Calcitonin-secreting neuroendocrine tumor of the larynx, a diagnostic challenge of a rare neoplasm: a case report and literature review.

Background: Laryngeal neuroendocrine tumors (NETs) represent less than 1% of all malignancies originating from the larynx and available data are limited on case reports. Calcitonin secreting laryngeal NETs are extremely rare and serial dosing of calcitonin in these patients might reveal early relapse or persistence. Case Description: We report the case of a 71-year-old woman with persistent pharyngodynia who underwent surgery for an initial diagnosis of small cell undifferentiated neuroendocrine carcinoma (SCUNC) of the larynx (on the epiglottis extended to the left glosso-epiglottic vallecula). The immunohistochemical profile showed the presence of synaptophysin, neuron-specific enolase (NSE), chromogranin A, pan-cytokeratin, including cytokeratin AE1-AE2, and focally calcitonin. The circulating NSE was 13.4 microg/L (normal level <12.5 microg/L) and the basal serum level of calcitonin was 237 pg/mL (normal level <11.5 pg/mL). The patient was started on first-line carboplatin-etoposide chemotherapy because of early relapse to an axillary lymph node. After 4 cycles of treatment, a radiological stability and metabolic response were demonstrated together with a drastic decrease of circulating serum level of calcitonin (from 237 to 57.9 pg/mL). During the follow up, locoregional relapse of disease occurred, associated with an increase of serum calcitonin (89.3 pg/mL). Disease further progressed on and rechallenge with platinum-etoposide chemotherapy was administered, during which clinical progression was confirmed. Due to the lack of response, a revision of the histology was performed and concluded for a definitive diagnosis of moderately differentiated G2 NET, with a Ki-67 index of 22.6%. Conclusions: This is the eighth case report of laryngeal NET, highlighting the challenge in pathological differential diagnosis and therapeutic strategies. The association with elevated serum calcitonin and the trend of this parameter during clinical progression suggest a role of this marker in the diagnosis and early identification of recurrent laryngeal NETs.

HER2-targeted therapies for salivary gland cancers.

Salivary gland cancers (SGCs) are a heterogeneous group of rare tumors including various histological subtypes with different molecular profiling. Human epidermal growth factor receptor 2 (HER2) is one of the most intriguing and studied molecular alterations with prognostic and predictive roles. Indeed, HER2 overexpression is commonly correlated with aggressive histological subtypes and poorer prognosis. However, HER2 may represent the target of personalized treatment. We performed a literature review of use of anti-HER2 targeted agents for treatment of recurrent or metastatic SGCs. The efficacy and safety of anti-HER2 were firstly evaluated in patients affected with other solid tumors, mostly breast and gastric cancers. For SGCs the literature is mainly comprised of case reports or case series and small clinical trials. The most common used drug is trastuzumab in combination with chemotherapy (i.e. taxanes, capecitabine, carboplatin, eribulin) or with another anti-HER2 targeted agent (i.e. pertuzumab). The use of anti-HER2 therapies induces improvement in clinical responses, which are mostly durable. Besides, new anti-HER2 drugs such as antibody-drug conjugates (ADC) (i.e. trastuzumab emtansine, trastuzumab deruxtecan) have been introduced in this setting inducing further therapeutic advances. Anti-HER2 treatment strategy is emerging as potentially effective in selected HER2 overexpressing SGCs. However, prospective and multicentric clinical trials are needed to evaluate the efficacy of these therapeutic regimens within larger cohorts and to assess the most appropriate treatment sequence strategy.

Unexpected response to fourth-line paclitaxel in a patient with metastatic oropharyngeal squamous cell carcinoma, immunotherapy-refractory: a case report.

In recent years, immune checkpoint inhibitors (ICIs), including nivolumab and pembrolizumab have revolutionized the treatment landscape in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). However, many patients do not respond to ICIs for reasons that remain largely unknown. For patients who progress on ICIs, chemotherapy and/or biologic therapies are the most widely used treatments based on the clinician's choice, with no defined sequence strategy. We report the experience of a patient with metastatic oropharyngeal squamous cell cancer p16 and human papillomavirus-DNA positive who received chemotherapy with weekly paclitaxel after progressing on nivolumab. Our patient presented a partial response to fourth line paclitaxel, which lasted more than 2 years, with an improvement of his quality of life too. These results support the hypothesis of synergism between immunotherapy and conventional chemotherapies. Even in the setting of immune-refractory disease, immunotherapy may affect tumor immune microenvironment thus leading to a synergistic effect with conventional chemotherapy and achieving unexpected results.

Systemic and liver-directed therapies in metastatic uveal melanoma: state-of-the-art and novel perspectives.

Metastatic uveal melanoma (MUM) is the most common form of noncutaneous melanoma. It is different from its cutaneous counterpart and is characterized by a very poor prognosis. Despite groundbreaking improvements in the treatment of cutaneous melanoma, there have been few advances in the treatment of MUM, and standard treatments for MUM have not been defined. We performed a systematic review focusing our attention on all interventional studies, ongoing or already published, concerning the treatment of MUM. We present results from studies of chemotherapy, targeted therapy, immunotherapy and liver-directed therapies. Although the results in this setting have been disappointing until now, trials investigating novel immunotherapeutic strategies alone and in combination with targeted agents and liver-directed therapies are ongoing.

PD-L1 Expression in Circulating Tumor Cells as a Promising Prognostic Biomarker in Advanced Non-small-cell Lung Cancer Treated with Immune Checkpoint Inhibitors.

BACKGROUND: Circulating tumor cells (CTCs) are a promising source of biological information in cancer. Data correlating PD-L1 expression in CTCs with patients' response to immune checkpoint inhibitors (ICIs) in non-small-cell lung cancer (NSCLC) are still lacking. METHODS: This is a prospective single-center cohort study enrolling patients with advanced NSCLC. CTCs were identified and counted with the CellSearch system. PD-L1 expression on CTCs was assessed with phycoerythrin-conjugated anti-human PD-L1 antibody, clone MIH3 (BioLegend, USA). Primary endpoint was the correlation between the CTCs PD-L1 expression and overall survival (OS). Among secondary objectives, we evaluated the correlation between PD-L1 expression on CTCs and matched tumor tissue and the correlation of CTC number and baseline tumor size (BTS). RESULTS: Thirty-nine patients treated with anti-PD-1/PD-L1 agents as second- or third-line therapy were enrolled. Patients were divided into 3 groups: no CTC detectable (CTCnull, n = 15), PD-L1 positive CTC (CTCpos, n = 13), and PD-L1 negative CTC (CTCneg, n = 11). Median OS in patients with CTCneg was 2.2 months, 95% confidence interval (CI), 0.8-3.6 (reference) versus 3.7 months, 95% CI, 0.1-7.5 (hazard ratio [HR] 0.33; 95% CI, 0.13-0.83; P = .019) in patients with CTCpos versus 16.0 months, 95% CI, 2.2-29.8 (HR 0.17; 95% CI, 0.06-0.45; P< .001) in patients with CTCnull. No correlation was found between PD-L1 expression on CTCs and on tumor tissue. CTC number was correlated with BTS. CONCLUSION: PD-L1 expression on CTCs is a promising biomarker in patients with NSCLC treated with ICIs. Further validation as predictive biomarker is needed.

Experimental HER2- targeted therapies for biliary tract cancer.

Introduction: Biliary tract cancers (BTCs) constitute a heterogeneous group of poor-prognosis solid tumors with limited treatment options. In the last decade, global efforts have tried to identify therapeutic targets by genomic profiling of BTC, unveiling several genetic aberrations that could play a prognostic and/or a predictive role in these malignancies.Areas covered: In this review, we will present an overview regarding the role of HER2 targeted therapies in BTC, with a particular focus on clinical studies carried out in this field to date and ongoing trials. A literature search was conducted in August 2020 of Pubmed/Medline, Cochrane library and Scopus databases for published preclinical and clinical studies; moreover, abstract of international cancer meetings (AACR, ASCO, and ESMO) were reviewed.Expert opinion: Despite recent advances in medical oncology, the overall survival of BTC patients remains low and there is an urgent need for novel and more effective treatments. Although HER2 blockade has been suggested to induce durable tumor responses in selected subjects with BTC, controversial results have been reported so far and data from ongoing prospective clinical trials are awaited to further clarify the role of anti-HER2 therapies in BTC.

The (Eternal) Debate on Microwave Ablation Versus Radiofrequency Ablation in BCLC-A Hepatocellular Carcinoma.

BACKGROUND/AIM: While percutaneous radiofrequency ablation (RFA) is considered the standard ablative modality for the treatment of early-stage hepatocellular carcinoma (HCC), percutaneous microwave ablation (MWA) is being increasingly used in recent years. We performed a systematic review and meta-analysis to compare percutaneous MWA versus percutaneous RFA in BCLC-A HCC across randomized controlled trials (RCTs). PATIENTS AND METHODS: Eligible studies included RCTs assessing MWA versus RFA in BCLC-A HCC. Outcomes of interest included: complete ablation (CA) rate, local recurrence (LR) rate, 1-year overall survival (OS) rate, 3-year OS rate and major complications rate. RESULTS: We retrieved all the relevant RCTs through PubMed/Medline, Cochrane library and EMBASE; five eligible studies involving a total of 794 patients (MWA: 409; RFA: 385) and 1008 nodules of HCC (MWA: 519; RFA: 489) were included in our analysis. No significant differences were found between MWA and RFA regarding CA, LR, 3-year OS and major complications rate. Regarding 1-year OS, a higher rate was observed in the MWA group. CONCLUSION: MWA and RFA are effective and safe techniques in early stage, BCLC-A, HCCMWA resulted in better 1-year OS, although this benefit was not confirmed in the 3-year analysis.

PARP Inhibitors in Biliary Tract Cancer: A New Kid on the Block?

Poly adenosine diphosphate-ribose polymerase inhibitors (PARPi) represent an effective therapeutic strategy for cancer patients harboring germline and somatic aberrations in DNA damage repair (DDR) genes. BRCA1/2 mutations occur at 1-7% across biliary tract cancers (BTCs), but a broader spectrum of DDR gene alterations is reported in 28.9-63.5% of newly diagnosed BTC patients. The open question is whether alterations in genes that are well established to have a role in DDR could be considered as emerging predictive biomarkers of response to platinum compounds and PARPi. Currently, data regarding PARPi in BTC patients harboring BRCA and DDR mutations are sparse and anecdotal; nevertheless, a variety of clinical trials are testing PARPi as monotherapy or in combination with other anticancer agents. In this review, we provide a comprehensive overview regarding the genetic landscape of DDR pathway deficiency, state of the art and future therapeutic implications of PARPi in BTC, looking at combination strategies with immune-checkpoint inhibitors and other anticancer agents in order to improve survival and quality of life in BTC patients.

Second-line Treatment in Advanced Biliary Tract Cancer: Today and Tomorrow.

Biliary tract cancer (BTC) patients usually have poor prognosis. Whereas combination chemotherapy has been shown to improve survival in the frontline setting, second-line treatment is subject to a lot of debate in the scientific community. Recent data of the ABC-06 trial has provided slight evidence for the use of second-line chemotherapy after progression on cisplatin plus gemcitabine combination. In this study, mFOLFOX plus active symptom control (ASC) improved overall survival (OS) after progression on cisplatin-gemcitabine combination compared with ASC alone, with an increase in 6- and 12-month OS rate. Although genomic studies have paved the way for a new age in cancer management, the "Precision Medicine Era" in BTC is still limited to intrahepatic cholangiocarcinoma and primarily focused on isocitrate dehydrogenase (IDH) and fibroblast growth factor receptor (FGFR) targeted therapies. We herein review recent published data regarding the use of second-line treatment after failure of standard first-line therapies in BTC patients, with a particular focus on ongoing active and recruiting clinical trials.

Landscape and Future Perspectives of Immunotherapy in Neuroendocrine Neoplasia.

BACKGROUND: Neuroendocrine neoplasms are rare entities consisting of a heterogeneous group of tumors that can originate from neuroendocrine cells present in the whole body. Their different behavior, metastatic potential, and prognosis are highly variable, depending on site of origin, grade of differentiation, and proliferative index. The aim of our work is to summarize the current knowledge of immunotherapy in different neuroendocrine neoplasms and its implication in clinical practice. RESULTS: Several studies evaluated the efficacy and safety of immunotherapy in neuroendocrine neoplasms, in any setting of treatment, alone or in combination. Studies led to approval in neuroendocrine neoplasia of the lung, in combination with chemotherapy as first-line treatment or as a single-agent in a third-line setting, and Merkel cell carcinoma as a single agent. Results in other settings have been disappointing so far. CONCLUSIONS: Immunotherapy seems a valid treatment option for high grade, poorly differentiated neoplasms. Future trials should explore the combination of immunotherapy with other agents, such as anti-angiogenic or other immunotherapy agents, in order to evaluate potential efficacy in low and intermediate grades, well differentiated tumors.

Specific Toxicity of Maintenance Olaparib Versus Placebo in Advanced Malignancies: A Systematic Review and Meta-analysis.

BACKGROUND/AIM: We performed a systematic review and meta-analysis to investigate the safety of maintenance with olaparib after platinum-based chemotherapy in cancer patients. MATERIALS AND METHODS: Eligible studies included randomized controlled trials (RCTs) regarding the clinical role of olaparib maintenance therapy versus placebo in BRCA-mutated, advanced cancers. Safety profile from each selected study was investigated for all-grade and G3-G4 haematological and non-haematological adverse drug events (ADEs). RESULTS: Four RTCs that involved 1099 patients were included in the analysis. Overall incidences of all-grade and G3-4 ADEs in olaparib group were 97.6% and 41%, respectively. Patients treated with maintenance olaparib showed higher risk of all-grade and G3-G4 anaemia, all-grade neutropenia and thrombocytopenia. Moreover, all-grade and G3-G4 fatigue, all-grade vomiting, diarrhoea, nausea and decreased appetite were more common in the olaparib group compared to placebo. CONCLUSION: Despite an increased risk and incidence of several haematological and non-haematological toxicities, olaparib is a relatively safe agent for the treatment of advanced solid tumors. Prompt identification of ADEs is mandatory to avoid therapy discontinuation and optimize treatment.

Long-term eribulin treatment in patients with a single kidney and retroperitoneal liposarcoma.

Retroperitoneal sarcomas are extremely rare malignant tumors. The most common type of sarcomas arising in the retroperitoneum are liposarcomas, occurring mostly in the sixth and seventh decades of life. The only potentially curative approach to liposarcomas is the complete surgical resection of the tumor with negative microscopic margins. However, retroperitoneal liposarcomas exhibit a propensity for local recurrence and distant metastasis despite the negative surgical margins, thus requiring additional therapy. Eribulin demonstrated a benefit in terms of overall survival in patients with advanced or metastatic liposarcoma. We report two cases of patients, both submitted to concomitant right nephrectomy, who experienced a long-lasting control of recurrent retroperitoneal liposarcoma before being submitted to eribulin-based therapeutic regimens (23 and 24 treatment cycles completed, respectively).

[Effectiveness of school-based interventions to prevent traffic accidents: an overview of secondary literature]. / Efficacia degli interventi scolastici per la prevenzione degli incidenti stradali: una overview della letteratura secondaria.

INTRODUZIONE: gli incidenti stradali sono l'ottava causa di morte al mondo e la prima tra i giovani di 15-29 anni. In Italia il Piano nazionale sicurezza stradale raccomanda l'educazione scolastica per la prevenzione degli incidenti stradali; ad oggi non esistono documenti che raccolgano evidenze di efficacia sugli interventi educativi stradali e le rapportino al contesto italiano. OBIETTIVI: riassumere e discutere ciò che è noto in letteratura riguardo agli interventi scolastici per la prevenzione degli incidenti stradali. METODI: sono state ricercate linee guida e revisioni sistematiche usando i seguenti criteri di inclusione: popolazione di età inferiore ai 25 anni di entrambi i sessi; interventi scolastici di educazione stradale; effetti su indicatori primari di esito come riduzione degli incidenti stradali, astinenza dalla guida sotto l'effetto di alcol e dall'accettare passaggi in macchina da guidatori che sono sotto l'effetto di alcol; effetti su indicatori secondari di esito come conoscenze e competenze sui comportamenti di guida sicura. RISULTATI: sono state identificate due revisioni sistematiche. L'educazione stradale nelle scuole non mostra evidenza di efficacia (rischio relativo 1,03; IC95% 0,98-1,08) nel ridurre gli incidenti. Programmi scolastici più specifici mostrano risultati solo in parte convincenti per l'adozione di comportamenti sicuri come l'astinenza dal guidare sotto l'effetto di alcol e dall'accettare passaggi in macchina da guidatori che sono sotto l'effetto di alcol. DISCUSSIONE: le revisioni incluse non hanno trovato programmi efficaci nella riduzione degli incidenti stradali o dei fattori che possano determinarli. Nell'attesa di studi più recenti, appare opportuno promuovere l'implementazione di interventi misti, scolastici e di comunità, che hanno mostrato maggiori prove di efficacia.