Early Detection of Disease Progression in Metastatic Cancers: Could CTCs Improve RECIST Criteria?

Early detection of disease progression is a crucial issue in the management of cancer patients, especially in metastatic settings. Currently, treatment selection mostly relies on criteria based on radiologic evaluations (RECIST). The aim of the present retrospective study is to evaluate the potential inclusion of circulating tumor cells (CTCs) in hybrid criteria. CTC counts from a total of 160 patients with different metastatic tumors were analyzed for this purpose. In our cohort, 73 patients were affected by breast cancer, 69 by colorectal cancer and 18 by prostate cancer. PFS and OS were evaluated according to the corresponding prediction of disease progression by CTCs and RECIST criteria. In breast cancer, CTC-I has an important impact on the progression-free survival (PFS) and overall survival (OS) values. When CTC-I predicted earlier than RECIST-I, the disease progression, the PFS and OS were shorter with respect to the opposite case. In particular, PFS was 11 (5-16) vs. 34 (23-45)-with p < 0.001-and OS was 80 (22-138) vs. 116 (43-189), p = 0.33. The results suggest a promising role of CTCs as complementary information which could significantly improve the clinical outcomes, and they encourage consideration of future trials to evaluate new hybrid criteria, particularly for patients with breast cancer.

Cefiderocol use for the treatment of infections by carbapenem-resistant Gram-negative bacteria: an Italian multicentre real-life experience.

BACKGROUND: Cefiderocol is a novel siderophore cephalosporin with promising activity against most carbapenem-resistant Gram-negative bacteria (CRGNB). However, extensive postmarketing experiences are lacking. This study aimed to analyse the early experience on cefiderocol postmarketing use at three tertiary care hospitals in Italy. METHODS: We retrospectively included patients with infections caused by CRGNB treated with cefiderocol at three Italian tertiary care hospitals from 1 March 2021 to 30 June 2022. A multivariate Cox model was used to identify predictors of 30 day mortality. A propensity score (PS) analysis with inverse probability weighting (IPW) was also performed to compare the treatment effect of cefiderocol monotherapy (CM) versus combination regimens (CCRs). RESULTS: The cohort included 142 patients (72% male, median age 67 years, with 89 cases of Acinetobacter baumannii infection, 22 cases of Klebsiella pneumoniae, 27 cases of Pseudomonas aeruginosa and 4 of other pathogens). The 30 day all-cause mortality was 37% (52/142). We found no association between bacterial species and mortality. In multivariate analysis, a Charlson Comorbidity Index >3 was an independent predictor of mortality (HR 5.02, 95% CI 2.37-10.66, P < 0.001). In contrast, polymicrobial infection (HR 0.41, 95% CI 0.21-0.82, P < 0.05) was associated with lower mortality. There was no significant difference in mortality between patients receiving CM (n = 70) and those receiving a CCR (n = 72) (33% versus 40%, respectively), even when adjusted for IPW-PS (HR 1.11, 95% CI 0.63-1.96, P = 0.71). CONCLUSIONS: Real-life data confirm that cefiderocol is a promising option against carbapenem-resistant Gram-negative infections, even as monotherapy.

Obesity as a Risk Factor of Severe Outcome of COVID-19: A Pair-Matched 1:2 Case-Control Study.

BACKGROUND AND AIM: The nature of the association between obesity and poor prognosis of COVID-19 without the evaluation of other co-pathologies associated has not yet been clearly evaluated. The aim of the present pair-matched case-control study was to investigate the outcome of patients with SARS-CoV-2 infection in obese and non-obese patients matched considering gender, age, number of comorbidities, and Charlson Comorbidity Index. METHODS: All the adults hospitalized for SARS-CoV-2 infection and with BMI ≥ 30 kg/m2 were included (Cases). For each Case, two patients with BMI < 30 kg/m2 pair matched for gender, age (±5 years), number of comorbidities (excluding obesity), and Charlson Comorbidity Index (±1) were enrolled (Controls). RESULTS: Of the 1282 patients with SARS-CoV-2 infection followed during the study period, 141 patients with obesity and 282 patients without were enrolled in the case and control groups, respectively. Considering matching variables, there was no statistical difference between the two groups. Patients in the Control group developed more frequently a mild-moderate disease (67% vs. 46.1%, respectively), whereas obese patients were more prone to need intensive care treatment (41.8% vs. 26.6%, respectively; p = 0.001). Moreover, the prevalence of death during hospitalization was higher in the Case group than in the Control group (12.1% vs. 6.4%, p = 0.046). DISCUSSION: We confirmed an association between obesity and severe outcome of patients with COVID-19, also considering other factors associated with a severe outcome of COVID-19. Thus, in the case of SARS-CoV-2 infection, the subjects with BMI ≥ 30 kg/m2 should be evaluated for early antiviral treatment to avoid the development of a severe course.

Lenvatinib Versus Sorafenib in Advanced Hepatic Cell Carcinoma: A Double Center Retrospective Analysis.

BACKGROUND/AIM: We conducted a retrospective analysis in our center (Umberto I Polyclinic) in collaboration with Campus Biomedico Polyclinic to assess the results of the REFLECT study, which was the first study that demonstrated the non-inferiority of Lenvatinib to Sorafenib. PATIENTS AND METHODS: We identified 21 patients affected by advanced hepatocellular carcinoma during the last 3 years who were treated in our centers. They were subdivided according to the treatment administered (Lenvatinib or Sorafenib). Progression-free survival (PFS) and overall survival (OS) were calculated, and subgroups were compared using the log-rank test. Specific predictive and prognostic factors were identified. The safety profile of the two drugs and the collateral effects were evaluated. RESULTS: The OS in patients in the Lenvatinib arm was 19 (months and 12.5 months in the Sorafenib arm. PFS in patients in the Lenvatinib arm was 6 months and 2.5 months in the Sorafenib arm. OS and PFS in patients treated with Lenvatinib were higher in any subcategory analyzed whereas no positive predictors of response to Sorafenib were found. Based on data from literature, the albumin bilirubin index (ALBI) grade was found to be a key prognostic factor. Patients treated with Sorafenib had more adverse events than those treated with Lenvatinib (100% versus 81.8%, respectively). Patients treated with Sorafenib had more frequently hand-foot syndromes, diarrhea, and nausea whereas patients treated with Lenvatinib commonly had hypertension, proteinuria, and weight loss. CONCLUSION: Lenvatinib was found to be better than Sorafenib in terms of both survival and toxicity, in advanced hepatic cell carcinoma patients.

Sclerotherapy with 3% polidocanol foam to treat second-degree haemorrhoidal disease: Three-year follow-up of a multicentre, single arm, IDEAL phase 2b trial.

BACKGROUND: Sclerotherapy with 3% polidocanol foam is becoming increasingly popular for the treatment of symptomatic I-II or III degree haemorrhoidal disease (HD). However, there are no studies that have reported a follow-up of more than 1 year. The purpose of this study was to analyse the long-term outcomes of sclerotherapy with 3% polidocanol foam in the treatment of II-degree HD. METHODS: This was an open label, single-arm, phase 2b trial conducted in 10 tertiary referral centres for HD. A total of 183 patients with II-degree HD, aged between 18 and 75 years with symptomatic HD according to the Goligher classification and unresponsive to medical treatment, were included in the study and underwent sclerotherapy with 3% polidocanol foam. The efficacy was evaluated in terms of bleeding score, haemorrhoidal disease symptom score (HDSS) and short health scale for HD (SHS-HD) score. Successful treatment was defined as the complete absence of bleeding episodes after 7 days (T1) according to the bleeding score. RESULTS: The overall success rate ranged from 95.6% (175/183) at 1 year to 90.2% (165/183) after the final 3 year follow-up. The recurrence rate, based on the primary outcome, ranged from 12% (15/125) to 28% (35/125). The greatest increase in recurrence (15) was recorded between 12 and 18 months of follow-up, then another five between 18 and 24 months. Both the HDSS and the SHS score remained statistically significant (p < 0.001) from a median preoperative value of 11 (10-13) and 18 (15-20) to 0 (0-2) and 4 (0-4), respectively. Symptom-free (HDSS = 0) patients, excluding patients converted to surgery, increased from 55.5% (101/182) at 1 year to 65.1% at 3 years (110/169). There were no intraoperative complications in redo-sclerotherapy nor additional adverse events (AEs) compared to the first 12 months. CONCLUSIONS: Sclerotherapy with 3% polidocanol foam is gradually establishing itself in the treatment of bleeding HD due to its repeatability, safety, convenience in terms of direct and indirect costs with the absence of discomfort for the patient as well as AEs rather than an excellent overall success rate.

Superinfections caused by carbapenem-resistant Enterobacterales in hospitalized patients with COVID-19: a multicentre observational study from Italy (CREVID Study).

Objectives: To describe clinical characteristics and outcomes of COVID-19 patients who developed secondary infections due to carbapenem-resistant Enterobacterales (CRE). Methods: Retrospective observational study including COVID-19 patients admitted to 12 Italian hospitals from March to December 2020 who developed a superinfection by CRE. Superinfection was defined as the occurrence of documented bacterial infection >48 h from admission. Patients with polymicrobial infections were excluded. Demographic, clinical characteristics and outcome were collected. Isolates were classified as KPC, metallo-ß-lactamase (MBL) and OXA-48-producing CRE. A Cox regression analysis was performed to identify factors independently associated with 30 day mortality. Results: Overall, 123 patients (median age 66 years, IQR 59-75) were included. The majority of infections occurred in the ICU (81, 65.9%), while 42 (34.1%) in medical wards. The most common types of infection were bloodstream infections (BSI) (n = 64, 52%), followed by urinary-tract infections (UTI) (n = 28, 22.8%), hospital-acquired/ventilator-associated pneumonia (HAP/VAP) (n = 28, 22.8%), intra-abdominal infections (n = 2, 1.6%) and skin infections (n = 1, 0.8%). Sixty-three (51.2%) infections were caused by KPC-, 54 (43.9%) by MBL-, and 6 (4.8%) by OXA-48-producing CRE. Thirty-day mortality was 33.3% (41/123). On Cox regression analysis, HAP/VAP compared with UTI (HR 7.23, 95% CI 2.09-24.97, P = 0.004), BSI compared with UTI (HR 3.96, 95% CI, 1.33-11.77, P = 0.004), lymphopenia on admission (HR 3, 95% CI 1.44-6.26, P = 0.003) and age (HR 1.05, 95% CI 1.02-1.08, P = 0.002) were predictors of 30 day mortality. Conclusions: Superinfections by CRE were associated with high risk of 30 day mortality in patients with COVID-19. HAP/VAP was the strongest predictor of death in these patients.

Combined Resistance to Ceftolozane-Tazobactam and Ceftazidime-Avibactam in Extensively Drug-Resistant (XDR) and Multidrug-Resistant (MDR) Pseudomonas aeruginosa: Resistance Predictors and Impact on Clinical Outcomes Besides Implications for Antimicrobial Stewardship Programs.

A retrospective case-control study was conducted at Modena University Hospital from December 2017 to January 2019 to identify risk factors and predictors of MDR/XDR Pseudomonas aeruginosa (PA) isolation with resistance to ceftazidime/avibactam (CZA) and ceftolozane/tazobactam (C/T), and of mortality among patients infected/colonized. Among 111 PA isolates from clinical/surveillance samples, 60 (54.1%) were susceptible to both drugs (S-CZA-C/T), while 27 (24.3%) were resistant to both (R-CZA-C/T). Compared to patients colonized/infected with S-CZA-C/T, those with R-C/T + CZA PA had a statistically significantly higher Charlson comorbidity score, greater rate of previous PA colonization, longer time before PA isolation, more frequent presence of CVC, higher exposure to C/T and cephalosporins, longer hospital stay, and higher overall and attributable mortality. In the multivariable analysis, age, prior PA colonization, longer time from admission to PA isolation, diagnosis of urinary tract infection, and exposure to carbapenems were associated with the isolation of a R-C/T + CZA PA strain, while PA-related BSI, a comorbidity score > 7, and ICU stay were significantly associated with attributable mortality. C/T and CZA are important therapeutic resources for hard-to-treat PA-related infections, thus specific antimicrobial stewardship interventions should be prompted in order to avoid the development of this combined resistance, which would jeopardize the chance to treat these infections.

Ceftazidime/avibactam and ceftolozane/tazobactam for the treatment of extensively drug-resistant Pseudomonas aeruginosa post-neurosurgical infections: three cases and a review of the literature.

PURPOSE: Post-neurosurgical infection caused by extensively drug resistant Pseudomonas aeruginosa (XDR-PA) are becoming a matter of great concern due to limited therapeutic options. Although not approved for these indications, the new BetaLactam-BetaLactamase Inhibitor combinations (BLBLIs) could represent a valid salvage treatment. We describe one nosocomial meningitis and two cervical osteomyelitis due to an XDR-PA who were treated with ceftazidime/avibactam (CZA) and ceftolozane/tazobactam (C/T) and review the literature. METHODS: The first and the third patients developed an osteomyelitis following cervical stabilization surgery due to an XDR-PA. Although the first patient started treatment with a high dose of C/T, resistance to C/T occurred, so therapy was switched to CZA plus aztreonam. The third patient switched to aztreonam plus CZA due to development of acute kidney injury during therapy with colistin. The second patient had an XDR-PA meningitis following the insertion of an external ventricular catheter and he was treated with C/T plus meropenem and amikacin. RESULTS: All three cases reported were successfully conservatively treated thanks to the use of the new BLBLIs with different combinations. Only few experiences demonstrated an equally favorable outcome: one patient treated with C/T plus fosfomycin for otogenic meningitis caused by an XDR-PA and another case of XDR-PA post-surgical meningitis with CZA in combination with colistin. Finally, the combination of CZA plus aztreonam has proven to be effective on XDR-PA only in limited mostly in vitro studies. CONCLUSION: These recently developed antibiotics, C/T and CZA are promising and complementary therapy options against post-neurosurgical hard-to-treat P. aeruginosa infections. Further prospective real-life studies are required to validate these findings in this special setting.

Forecasting Energy Consumption in the EU Residential Sector.

The present paper aims to introduce a top down methodology for the forecasting of residential energy demand in four European countries, namely Germany, Italy, Spain, and Lithuania. The methodology employed to develop the estimation is based on econometric techniques. In particular, a logarithmic dynamic linear constant relationship of the consumption is proposed. Demand is estimated as a function of a set of explaining variables, namely heating degree days and gross domestic product per capita. The results confirm that the methodology can be applied to the case of Germany, Italy, and Spain, whereas it is not suitable for Lithuania. The analysis of elasticities of the demand with respect to the gross domestic product per capita shows a negative value for Germany, -0.629, and positive values for Italy, 0.837, and Spain, 0.249. The forecasting of consumption shows that Germany and Italy are more sensitive to weather conditions with respect to Spain and an increase in the demand of 8% and 9% is expected in case of cold climatic conditions.

Measles in pregnant women: A systematic review of clinical outcomes and a meta-analysis of antibodies seroprevalence.

OBJECTIVES: Pregnant women represent a category at high risk of severe measles infection, that negatively affects the fetus as well. A systematic review of clinical outcomes of measles infection in gravid subjects and a meta-analysis of antibodies prevalence among pregnant women was conducted. METHODS: MEDLINE and EMBASE databases were searched up to 18 June 2018. The screening focused on: (i) articles describing the outcome of measles in pregnancy, synthesized in a descriptive fashion; (ii) articles addressing the measles seroprevalence in cohorts of gravid women, analysed quantitatively. RESULTS: Twenty-nine articles met inclusion criteria. A total of 420 cases of measles in gravid subjects were described, from 1941 to 2012. Among women, 18 deaths (4.3%) occurred, and the most frequent complication was pneumonia (75/420, 17.9%). Prematurity was the most important complication concerning fetal outcomes (55 out of 410 cases with available data, 13.4%). The random-effects pooled seroprevalence of measles in 20,546 gravid women worldwide was 89.3% (95% CI: 87.3-91.1%), that decreased, although not in a statistically significant way, over time (p = 0.54). CONCLUSIONS: Measles infection in pregnancy is dangerous both for the mother and the foetus. Antibody seroprevalence among gravid women on a global scale is lower than the herd immunity threshold.

Prexasertib, a checkpoint kinase inhibitor: from preclinical data to clinical development.

Checkpoint kinases 1 and 2 (CHK1 and CHK2) are important multifunctional proteins of the kinase family. Their main function is to regulate DNA replication and DNA damage response. If a cell is exposed to exogenous damage to its DNA, CHK1/CHK2 stops the cell cycle to give time to the cellular mechanisms to repair DNA breakage and apoptosis too, if the damage is not repairable to activate programmed cell death. CHK1/CHK2 plays a crucial role in the repair of recombination-mediated double-stranded DNA breaks. The other important functions performed by these proteins are the beginning of DNA replication, the stabilization of replication forks, the resolution of replication stress and the coordination of mitosis, even in the absence of exogenous DNA damage. Prexasertib (LY2606368) is a small ATP-competitive selective inhibitor of CHK1 and CHK2. In preclinical studies, prexasertib in monotherapy has shown to induce DNA damage and tumor cells apoptosis. The preclinical data and early clinical studies advocate the use of prexasertib in solid tumors both in monotherapy and in combination with other drugs (antimetabolites, PARP inhibitors and platinum-based chemotherapy). The safety and the efficacy of combination therapies with prexasertib need to be better evaluated in ongoing clinical trials.

[Bevacizumab e altri farmaci. Attività e sicurezza degli agenti anti-VEGF nel carcinoma ovarico.] / Bevacizumab and others. Activity and safety of anti-VEGF agents in ovarian cancer.

Riassunto. L'angiogenesi svolge un ruolo importante sia nei tessuti epiteliali normali sia in quelli maligni. Negli ultimi anni questo fenomeno è stato ampiamente studiato in oncologia sperimentale e clinica perché ci sono evidenze che sia coinvolto nella diffusione e nella diffusione metastatica del carcinoma ovarico. Il fattore di crescita dell'endotelio vascolare (vascular endothelial growth factor - VEGF) è l'attore principale nel meccanismo di angiogenesi e svolge un ruolo strategico nella proliferazione e migrazione delle cellule neoplastiche, con un impatto significativo sulla sopravvivenza e sull'outcome clinico. Secondo quanto emerge da molti studi sperimentali e clinici, le nostre conoscenze sulla biologia dell'angiogenesi e del VEGF sono aumentate portando allo sviluppo farmacologico di specifici agenti in grado di targeting VEGF. Questo nuovo campo di indagine offre agli scienziati l'opportunità di testare nuove possibilità terapeutiche nei pazienti con carcinoma ovarico con nuovi agenti mirati. Il bevacizumab, un anticorpo monoclonale anti-VEGF umanizzato, è stato il primo farmaco anti-VEGF scoperto ed è usato oggi per il trattamento di diversi tumori solidi. Negli ultimi anni questo agente è stato ampiamente testato nei pazienti con carcinoma ovarico, mostrando un'attività clinica interessante e un profilo di tossicità tollerabile sia nelle pazienti giovani sia in quelle anziane. Il bevacizumab, combinato con carboplatino e paclitaxel e successivamente utilizzato come agente singolo, è indicato per il trattamento del carcinoma epiteliale dell'ovaio di stadio III o IV, tuba di Falloppio o carcinoma peritoneale primario dopo iniziale resezione chirurgica. Il bevacizumab è anche usato per il trattamento di pazienti con carcinoma ovarico epiteliale ricorrente e resistente al platino, delle tube di Falloppio o dal tumore peritoneale primario che hanno ricevuto non più di 2 regimi precedenti di chemioterapia. Inoltre, il bevacizumab, combinato con carboplatino e paclitaxel o con carboplatino e gemcitabina (e usato come agente singolo), è indicato per il trattamento di pazienti con carcinoma epiteliale dell'ovario sensibile al platino, tuba di Falloppio o tumore peritoneale primario. Le linee guida più accreditate suggeriscono quando bevacizumab deve essere usato nel trattamento del carcinoma ovarico avanzato e ricorrente. Altri agenti anti-VEGF, come gli inibitori della tirosin-chinasi del recettore VEGF (VEGFR), sono stati ampiamente testati nel carcinoma ovarico e molti altri sono in corso di studi al fine di testare la loro attività e sicurezza rispetto a bevacizumab. Gli agenti anti-VEGF e gli inibitori di PARP svolgono oggi un ruolo strategico nel trattamento del cancro ovarico con agenti mirati in associazione con la chemioterapia e la chirurgia in un'ottica multidisciplinare e personalizzata.

Risk of professional accidental exposure to biological agents in health care workers: a retrospective analysis carried out in a southern Italian tertiary hospital.

Worldwide the needlestick injuries of health care workers (HCWs) still represent a major health problem. The authors aimed to evaluate the risk of HCW needlestick injuries in a tertiary university hospital in southern Italy in relation to some HCW characteristics (age, sex, professional profile, work department) and the source of infection. All HCWs of the University Hospital "Federico II" in Naples, Italy, attending the Infectious Diseases Unit after potential accidental contact to blood-borne viruses through needlestick injuries were enrolled during a 22-year period. HCWs underwent clinical analysis and were administered a specific questionnaire to collect (in anonymous fashion) data about age, sex, professional profile and work department. From 1995 to 2016 1,477 needlestick injuries in the same number of people (one accident per person) were recorded by our service. The HCWs were predominately males (n = 806, 55%) and the mean age was 39.4 years (±10.1 SD). The job categories most involved were: physicians (41%), followed by nurses (33%) and healthcare assistants (HCAs, 10%). The incidence proportion was calculated for these highest-risk categories in three defined time points (at the beginning, in the middle and at the end of the study period): 104/2149 (4.86%) in 1995, 41/2498 (1.64%) in 2005 and 25/2057 (1.22%) in 2015. Most injuries occurred in General Surgery (14.21%), Gynecology and Obstetrics (9%) and Pediatrics (6.49%). In about 34% the HCWs had been exposed to HCV infected fluids. Over time, a significant decrease in accidental exposure was recorded for physicians (p= 0.019), nurses (p< 0.0001) and HCAs (p< 0.0001). Our results confirm that some profiles, namely physicians, nurses and healthcare assistants, are still at risk of needlestick injuries, especially in surgical areas, including obstetric wards. Further primary and secondary prevention strategies are needed to decrease the incidence of new cases of needlestick injuries.

Radium-223 in patients with metastatic castration-resistant prostate cancer: Efficacy and safety in clinical practice.

Radium-223 has improved overall survival (OS) and reduced symptomatic skeletal events (SSE) in patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases (ALSYMPCA trial). Our aim was to assess clinical and biochemical factors related to survival, safety and survival outcomes of Radium-223 in a clinical practice setting. We retrospectively analysed 32 mCRPC patients treated with Radium-223, assessing bone scan, pain reduction, alkaline phosphatase (ALP) and prostate-specific antigen (PSA) response (≥30% reduction). At scintigraphic assessment, 41% had partial response with a disease control rate of 91%; 56% had ALP response and 25% had PSA response; 41% had pain reduction with pain control of 72%. Scintigraphic response and stability were correlated with longer median progression-free survival (mPFS) (13 and 12 vs. 6 months; P=0.002) and mOS (16 and 12 vs. 6 months; P=0.003). ALP response was associated with longer mPFS (13 vs. 12 months; P=0.2) and mOS (16 vs. 12 months; P=0.2). PSA response was associated with longer mPFS (13 vs. 12 months; P=0.02), whereas mOS could not be computed. Pain response and stability were associated with survival benefit according to mPFS (13 and 12 vs. 9 months) and mOS (both 16 vs. 12 months) without statistical significance. Baseline ALP <220 UI/l, Eastern Cooperative Oncology Group (ECOG) performance status 0 and absence of previous chemotherapy correlated with statistically significantly longer survival outcomes. Skeletal-related events (SRE) occurred in three patients and median time to first SRE was 9.5 months, mPFS was 12 months and mOS 14 months. G3-G4 toxicities developed in 16% of patients. Our results are in line with those reported in the pivotal trial and in other retrospective studies. In conclusion, Radium-223 was associated with high scintigraphic, biochemical and pain response rates and was tolerated well by most patients. Response to Radium-223 and better baseline factors correlated to longer survival in clinical practice experience as in the clinical trial setting.

Multimodal treatment for local recurrent malignant gliomas: Resurgery and/or reirradiation followed by chemotherapy.

The therapeutic management of recurrent malignant gliomas (MGs) is not determined. Therefore, the efficacy of a multimodal approach and a combination systemic therapy was investigated. A retrospective analysis of 26 MGs patients at first relapse treated with multimodal therapy (chemotherapy plus surgery and/or reirradiation) or chemotherapy alone was performed. Second-line chemotherapy consisted of fotemustine (FTM) in combination with bevacizumab (BEV) (cFTM/BEV) or followed by third-line BEV (sFTM/BEV). Subgroup analyses were performed. Multimodal therapy provided a higher overall response rate (ORR) (73 vs. 47%), disease control rate (DCR) (82 vs. 67%), median progression-free survival (mPFS) (11 vs. 7 months; P=0.08) and median overall survival (mOS) (13 vs. 8 months; P=0.04) compared with chemotherapy. Concomitant FTM/BEV resulted in higher ORR (84 vs. 36%), DCR (92 vs. 57%), mPFS (10 vs. 5 months; P=0.22) and mOS (11 vs. 5.2 months; P=0.15) compared with sFTM/BEV. Methylated patients did not experience additional survival benefits with multimodality treatment but had higher mPFS (10 vs 7.1 months; P=0.33) and mOS (11 vs. 8 months; P=0.33) with cFTM/BEV. Unmethylated patients experienced the greatest survival benefit with the multimodal approach (mPFS: 10 vs. 5 months; mOS 11 vs 6 months; both P=0.02) and cFTM/BEV (mPFS: 5 vs. 2 months; mOS 6 vs. 3.2 months; both P=0.01). In conclusion, in recurrent MGs, multimodal therapy and cFTM/BEV provide survival and response benefits. Methylated patients benefit from a cFTM/BEV but not from a multimodal approach. Notably, unmethylated patients had the highest survival benefit with the two strategies.

Non-conventional fotemustine schedule as second-line treatment in recurrent malignant gliomas: Survival across disease and treatment subgroup analysis and review of the literature.

Fotemustine (FTM) is a treatment option in recurrent malignant gliomas (MGs) after first-line Stupp treatment. The efficacy and the safety of fractionated FTM schedule proposed by Addeo et al was analysed in the present study in recurrent MGs patients. A retrospective analysis on 40 recurrent MGs patients and second-line fractionated FTM chemotherapy was performed. Response evaluation was assessed using RANO criteria and safety was assessed using CTCAE v.4.03. Subgroup analyses based on MGMT methylation, resurgery and reirradiation were performed. A review of the literature was also performed. The results revealed 5 partial responses (13%) and 19 stable diseases (47%) with a disease-control rate of 60%. Median progression-free survival (PFS) was 4 months, with a PFS of 33% at 6 months and 13% at 1 year. The median overall survival (OS) was 9 months and OS at 6 months was of 55% and at 1 year of 30%. Methylated patients experienced longer mPFS (6 vs. 3 months; p=0.004) and mOS (10 vs. 4 months; p<0.0001) compared with unmethylated patients. Patients treated with reirradiation experienced longer mPFS (5 vs. 3.5 months; p=0.48) and mOS (10 vs. 5 months; p=0.11). No survival benefit with resurgery was observed. Furthermore, the fractioned schedule was well tolerated, only 15% of patients developed severe myelotoxicities. Considering the present findings, fractionated FTM schedule is an efficient second-line option for MGs associated with an acceptable myelotoxicity profile. Additionally, MGMT methylation is associated with improved survival outcomes. However, this study highlights the requirement for further prospective randomized studies on resurgery and reirradiation.

Therapeutic approach in glioblastoma multiforme with primitive neuroectodermal tumor components: Case report and review of the literature.

Glioblastoma multiforme (GBM) is the most common and aggressive malignant glioma that is treated with first-line therapy, using surgical resection followed by local radiotherapy and concomitant/adjuvant temozolomide (TMZ) treatment. GBM is characterised by a high local recurrence rate and a low response to therapy. Primitive neuroectodermal tumour (PNET) of the brain revealed a low local recurrence rate; however, it also exhibited a high risk of cerebrospinal fluid (CSF) dissemination. PNET is treated with surgery followed by craniospinal irradiation (CSI) and platinum-based chemotherapy in order to prevent CSF dissemination. GBM with PNET-like components (GBM/PNET) is an emerging variant of GBM, characterised by a PNET-like clinical behaviour with an increased risk of CSF dissemination; it also may benefit from platinum-based chemotherapy upfront or following failure of GBM therapy. The results presented regarding the management of GBM/PNET are based on case reports or case series, so a standard therapeutic approach for GBM/PNET is not defined, constituing a challenging diagnostic and therapeutic dilemma. In this report, a case of a recurrent GBM/PNET treated with surgical resection and radiochemotherapy as Stupp protocol, and successive platinum-based chemotherapy due to the development of leptomeningeal dissemintation and an extracranial metastasis, is discussed. A review of the main papers regarding this rare GBM variant and its therapeutic approach are also reported. In conclusion, GBM/PNET should be treated with a multimodal approach including surgery, chemoradiotherapy, and/or the early introduction of CSI and platinum-based chemotherapy upfront or at recurrence.

Epidemiology and pathogenesis of fulminant viral hepatitis in pregnant women.

INTRODUCTION: The pregnancy-associated immunological and hormonal changes may alter the immune response to infectious agents, including hepatitis viruses. Therefore, this phenomenon may affect the clinical course and the outcome of acute viral hepatitis in pregnant women. EVIDENCE ACQUISITION: For this reason, we have focused on epidemiological and pathogenetic aspects of the fulminant liver failure caused by acute viral hepatitis reviewing PubMED in April of 2017. EVIDENCE SYNTHESIS: Although all the viruses might cause a fulminant acute viral hepatitis in a pregnant woman, the large majority of fulminant failure reported in the literature had been related to hepatits E virus (HEV) mainly and had been concentrated in Indian subcontinent and some African areas, whereas the problem seems to be very low or absent in the remaining geographical areas. However, the rate of maternal mortality due to fulminant E hepatitis may vary inside the endemic areas of India and Africa, likely due to the circulation of HEV genotypes with different degree of virulence. The other hepatitis viruses have not been reported to cause a greater risk for fulminant hepatitis in pregnant women respect to non-pregnant ones, except Herpes simplex virus, that has been associated to some cases of fatal hepatitis in absence of a prompt antiviral therapy. CONCLUSIONS: AVH should be considered when the pregnant woman develop fever, abdominal pain, malaise, nausea and anicteric hepatic dysfunction.