Serum Exosomal microRNA-21, 222 and 124-3p as Noninvasive Predictive Biomarkers in Newly Diagnosed High-Grade Gliomas: A Prospective Study

Background: High-grade gliomas (HGG) are malignant brain tumors associated with frequent recurrent disease. Clinical management of HGG patients is currently devoid of blood biomarkers for early diagnosis, monitoring therapeutic effects and predicting recurrence. Different circulating miRNAs, both free and associated with exosomes, are described in patients with HGG. We previously identified miR-21, miR-222 and miR-124-3p purified from serum exosomes as molecular signature to help pre-operative clinical diagnosis and grading of gliomas. The aim of the present study was to verify this signature as a tool to assess the effect of treatment and for the early identification of progression in newly diagnosed HGG patients. Material and Methods: Major inclusion criteria were newly diagnosed, histologically confirmed HGG patients, no prior chemotherapy, ECOG PS 0-2 and patients scheduled for radiochemotherapy with temozolomide as first-line treatment after surgery. RANO criteria were used for response assessment. Serum was collected at baseline and subsequently at each neuroradiological assessment. mir-21, -222 and -124-3p expression in serum exosomes was measured in all samples. Results: A total number of 57 patients were enrolled; 41 were male, 52 with glioblastoma and 5 with anaplastic astrocytoma; 18 received radical surgery. HGG patients with higher exosomal miRNA expression displayed a statistically significant lower progression-free survival and overall survival. Increased expression of miR-21, -222 and -124-3p during post-operative follow-up was associated with HGG progression. Conclusions: These data indicate that miR-21, -222 and -124-3p in serum exosomes may be useful molecular biomarkers for complementing clinical evaluation of early tumor progression during post-surgical therapy in patients with HGG

Case report: The lesson from opioid withdrawal symptoms mimicking paraganglioma recurrence during opioid deprescribing in cancer pain

Pain is one of the predominant and troublesome symptoms that burden cancer patients during their whole disease trajectory: adequate pain management is a fundamental component of cancer care. Opioid are the cornerstone of cancer pain relief therapy and their skillful management must be owned by physicians approaching cancer pain patients. In light of the increased survival of cancer patients due to advances in therapy, deprescription should be considered as a part of the opioid prescribing regime, from therapy initiation, dose titration, and changing or adding drugs, to switching or ceasing. In clinical practice, opioid tapering after pain remission could be challenging due to withdrawal symptoms’ onset. Animal models and observations in patients with opioid addiction suggested that somatic and motivational symptoms accompanying opioid withdrawal are secondary to the activation of stress-related process (mainly cortisol and catecholamines mediated). In this narrative review, we highlight how the lack of validated guidelines and tools for cancer patients can lead to a lower diagnostic awareness of opioid-related disorders, increasing the risk of developing withdrawal symptoms. We also described an experience-based approach to opioid withdrawal, starting from a case-report of a symptomatic patient with a history of metastatic pheochromocytoma-paraganglioma

Recurrent glioblastoma: From molecular landscape to new treatment perspectives

Glioblastoma is the most frequent and aggressive form among malignant central nervous system primary tumors in adults. Standard treatment for newly diagnosed glioblastoma consists in maximal safe resection, if feasible, followed by radiochemotherapy and adjuvant chemotherapy with temozolomide; despite this multimodal treatment, virtually all glioblastomas relapse. Once tumors progress after first-line therapy, treatment options are limited and management of recurrent glioblastoma remains challenging. Loco-regional therapy with re-surgery or re-irradiation may be evaluated in selected cases, while traditional systemic therapy with nitrosoureas and temozolomide rechallenge showed limited efficacy. In recent years, new clinical trials using, for example, regorafenib or a combination of tyrosine kinase inhibitors and immunotherapy were performed with promising results. In particular, molecular targeted therapy could show efficacy in selected patients with specific gene mutations. Nonetheless, some molecular characteristics and genetic alterations could change during tumor progression, thus affecting the efficacy of precision medicine. We therefore reviewed the molecular and genomic landscape of recurrent glioblastoma, the strategy for clinical management and the major phase I-III clinical trials analyzing recent drugs and combination regimens in these patients

Epidemiology and clinical course of severe acute respiratory syndrome coronavirus 2 infection in cancer patients in the Veneto Oncology Network: The Rete Oncologica Veneta covID19 study

Introduction: Coronavirus disease 2019 (COVID-19) pandemic started in Italy with clusters identified in Northern Italy. The Veneto Oncology Network (Rete Oncologica Veneta) licenced dedicated guidelines to ensure proper care minimising the risk of infection in patients with cancer. Rete Oncologica Veneta covID19 (ROVID) is a regional registry aimed at describing epidemiology and clinical course of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with cancer. Materials and methods: Patients with cancer diagnosis and documented SARS-CoV-2 infection are eligible. Data on cancer diagnosis, comorbidities, anticancer treatments, as well as details on SARS-CoV-2 infection (hospitalisation, treatments, fate of the infection), have been recorded. Logistic regression analysis was applied to calculate the association between clinical/laboratory variables and death from any cause. Results: One hundred seventy patients have been enrolled. The median age at time of the SARS-CoV infection was 70 years (25-92). The most common cancer type was breast cancer (n = 40). The majority of the patients had stage IV disease. Half of the patients had two or more comorbidities. The majority of the patients (78%) presented with COVID-19 symptoms. More than 77% of the patients were hospitalized and 6% were admitted to intensive care units. Overall, 104 patients have documented resolution of the infection. Fifty-seven patients (33%) have died. In 29 cases (17%), the cause of death was directly correlated to SARS-CoV-2 infection. Factors significantly correlated with the risk of death were the following: Eastern Cooperative Oncology Group performance status (PS), age, presence of two or more comorbidities, presence of dyspnoea, COVID-19 phenotype ≥ 3, hospitalisation, intensive care unit admission, neutrophil/lymphocyte ratio and thrombocytopenia. Conclusions: The mortality rate reported in this confirms the frailty of this population. These data reinforce the need to protect patients with cancer from SARS-CoV-2 infection

Spinal ependymoma in adults: from molecular advances to new treatment perspectives

Ependymomas are rare glial tumors with clinical and biological heterogeneity, categorized into supratentorial ependymoma, posterior fossa ependymoma, and spinal cord ependymoma, according to anatomical localization. Spinal ependymoma comprises four different types: spinal ependymoma, spinal ependymoma MYCN-amplified, myxopapillary ependymoma, and subependymoma. The clinical onset largely depends on the spinal location of the tumor. Both non-specific and specific sensory and/or motor symptoms can be present. Owing to diverse features and the low incidence of spinal ependymomas, most of the current clinical management is derived from small retrospective studies, particularly in adults. Treatment involves primarily surgical resection, aiming at maximal safe resection. The use of radiotherapy remains controversial and the optimal dose has not been established; it is usually considered after subtotal resection for WHO grade 2 ependymoma and for WHO grade 3 ependymoma regardless of the extent of resection. There are limited systemic treatments available, with limited durable results and modest improvement in progression-free survival. Thus, chemotherapy is usually reserved for recurrent cases where resection and/or radiation is not feasible. Recently, a combination of temozolomide and lapatinib has shown modest results with a median progression-free survival (PFS) of 7.8 months in recurrent spinal ependymomas. Other studies have explored the use of temozolomide, platinum compounds, etoposide, and bevacizumab, but standard treatment options have not yet been defined. New treatment options with targeted treatments and immunotherapy are being investigated. Neurological and supportive care are crucial, even in the early stages. Post-surgical rehabilitation can improve the consequences of surgery and maintain a good quality of life, especially in young patients with long life expectancy. Here, we focus on the diagnosis and treatment recommendations for adults with spinal ependymoma, and discuss recent molecular advances and new treatment perspectives

Valutazione dell'attività di pembrolizumab in pazienti con recidiva di glioma di alto-grado e perdita parziale o completa di espressione delle proteine del mismatch repair: studio monocentrico, osservazionale, prospettico

Background Pembrolizumab, un inibitore del checkpoint immunitario anti PD-1, ha mostrato un' importante attività in diversi tipi di tumori con fenotipo ipermutato. La perdita di espressione delle proteine del mismatch repair (MMR) all'analisi immunoistochimica sembra essere associata all' ipermutazione nei gliomi di alto-grado (HGG). Questo studio ha valutato l'efficacia e la sicurezza di pembrolizumab in pazienti con recidiva di glioma di alto-grado e perdita immunoistochimica di almeno una delle proteine MMR. Inoltre, sono stati valutati potenziali biomarcatori molecolari che possano predire l'attività di pembrolizumab Materiali e Metodi Abbiamo arruolato prospetticamente pazienti con recidiva di HGG e perdita parziale o completa dell'espressione delle proteine MMR. Pembrolizumab è stato somministrato per infusione endovenosa alla dose standard di 200 mg una volta ogni 3 settimane fino a tossicità inaccettabile o progressione della malattia. L'endpoint primario era il tasso di controllo della malattia (DCR). Come analisi esplorative post hoc, sono stati eseguiti il ​​sequenziamento di nuova generazione (NGS) per la valutazione del carico mutazionale del tumore (TMB) e l'immunocolorazione per le cellule T CD8 + e i macrofagi CD68 +. Risultati Sono stati selezionati 310 pazienti con recidiva di HGG; 13 di loro con perdita parziale o completa dell' espressione di almeno una delle proteine del MMR sono stati arruolati e trattati con pembrolizumab. Di questi 13 casi, otto avevano una diagnosi di glioblastoma, quattro di astrocitoma anaplastico e uno di oligodendroglioma anaplastico. L'età media era di 43 anni. La DCR è stata del 31% con quattro pazienti che hanno mostrato una stabilità di malattia come miglior risposta e nessuno con risposta parziale o completa. Il TMB variava tra 6,8 e 23,4 mutazioni/megabase. Le mutazioni riscontrate nei pazienti trattati, il TMB, la presenza di cellule T CD8 + e macrofagi CD68 + non sembrano essere associati all'attività di pembrolizumab. Conclusioni Pembrolizumab non ha dimostrato alcun beneficio in questa popolazione di pazienti e non sono stati identificati biomarcatori molecolari associati all'attività di pembrolizumab.Background Pembrolizumab, an anti PD-1 immune checkpoint inhibitor, has shown important activity in several cancers with hypermutated phenotype. Expression loss of mismatch repair (MMR) protein on immunohistochemical analysis appears to be associated with hypermutation in high-grade gliomas. This study evaluated the efficacy and safety of pembrolizumab in patients with HGGs and immunohistochemical loss of at least one MMR protein. In addition, potential molecular biomarkers predicting pembrolizumab activity were evaluated Materials and Methods We prospectively enrolled patients with recurrent HGG and partial or complete loss of MMR protein expression. Pembrolizumab was administered by intravenous infusion at the standard dose of 200 mg once every 3 weeks until unacceptable toxicity or disease progression. Primary end point was disease control rate (DCR). As exploratory post hoc analyzes, next generation sequencing (NGS) for the evaluation of tumor mutational burden (TMB) and immunostaining for CD8 + T-cells and CD68 + macrophages were performed. Results: 310 patients with recurrent HGG were screened; 13 of them with MMR expression loss were enrolled and treated with pembrolizumab. Of these 13 cases, eight were glioblastoma, four anaplastic astrocytoma, and one anaplastic oligodendroglioma. Median age was 43 years. DCR was 31% with four patients showing stable disease as the best response and none with partial or complete response. TMB ranged between 6.8 and 23.4 mutations/megabase. Mutations found in treated patients, TMB, CD8 + T-Cell and CD68 + macrophage do not appear to be associated with pembrolizumab activity. Conclusions Pembrolizumab demonstrated no benefit in this patient population and no molecular biomarkers associated with pembrolizumab activity were found

Adjuvant therapy for resected early-stage small-cell lung cancer: is now time to rethink about that?

Small-cell lung cancer (SCLC) has historically been considered a highly chemo-radiosensitive malignancy, rarely susceptible of surgical resection due to advanced stage presentation with bulky nodal disease and frequent systemic involvement. Actually, surgical series documented SCLC in just 2\u20133% of patients (1) and, although several randomized trials contributed to define the management of extensive and limited stage SCLC, very few data are available for the early stage, possibly resectable, disease

Endocarditis caused by nutritionally variant streptococci: a case report and literature review.

Infective endocarditis (IE) due to Abiotrophia and Granulicatella species, previously referred to as nutritionally variant streptococci (NVS), occurs rarely and is often associated with negative blood cultures. Rates of treatment failure, infection relapse and mortality are higher than those of endocarditis caused by other viridans streptococci. We report a case of endocarditis caused by Granulicatella adiacens in a young man with no risk factors, who was successfully treated with surgery and combination antimicrobial chemotherapy, and provide a literature review of endocarditis attributable to these rare species of fastidious gram-positive cocci which have proven exceedingly difficult to treat, with high rates of relapse and therapeutic failure despite in vitro effective antibiotic treatment regimens. Analysis of literature revealed a high prevalence (61%) of valvular heart predisposing conditions associated with endocarditis caused by NVS, such as congenital valvular heart disease or heart valve prosthesis. On the other hand, 39% of cases showed no evidence of risk factors. Combination antimicrobial chemotherapy with penicillin and gentamicin represents the antimicrobial treatment of choice in the management of patients with IE attributable to NVS. Heart valve replacement surgery should be considered in cases of hemodynamic derangement due to significant valve destruction