Oxaliplatin prior to PARP inhibitor in BRCA-mutated ovarian cancer.

Background: The use of PARP inhibitor (PARPi) has shown a considerable benefit in progression-free survival (PFS) in relapsed, platinum-sensitive epithelial ovarian cancer (OC). Objective: Our study aimed to investigate the impact of the last platinum-based chemotherapy treatment in response to PARPi. Design: Retrospective cohort study. Patients and methods: The study involved 96 consecutive, pretreated, platinum-sensitive advanced OC patients. Demographics and clinical data were retrieved from clinical records. PFS and overall survival (OS) were calculated from the start of PARPi. Results: Germline BRCA mutation was investigated in all cases. Platinum-based chemotherapy before PARPi maintenance therapy included pegylated liposomal doxorubicin-oxaliplatin (PLD-Ox) in 46 patients (48%) and other platinum-based chemotherapy in 50 patients (52%). During a median follow-up of 22 months from the beginning of PARPi therapy, 57 patients relapsed (median PFS: 12 months) and 64 patients died (median OS: 23 months). During multivariable analysis, receiving PLD-Ox before PARPi was associated with improved PFS [hazard ratio (HR): 0.46, 95% CI: 0.26-0.82] and OS (HR: 0.48, 95% CI: 0.27-0.83). In 36 BRCA-mutated patients, PLD-Ox was associated with improved PFS (2-year PFS: 70.0% versus 25.0%, p = 0.02). Conclusion: Receiving PLD-Ox before PARPi may improve prognosis in platinum-sensitive advanced OC patients and may provide advantages in the BRCA-mutated subgroup.

Effectiveness of body size stratification for patient exposure optimization in Computed Tomography.

PURPOSE: To establish size-dependent DRL and to estimate the effectiveness of the size-dependent DRLs over size-independent DRLs for a CT exposure optimization process. METHODS: The study included 16,933 adult CT body examinations of the most common CT protocols. Acquisitions were included following an image quality assessment. Patients were grouped into five different classes by means of the water equivalent diameter (Dw): 21 ≤ Dw < 25, 25 ≤ Dw < 29, 29 ≤ Dw < 33,33 ≤ Dw < 37 (in cm). CTDIvol, DLP, DLPtot. and SSDE median values were provided both for the sample as a whole (size-independent approach) and for each Dw class (size-dependent approach). The performance of the two approaches in classifying sub-optimal examinations was evaluated through the confusion matrix and Matthews Correlation Coefficient (MCC) metric. The 75th percentile of the CTDIvol distribution was arbitrarily chosen as a threshold level above which the acquisitions are considered sub-optimal. RESULTS: CTDIvol, DLP, DLPtot and SSDE typical values (median values) are statistically different across Dw groups. The confusion matrix analysis suggests that size-independent DRL could not mark potential suboptimal protocols for small and large patients. The agreement between the size-dependent and size-independent methods is strong only for the most populous classes (MCC > 0.7). For small and large patients size-independent approach fails to identify as sub-optimal around 20 % of the acquisition (MCC≪0.2). CONCLUSIONS: It was proven by means of the confusion matrix and MCC metric that stratifying DRLs by patient size, size-dependent DRL can be a powerful strategy in order to improve the dose optimization process shown that a size-independent DRL fails to identify sub-optimal examinations for small and large patients.

A rare case of extrarenal Wilms tumor of the uterine corpus: comprehensive genomic profile and review of the literature.

Wilms tumor (WT), or nephroblastoma, is an uncommon malignant neoplasm occurring in the kidney of pediatric patients. Its extrarenal location is extremely rare and has been reported in various sites, including the female genital tract, with only 9 cases arising in the uterine corpus. We present the case of an adult woman who underwent total abdominal hysterectomy due to a uterine mass causing persistent abdominal pain. The characteristic triphasic morphology (composed of epithelial, stromal, and blastemal elements) supported by a broad immunohistochemical panel, along with the imaging exclusion of a renal neoplasm, was diagnostic of WT of the uterus. For the first time, a comprehensive genomic profiling of a uterine primary WT was also performed by next-generation sequencing, disclosing alterations at the level of copy number variations in the genes ERBB2, FGFR23, FGF6, FGFR2, and RPS6KB1. All previously reported uterine cases were reviewed, with a summary of their main clinicopathologic characteristics, and the main differential diagnoses are presented. Further reports are needed to improve our knowledge about prognostic factors, clinical behavior and molecular alterations that could guide appropriate therapeutic decision making.

Thromboembolic events and antithrombotic prophylaxis in advanced ovarian cancer patients treated with bevacizumab: secondary analysis of the phase IV MITO-16A/MaNGO-OV2A trial.

INTRODUCTION: The use of routine antithrombotic prophylaxis is not recommended for advanced cancer patients receiving chemotherapy. The effect of bevacizumab-containing therapy on the risk of thromboembolic events remains controversial in ovarian cancer patients. We report on the incidence of thromboembolic events and the prevalence of antithrombotic therapy in patients enrolled in the single arm, phase IV, MITO-16A/MaNGO-OV2A trial. METHODS: In this trial, potential prognostic factors for patients with previously untreated ovarian cancer receiving a combination of platinum-based chemotherapy and bevacizumab were explored and the final analysis has already been reported. In this secondary analysis, the occurrence of thromboembolic events and the use of antithrombotic therapy were described according to the clinical characteristics of the patients. The prognostic role of thromboembolic events for progression-free and overall survival were also evaluated. RESULTS: From October 2012 to November 2014, 398 eligible patients were enrolled. 76 patients (19.1%) were receiving some type of anticoagulant or anti-aggregant treatment at baseline. Overall, 24 thromboembolic events were reported (cumulative incidence of 6.0%). The occurrence of thromboembolic events was not associated with baseline patient characteristics and was not modified by the use of antithrombotic prophylaxis (HR 0.60, 95% CI 0.18 to 2.0). Occurrence of thromboembolic events was not associated with progression-free survival (HR 1.34, 95% CI 0.83 to 2.15) or overall survival (HR 0.78, 95% CI 0.37 to 1.61). CONCLUSIONS: In our study, a 6.0% rate of thromboembolic events was reported during treatment with bevacizumab plus chemotherapy. Thromboembolic events were not associated with the clinical characteristics of the patients or with the use of antithrombotic prophylaxis, nor did they significantly affect the long-term prognosis. TRIAL REGISTRATION NUMBER: NCT01706120.

Bevacizumab, carboplatin, and paclitaxel in the first line treatment of advanced ovarian cancer patients: the phase IV MITO-16A/MaNGO-OV2A study.

OBJECTIVE: To explore the clinical and biological prognostic factors for advanced ovarian cancer patients receiving first-line treatment with carboplatin, paclitaxel, and bevacizumab. METHODS: A multicenter, phase IV, single arm trial was performed. Patients with advanced (FIGO (International Federation of Gynecology and Obstetrics) stage IIIB-IV) or recurrent, previously untreated, ovarian cancer received carboplatin (AUC (area under the curve) 5), paclitaxel (175 mg/m2) plus bevacizumab (15 mg/kg) on day 1 for six 3-weekly cycles followed by bevacizumab single agent (15 mg/kg) until progression or unacceptable toxicity up to a maximum of 22 total cycles. Here we report the final analysis on the role of clinical prognostic factors. The study had 80% power with a two-tailed 0.01 α error to detect a 0.60 hazard ratio with a factor expressed in at least 20% of the population. Both progression-free and overall survival were used as endpoints. RESULTS: From October 2012 to November 2014, 398 eligible patients were treated. After a median follow-up of 32.3 months (IQR 24.1-40.4), median progression-free survival was 20.8 months (95% CI 19.1 to 22.0) and median overall survival was 41.1 months (95% CI 39.1 to 43.5). Clinical factors significantly predicting progression-free and overall survival were performance status, stage, and residual disease after primary surgery. Neither baseline blood pressure/antihypertensive treatment nor the development of hypertension during bevacizumab were prognostic. There were two deaths possibly related to treatment, but no unexpected safety signal was reported. CONCLUSIONS: Efficacy and safety of bevacizumab in combination with carboplatin and paclitaxel and as maintenance were comparable to previous data. Hypertension, either at baseline or developed during treatment, was not prognostic. Performance status, stage, and residual disease after primary surgery remain the most important clinical prognostic factors. TRIAL REGISTRATION NUMBER: EudraCT 2012-003043-29; NCT01706120.

Temozolomide treatment of a malignant pheochromocytoma and an unresectable MAX-related paraganglioma.

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors with a strong genetic background. The mainstay of treatment for PCC/PGLs is surgery. However, for unresectable lesions, no curative treatment is currently available. Temozolomide (TMZ) has been shown to determine radiological and biochemical response in malignant PCC/PGLs. We report two cases of PCC/PGLs treated with TMZ. Case 1 is a 51-year-old man with local and distant recurrence (liver and bone metastases) of right adrenal PCC. Case 2 is a 54-year-old woman with a PCC/PGL syndrome caused by a mutation in MAX gene (c.171+1G>A), operated on for bilateral adrenal PCC and presenting with a large unresectable abdominal PGL. Both patients presented hypertension due to catecholamine hypersecretion. TMZ determined radiological response according to RECIST criteria, reduction of urinary catecholamine levels, and controlled hypertension in both patients. Furthermore, the current study demonstrates, for the first time, that MAX-related PGLs are responsive to TMZ.

Diagnostic and prognostic evaluation of fluorodeoxyglucose positron emission tomography/computed tomography and its correlation with serum cancer antigen-125 (CA125) in a large cohort of ovarian cancer patients.

OBJECTIVE: We evaluated the efficacy of 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in recurrent disease, response to therapy, and long-term follow-up of ovarian cancer (OC) patients in relation to cancer antigen-125 (CA125) levels and the prognostic meaning of this modality in this subset of subjects. MATERIAL AND METHODS: Between 2005 and 2015, we retrospectively evaluated 125 patients affected by OC who underwent FDG PET/CT imaging at our institution. The indications for PET/CT were recurrence of disease in 78 patients, therapy response assessment in 29, and follow-up in 18. The results of FDG PET/CT were compared with those of histopathology and clinical and radiological progression during follow-up for at least 6 months. The median long-term follow-up was 33 months. The diagnostic accuracies for the different clinical settings were evaluated. The relationships among global survival (GS), FDG PET/CT results, and CA125 levels were evaluated by both Kaplan-Meier and Cox regression analysis. RESULTS: CA125 results were positive (>35 UI/mL) in 62 patients and negative in 63 (49% vs. 51%). The sensitivity and specificity of CA125 were 72% and 91%, respectively. PET/CT imaging showed a sensitivity of 98.6% and a specificity of 77.8% for the assessment of recurrent disease, and a sensitivity of 72.7% and a specificity of 88.9% for therapy evaluation. Meanwhile, in 18 patients evaluated during follow-up, the specificity was 82.3%. GS was significantly higher in case of negative CA125 values at the time of FDG PET/CT, of a negative PET/CT scan and when no evidence of peritoneum recurrence and distant metastases was determined by PET. Multivariate regression analysis showed that only age and peritoneum recurrence as determined by PET were identified as independent predictors of poor prognosis. CONCLUSION: Metabolic imaging with FDG PET/CT proved useful in patients where OC recurrence was suspected, even when the value of tumor marker CA125 was in a normal range. A positive PET/CT scan and the presence of peritoneum recurrence at PET were associated with a poor prognosis after approximately 30 months.

Trabectedin plus pegylated liposomal doxorubicin: retrospective analysis in heavily pretreated platinum-sensitive ovarian cancer.

PURPOSE: This retrospective analysis evaluated treatment with trabectedin plus pegylated liposomal doxorubicin (PLD) in 34 heavily pretreated patients (median number of previous lines, 3; range, 2-10) with platinum-sensitive relapsed ovarian cancer (ROC) at a single center in Italy. METHODS: Trabectedin/PLD treatment consisted of trabectedin administered every 3 weeks as a 3-hour intravenous (i.v.) infusion at a dose of 1.1 mg/m2, immediately after PLD 30 mg/m2 i.v. infusion. Study objectives were the evaluation of the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). RESULTS: Three complete responses and 8 partial responses were observed, with an ORR of 32.4% (95% CI, 17.4-50.5%). Median PFS was 6.1 months (95% CI, 4.4-8.9 months). Median OS was 16.3 months (95% CI, 6.8-23.5). Most responses (9 of 11) were found in patients with partially platinum-sensitive disease (ORR 40.9% in this subset; median PFS 6.8 months and median OS 20.8 months). Grade 3 treatment-related adverse events consisted of nausea/vomiting (n = 5; 14.7%), mucositis (n = 2; 5.9%), alanine aminotransferase increase, anemia and neutropenia (n = 1 each; 2.9%). CONCLUSIONS: The overall findings appear consistent with those previously observed in a randomized controlled clinical trial, and support the use of trabectedin/PLD in heavily pretreated patients with platinum-sensitive ROC, especially those with partially platinum-sensitive disease.

Metformin: a modulator of bevacizumab activity in cancer? A case report.

Recurrent type I endometrial cancer (EC) has poor prognosis and demands novel therapeutic approaches. Bevacizumab, a VEGF-A neutralizing monoclonal antibody, has shown clinical activity in this setting. To our knowledge, however, although some diabetic cancer patients treated with bevacizumab may also take metformin, whether metformin modulates response to anti-VEGF therapy has not yet been investigated. Here, we report the case of a patient with advanced EC treated, among other drugs, with bevacizumab in combination with metformin. The patient affected by relapsed EC G3 type 1, presented in march 2010 with liver, lungs and mediastinic metastases. After six cycles of paclitaxel and cisplatin she underwent partial response. Later on, she had disease progression notwithstanding administration of multiple lines of chemotherapy. In march 2013, due to brain metastases with coma, she began steroid therapy with development of secondary diabetes. At this time, administration of Bevacizumab plus Metformin improved her performance status. CT scans performed in this time window showed reduced radiologic density of the lung and mediastinic lesions and of liver disease, suggestive of increased tumor necrosis. Strong (18)F-FDG uptake by PET imaging along with high levels of monocarboxylate transporter 4 and lack of liver kinase B1 expression in liver metastasis, highlighted metabolic features previously associated with response to anti-VEGF therapy and phenformin in preclinical models. However, clinical benefit was transitory and was followed by rapid and fatal disease progression. These findings--albeit limited to a single case--suggest that tumors lacking LKB1 expression and/or endowed with an highly glycolytic phenotype might develop large necrotic areas following combined treatment with metformin plus bevacizumab. As metformin is widely used among diabetes patients as well as in ongoing clinical trials in cancer patients, these results deserve further clinical investigation.

Positive experience of intraperitoneal chemotherapy followed by intravenous chemotherapy in heavily pretreated patients with suboptimal residual ovarian cancer and primary peritoneal cancer.

AIMS AND BACKGROUND: To assess feasibility and toxicity of intraperitoneal administration of cisplatin and paclitaxel, followed by intravenous chemotherapy in pretreated patients with suboptimal ovarian cancer (residuum >1 cm) or primary peritoneal tumor, and suffering from ascites and/or intestinal obstruction. METHODS: Fourteen relapsed ovarian cancer patients, 5 of whom were platinum sensitive (platinum-free interval >6 mo), 7 platinum-resistant (platinum-free interval <6 mo), and 2 platinum-refractory, received one cycle of intraperitoneal cisplatin, 100 mg/m2 on day 1, and two cycles of intraperitoneal paclitaxel, 120 mg/m2 on days 8 and 14. Intravenous chemotherapy was administrated 4 weeks following the last intraperitoneal paclitaxel instillation. Blood and peritoneal fluid samples were harvested at 0, 1, 4 and 24 h after ending paclitaxel delivery to guarantee proper tumor exposure and patient safety. RESULTS: Intraperitoneal cisplatin determined 6 cases of vomiting grade 1-2 (40% of the morbidity). Intraperitoneal paclitaxel was associated with 6 events of grade 1-2 abdominal pain; the only grade 4 toxicity was one case of neutropenia and one of mucositis. Ascites decreased in 11 patients: the median time to first need for paracentesis was 5 months, compared to a median baseline paracentesis of 4 weeks. Three intestinal normalizations were obtained. The median overall survival was 10 months for our cohort of patients. Intraperitoneal paclitaxel clearance was significantly higher in patients with suboptimal tumor and symptomatic disease than in patients with smaller residual masses and without ascites (P = 0.004). CONCLUSIONS: Intraperitoneal treatment was feasible, and enhanced response to the following intravenous chemotherapy was seen in these patients.