155): focus on the T category.

BACKGROUND: The prognostic value of T subclassification in patients with gastric carcinoma has been just implemented in the new AJCC TNM staging system, which has reclassified T2a and T2b into T2 and T3 tumors, respectively. The aim of the present study was to validate the prognostic significance of the new T categorization within the frame of the latest TNM staging system. METHODS: We retrospectively reviewed the records of 686 T2/T3 patients among 2155 subjects who underwent radical resection for gastric carcinoma at six Italian centers from 1988 through 2006. RESULTS: Upon multivariate analysis, the new T categories, extent of lymph node dissection (D) and patient's age were retained by the survival model as independent prognostic factors. In particular, the death risk for patients with T3 tumors was higher than that of patients with T2 tumors (HR: 1.42, P = 0.005). Among the 686 patients previously classified as having T2 tumors, patients with T2 and T3 disease were 270 (39.4%) and 416 (60.6%), respectively. After a median follow-up of 55 months, the 5-year overall survival rates were 67.3% and 52.3% for patients with T2 and T3 tumors, respectively (P < 0.001). The survival advantage for the T2 as compared to T3 category was maintained even when N0 and N+ patients were separately considered (P = 0.0154 and P < 0.001, respectively). CONCLUSIONS: Our data confirm the prognostic difference between the newly proposed T2 and T3 categories, which should be implemented in the routine clinical practice to improve risk stratification of patients with gastric cancer.

Maximizing the clinical usefulness of a nomogram to select patients candidate to sentinel node biopsy for cutaneous melanoma.

AIMS: Investigators from the Memorial Sloan Kettering Cancer Centre (MSKCC) have proposed a nomogram for predicting the sentinel node (SN) status in patients with cutaneous melanoma. The negative predictive value (NPV) of this test, which might help identify low-risk patients who might be safely spared SN biopsy (SNB), has not been yet investigated. METHODS: We tested the discrimination (area under the curve [AUC]), the calibration (linear regression) and the NPV of MSKCC nomogram in 543 patients treated at our institution. Different cut-off values were tested to assess the NPV, the reduction of SNB performed and the overall error rate obtained with the MSKCC nomogram. RESULTS: SN was positive in 147 patients (27%). Mean predicted probability was 17.8% (95%CI: 16.8-18.8%). Nomogram discrimination was significant (area under the curve = 0.68; P < 0.0001) and mean predicted probabilities of SN positivity well correlated with the observed risk (R(2) = 0.99). Cut-off values between 4% and 9% led to a NPV, SNB reduction and overall error rates ranging between 100 and 91.2%, 2.2 and 27.2%, and 0 and 2.3%, respectively. CONCLUSION: In our series, the nomogram showed a significant predictive accuracy, although the incidence of SN metastasis was higher than that observed in the MSKCC series (27% vs 16%). Using the nomogram, a NPV greater than 90% could be obtained, which would be associated with a clinically meaningful reduction of the SNB rate and an acceptable error rate. If validated in large prospective series, this tool might be implemented in the clinical setting for SNB patient selection.

The anticancer face of interferon alpha (IFN-alpha): from biology to clinical results, with a focus on melanoma.

Alpha interferons (IFN) are type I IFNs that have pleiotropic effects on cell functions. A wealth of evidence exists that these cytokines exhibit a variety of biological effects different from those on viral replication, including antitumor activity. IFNs-alpha represent the cytokines exhibiting the longest record of use in clinical oncology for the treatment of over a dozen of cancer types, including some hematological malignancies and solid tumors. Although targeted anticancer agents have recently replaced IFN-alpha in the treatment of certain hematological (e.g. chronic myeloid leukemia) and solid (e.g. renal cell carcinoma) malignancies, this cytokine is still used for the treatment of patients with specific tumor types, such as cutaneous melanoma. Despite the intense work in preclinical tumor models and considerable experience in the clinical use of IFN-alpha, the mechanisms of action underlying tumor response is still a matter of open debate. In this review we describe the evidence supporting the main mechanisms underlying IFN-alpha anticancer effects using both preclinical and clinical findings; moreover, we focus on the results of IFN-alpha for the treatment of patients with high-risk cutaneous melanoma, one of the malignancies most resistant to conventional chemotherapy.

Targeting death receptors to fight cancer: from biological rational to clinical implementation.

Considering that most currently available chemotherapeutic drugs work by inducing cell apoptosis, it is not surprising that many expectations in cancer research come from the therapeutic exploitation of the naturally occurring death pathways. Receptor mediated apoptosis depends upon the engagement of specific ligands with their respective membrane receptors and - within the frame of complex regulatory networks - modulates some key physiological and pathological processes such as lymphocyte survival, inflammation and infectious diseases. A pivotal observation was that some of these pathways may be over activated in cancer under particular circumstances, which opened the avenue for tumor-specific therapeutic interventions. Although one death-related ligand (e.g., tumor necrosis factor, TNF) is currently the basis of effective anticancer regimens in the clinical setting, the systemic toxicity is hampering its wide therapeutic exploitation. However, strategies to split the therapeutic from the toxic TNF activity are being devised. Furthermore, other death receptor pathways (e.g., Fas/FasL, TRAIL/TRAIL receptor) are being intensively investigated in order to therapeutically exploit their activity against cancer. This article summarizes the current knowledge on the molecular features of death receptor pathways that make them an attractive target for anticancer therapeutics. In addition, the results so far obtained in the clinical oncology setting as well as the issues to be faced while interfering with these pathways for therapeutic purposes will be overviewed.

Separate cavity margins excision as a complement to conservative breast cancer surgery.

BACKGROUND: Positive lumpectomy margins (LM) usually mandate re-excision. However, approximately half of these patients have no residual tumour in the re-excision specimen. The aim of this study was to investigate if separate cavity margin (CM) excision can safely reduce the need of re-operation. METHODS: Rate of re-operation for margin involvement and incidence of residual tumour in the re-excision specimen were retrospectively evaluated in 237 patients (group A) who underwent lumpectomy alone, and in 271 patients (group B) treated by lumpectomy and CM excision. Patients with positive LM (group A) or CM (group B) underwent re-excision. RESULTS: In the group A, 50/237 patients (21.1%) had LM+ and underwent re-excision. In the group B, 74/271 patients (27.3%) had LM+, but tumour was found within the CM specimen in 46 patients (17.0%), 24 LM+ and 22 LM-, and reached the CM cut edge in only 15 (5.5%), who finally underwent re-excision. Residual tumour was found in the re-excision specimen in 28/50 patients (56.0%) of the group A and in 7/15 patients (46.7%) of the group B. CONCLUSIONS: Separate CM excision strongly decreases the rate of re-operation for involved margin. However, the finding of various combinations of LM and CM status and the evidence that CM excision does not improve the positive predictive value of margin involvement suggest prudent conclusions. Only long term follow up of patients treated according to the CM status can exclude that the reduced rate of re-operations allowed by this procedure would expose to an increased risk of local recurrence.

Overall survival in BRCA-associated ovarian cancer: case-control study of an Italian series.

About 10% of all ovarian cancers are due to BRCA 1 and/or BRCA 2 mutations. Some studies have shown that patients belonging to this group have a better survival compared to sporadic groups but data are still inconclusive. The aim of this study was to investigate overall survival in patients with ovarian cancer and germ-line mutations in the BRCA1/2 genes in comparison to high-risk patients, defined as patients with ovarian cancer and a strong family history of breast and ovarian cancer, but who tested negative for the BRCA mutation. We collected all the clinical features and did follow-up. The two groups showed similar characteristics concerning age at diagnosis, histological type and stage. Grade 3 was more frequent in the BRCA group. Survival data did not show any advantage for the BRCA mutated group.

Peptide-based anticancer vaccines: recent advances and future perspectives.

Anticancer active immunotherapy embodies the ideal antitumor therapy, as it theoretically combines target specificity with long-term disease control. Peptide-based cancer vaccines represent the most specific approach to polarize the immune system against malignant cells, since they are preparations made of single epitopes, the minimal immunogenic region of an antigen. Despite the strong rational, the promising preclinical results and the frequent induction of antigen-specific immune responses, peptide-based cancer vaccines have yielded relatively poor results in the clinical setting, a phenomenon likely due to the immunosuppressive properties of the tumor microenvironment that allow malignant cells to evade both naturally occurring and therapeutically induced immune surveillance. Nevertheless, advances in the engineering of peptides and in our understanding of the molecular mechanisms underlying an effective immune response against tumors have renewed the enthusiasm for peptide-based vaccination regimens in the setting of cancer, and a variety of clinical trials are being conducted based on the use of peptides. This review will describe the most recent insights in the rational design of peptide-based cancer vaccines, as well as the challenges to successful anticancer immunotherapy based on these short amino acid chains.