MITO END-3: efficacy of avelumab immunotherapy according to molecular profiling in first-line endometrial cancer therapy.

BACKGROUND: Immunotherapy combined with chemotherapy significantly improves progression-free survival (PFS) compared to first-line chemotherapy alone in advanced endometrial cancer (EC), with a much larger effect size in microsatellite instability-high (MSI-H) cases. New biomarkers might help to select patients who may have benefit among those with a microsatellite-stable (MSS) tumor. PATIENTS AND METHODS: In a pre-planned translational analysis of the MITO END-3 trial, we assessed the significance of genomic abnormalities in patients randomized to standard carboplatin/paclitaxel without or with avelumab. RESULTS: Out of 125 randomized patients, 109 had samples eligible for next-generation sequencing analysis, and 102 had MSI tested. According to The Cancer Genome Atlas (TCGA), there were 29 cases with MSI-H, 26 with MSS TP53 wild type (wt), 47 with MSS TP53 mutated (mut), and 1 case with POLE mutation. Four mutated genes were present in >30% of cases: TP53, PIK3CA, ARID1A, and PTEN. Eleven patients (10%) had a BRCA1/2 mutation (five in MSI-H and six in MSS). High tumor mutational burden (≥10 muts/Mb) was observed in all MSI-H patients, in 4 out of 47 MSS/TP53 mut, and no case in the MSS/TP53 wt category. The effect of avelumab on PFS significantly varied according to TCGA categories, being favorable in MSI-H and worst in MSS/TP53 mut (P interaction = 0.003); a similar non-significant trend was seen in survival analysis. ARID1A and PTEN also showed a statistically significant interaction with treatment effect, which was better in the presence of the mutation (ARID1A P interaction = 0.01; PTEN P interaction = 0.002). CONCLUSION: The MITO END-3 trial results suggest that TP53 mutation is associated with a poor effect of avelumab, while mutations of PTEN and ARID1A are related to a positive effect of the drug in patients with advanced EC.

Intracranial complications of sinogenic and otogenic infections in children: an ESPN survey on their occurrence in the pre-COVID and post-COVID era.

BACKGROUND: COVID-19 pandemic is thought to have changed the epidemiology of some pediatric neurosurgical disease: among them are the intracranial complications of sinusitis and otitis (ICSO). According to some studies on a limited number of cases, both streptococci-related sinusitis and ICSO would have increased immediately after the pandemic, although the reason is not clear yet (seasonal changes versus pandemic-related effects). The goal of the present survey of the European Society for Pediatric Neurosurgery (ESPN) was to collect a large number of cases from different European countries encompassing the pre-COVID (2017-2019), COVID (2020-2021), and post-COVID period (2022-June 2023) looking for possible epidemiological and/or clinical changes. MATERIAL AND METHODS: An English language questionnaire was sent to ESPN members about year of the event, patient's age and gender, presence of immune-deficit or other favoring risk factors, COVID infection, signs and symptoms at onset, site of primary infection, type of intracranial complication, identified germ, type and number of surgical operations, type and duration of medical treatment, clinical and radiological outcome, duration of the follow-up. RESULTS: Two hundred fifty-four cases were collected by 30 centers coming from 14 different European countries. There was a statistically significant difference between the post-COVID period (129 children, 86 cases/year, 50.7% of the whole series) and the COVID (40 children, 20 cases/year, 15.7%) or the pre-COVID period (85 children, 28.3 cases/year, 33.5%). Other significant differences concerned the presence of predisposing factors/concurrent diseases (higher in the pre-COVID period) and previous COVID infection (higher in the post-COVID period). No relevant differences occurred as far as demographic, microbiological, clinical, radiological, outcome, morbidity, and mortality data were concerned. Paranasal sinuses and middle ear/mastoid were the most involved primary site of infection (71% and 27%, respectively), while extradural or subdural empyema and brain abscess were the most common ICSO (73% and 17%, respectively). Surgery was required in 95% of cases (neurosurgical and ENT procedure in 71% and 62% of cases, respectively) while antibiotics in 99% of cases. After a 12.4-month follow-up, a full clinical and radiological recovery was obtained in 85% and 84% of cases, respectively. The mortality rate was 2.7%. CONCLUSIONS: These results suggest that the occurrence of ICSO was significantly increased after the pandemic. Such an increase seems to be related to the indirect effects of the pandemic (e.g., immunity debt) rather than to a direct effect of COVID infection or to seasonal fluctuations. ICSO remain challenging diseases but the pandemic did not affect the management strategies nor their prognosis. The epidemiological change of sinusitis/otitis and ICSO should alert about the appropriate follow-up of children with sinusitis/otitis.

INOVATYON/ ENGOT-ov5 study: Randomized phase III international study comparing trabectedin/pegylated liposomal doxorubicin (PLD) followed by platinum at progression vs carboplatin/PLD in patients with recurrent ovarian cancer progressing within 6-12 months after last platinum line.

BACKGROUND: This trial investigated the hypothesis that the treatment with trabectedin/PLD (TP) to extend the platinum-free interval (TFIp) can improve overall survival (OS) in patients with recurrent ovarian cancer (OC). METHODS: Patients with OC (up to two previous platinum-based lines), with a TFIp of 6-12 months, were randomised to receive carboplatin/PLD (CP) or TP followed by platinum therapy at relapse. The primary endpoint was OS (HR: 0.75). RESULTS: The study enrolled 617 patients. The median TFIp was 8.3 months and 30.3% of patients had received two previous platinum lines. 74% and 73.9% of patients, respectively, received a subsequent therapy (ST) in the CP and TP arm; in the latter TP arm 87.2% of ST was platinum-based, as per protocol. The median OS was 21.4 for CP and 21.9 months for TP (HR 1.13; 95% CI: 0.94-1.35; p = 0.197). Grade 3-5 adverse reactions occurred in 37.1% of patients in the CP arm and 69.7% of patients in the TP arm, and the most frequent were neutropenia (22.8% CP, 39.5% TP), gastrointestinal (7.1% CP, 17.4% TP), hepatic (0.7% CP, 19.1% TP). CONCLUSIONS: This study did not meet the primary endpoint. CP combination remains the standard for patients with recurrent OC and a 6-12 months TFIp; TP is an effective treatment in patients suffering from persistent platinum toxicities. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, number NCT01379989.

Single-suture craniosynostosis: is there a correlation between preoperative ophthalmological, neuroradiological, and neurocognitive findings?

BACKGROUND: In spite of literature data stating that children with single-suture craniosynostosis have an increased risk for neuropsychological deficits, no data are present clarifying the potential risk factors. METHODS: All children with non-syndromic single-suture craniosynostosis operated on from January 2014 to January 2017 were enrolled. A comprehensive neurocognitive and neuro-ophthalmological evaluation was performed before surgery and 6 months after surgery. A further neurocognitive evaluation was performed 12 months after surgery. All children had a preoperative CT/MR study. RESULTS: One hundred forty-two patients were enrolled; 87 are affected by sagittal craniosynostosis, 38 by trigonocephaly, and 17 by plagiocephaly. A global neurocognitive impairment was documented in 22/87 children with scaphocephaly, 5/38 children with trigonocephaly, and 6/17 children with anterior plagiocephaly. There was a significant relationship between results of the ophthalmological evaluation, global IQ, and CT findings at diagnosis (r = 0.296, p < 0.001; r =0.187, p 0.05). Though a significant recovery was documented after surgery, a persistence of eye coordination deficits was present at 6 months in 1 out of 3 children with abnormal preoperative exams. A significant correlation was found between pathological CT findings and persistence of below average neuro-ophthalmological and neurocognitive findings 6 months after surgery, as well as between CT findings and neurocognitive scores at the 1 year follow-up (r = 0.411; p < 0.01). CONCLUSION: The presence of neuroradiological abnormalities appears to be related to both ophthalmological and neurocognitive deficits at diagnosis. This relationship is maintained in spite of the surgical treatment in children who show the persistence of ophthalmological and neurocognitive deficits during the follow-up.

Efficacy and safety of Everolimus and Exemestane in hormone-receptor positive (HR+) human-epidermal-growth-factor negative (HER2-) advanced breast cancer patients: New insights beyond clinical trials. The EVA study.

BACKGROUND: The BOLERO-2 trial reported efficacy and safety of Everolimus (EVE) and Exemestane (EXE) combination in HR+ advanced breast cancer (ABC) patients. The BALLET trial further evaluated the safety of EVE-EXE in HR+ ABC patients, without reporting efficacy data. Aim of the EVA real-life study was to collect data of efficacy and safety of EVE-EXE combination in the clinical setting, as well as exploring efficacy according to EVE Dose-Intensity (DI) and to previous treatment with Fulvestrant. PATIENTS AND METHODS: This study aimed to describe the outcome of ABC pts treated with EVE-EXE combination in terms of median duration of EVE treatment and ORR in a real-life setting. RESULTS: From July 2013 to December 2015, the EVA study enrolled 404 pts. Median age was 61 years (33-83). Main metastatic sites were: bone (69.1%), soft tissue (34.7%) and viscera (33.2%). Median number of previous treatments was 2 (1-7). 43.3% of the pts had received Fulvestrant. Median exposure to EVE was 31.0 weeks (15.4-58.3) in the whole population. No difference was observed in terms of EVE exposure duration according to DI (p for trend = 0.27) or type of previous treatments (p = 0.33). ORR and Disease Control Rate (DCR) were observed in 31.6% and 60.7% of the patients, respectively, with the lowest ORRs confined in CHT pre-treated patients or in those who received the lowest DI of EVE. Grade 3-4 adverse events (AEs) were reported in 37.9% of the patients. Main AEs were: stomatitis (11.2%), non-infectious pneumonitis - NIP (3.8%), anaemia (3.8%) and fatigue (3.2%). CONCLUSIONS: The EVA study provided new insights in the use of EVE-EVE combination in HR+ ABC pts many years after the publication of the pivotal trial. The combination is safe and the best response could be obtained in patients receiving the full dose of EVE and/or after hormone-therapy as Fulvestrant in ABC.

Preoperative neurocognitive evaluation as a predictor of brain tumor grading in pediatric patients with supratentorial hemispheric tumors.

OBJECTIVE: The objective of the present study was to retrospectively evaluate the relationship between tumor grading and a selective evaluation of neurocognitive and behavioral functions in children with supratentorial hemispheric brain tumors. METHODS: Children admitted with a diagnosis of supratentorial hemispheric tumors involving the cerebral hemispheres or the thalamus at the Pediatric Neurosurgery Unit of the Catholic University of Rome between January 2008 and January 2014 were considered for the present study. Exclusion criteria were represented by age less than 2 years, severe neurological deficits, seizures, and a metastatic disease. A selective neurocognitive and behavioral workout was used for children aged less and more than 5 years. RESULTS: Global cognitive functions as well as selective neurocognitive and behavioral profiles were found to be significantly worse in children with low-grade tumors, compared with those affected by higher-grades histotypes. Frontal locations for cortical tumors and thalamic lesions were significantly related with worse results, with a clear contribution of dominant vs. nondominant hemisphere involvement and an age higher than 5 years. CONCLUSIONS: Preoperative global and selective neurocognitive evaluation might contribute to the prediction of the tumor aggressiveness. Due to a longer clinical history, more benign tumors more frequently arrive to the diagnosis with a neurocognitive compromise in spite of an apparently mild presence of neurological symptoms and signs.

Combination chemotherapy of carboplatin and gemcitabine against solid tumors: a phase I trial.

BACKGROUND: Some trials have suggested that the combination of gemcitabine and platinum compounds can have a synergistic effect on several solid tumors, but, at present, the data concerning carboplatin-gemcitabine combinations are not sufficient to allow the planning of phase II trials. The present phase I trial was planned to define the maximum tolerated dose and the dose-limiting toxicity of a carboplatin-gemcitabine combination. METHODS: Thirty-two patients with advanced, pretreated solid tumors were treated with carboplatin on day 1 and gemcitabine on days 1, 8, and 15 every 28 days. The starting doses of carboplatin and gemcitabine were 3.5 mg/ml per min (area under the curve; AUC), and 600 mg/m2, respectively. The doses of the two agents were alternately increased to 4, 4.5, and 5 mg/ml per min and to 800 and 960 mg/m2, respectively. At each dose level, three patients were initially enrolled. If one of them experienced grade IV hematological toxicity or grade III-IV nonhematological toxicity (with the exception of alopecia), an additional three patients were enrolled at the same dose level. If two or more patients experienced grade IV hematological toxicity or grade III-IV non-hematological toxicity (with the exception of alopecia), the maximum tolerated dose was considered to have been reached, and the dose below this was recommended for further studies. All patients were evaluated weekly for toxicity and after every two courses of chemotherapy for response. RESULTS: Dose-limiting toxicity was hematological, and the maximum tolerated doses were 4.5 mg/ml per min for carboplatin and 800 mg/m2 for gemcitabine. The activity of the carboplatin/gemcitabine combination was encouraging, with a 21.9% response rate (7/32), three complete disease regressions, and a median time to progression of 30 weeks. The gemcitabine doses of day 15 or days 8 and 15 were omitted for hematological toxicity in 57 (50%) and 17 (14.9%) courses of chemotherapy, while no courses of chemotherapy were delayed for grade III-IV hematological or nonhematological toxicity. CONCLUSION: The maximum tolerated doses suggested by this trial are lower than those in other similar phase I trials, but they are consistent with those reported by most of the trials investigating gemcitabine either in combination with cisplatin or in heavily pretreated patients. Carboplatin 4.5 mg/ml per min on day 1 plus gemcitabine 800 mg/m2 on days 1, 8, and 15 every 28 days may represent a promising schedule for further phase II trials.

[Subacute cerebellar degeneration and pleural mesothelioma. Report of a case]. / Degenerazione cerebellare subacuta e mesotelioma pleurico. Descrizione di un caso.

Subacute cerebellar degeneration is an autoimmune disorder and represents the paraneoplastic neurologic syndrome most frequently occurring in the central nervous system. To our knowledge, until now, no case of such a paraneoplastic syndrome as been described in patients with mesothelioma; on the contrary, some non-neurologic paraneoplastic syndromes have been described in patients with mesothelioma, and an aberrant production of cytokines has been suggested as the main pathogenetic event. In our report it can be supposed that an aberrant production of cytokines might have triggered an autoimmune reaction, causing anti Purkinje cells antibodies production, neurological damage and clinical outcome.