Safety and Efficacy of Atezolizumab and Bevacizumab Combination as a First Line Treatment of Advanced Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common leading causes of cancer death worldwide. As most patients are diagnosed with advanced disease, systemic therapy remains the backbone of treatment. In recent years, we have witnessed the transformation of advanced HCC treatment landscapes from single-agent targeted therapies to immunotherapy combinations, with atezolizumab plus bevacizumab becoming the new first-line standard of care with an increase in overall survival, progression-free survival, and objective response rate compared to sorafenib, and a positive impact on quality of life. Although the efficacy and safety of this combination have been confirmed regardless of ethnicity, age, and etiology, only a subgroup of patients seems to benefit the most from this treatment. Currently, predictive serum and tissue biomarkers to select patients who are most likely to respond to atezolizumab plus bevacizumab are lacking. Moreover, the optimal subsequent therapy for patients who progress on first-line atezolizumab plus bevacizumab remains unknown, clinical trials are ongoing, and real-world data are needed to determine the most effective treatment sequence. Importantly, careful evaluation of bleeding risk and preservation of adequate liver function are fundamental to improve patients' prognosis, especially when subsequent treatments are administered.

Pancreatic Ductal Adenocarcinoma and Immune Checkpoint Inhibitors: The Gray Curtain of Immunotherapy and Spikes of Lights.

Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a poor 5-year overall survival rate (~10%). The revolution of immunotherapy in clinical oncology has not substantially changed clinical outcome for patients with PDAC. Despite outstanding efforts, neither immune checkpoint inhibitors (ICIs) alone, nor in combination with chemotherapy or targeted therapies have shown encouraging results. This failure mirrors the lack of knowledge about the real key players of immune system senescence and the complexity of the tumor microenvironment in PDAC. However, some hope can be derived from PARP-inhibitor combinations, vaccines, and CAR-T-cells therapy. In this review, we comprehensively summarize the latest updates about the use of ICIs in PDAC, focusing on clinical evidence and ongoing studies highlighting explanations for the failure of immunotherapy and possible solutions.

Advances in drug treatments for mesothelioma.

INTRODUCTION: The paucity of the therapeutic armamentarium currently available for patients with malignant mesothelioma clearly represents a huge unmet need. Over the last years, based on new advances in understanding the biology of mesothelioma, new therapeutic approaches have been investigated. AREAS COVERED: In this manuscript, the literature data regarding the advances in drug treatment for patients with mesothelioma are critically reviewed, focusing particularly on immunotherapy and targeted therapy. EXPERT OPINION: The latest findings on immunotherapy and targeted therapy are changing the therapeutic armamentarium for mesothelioma. However, mesothelioma comprises genomically different subtypes and the phenotypic diversity combined with the rarity of this disease represents a major criticality in developing new effective therapies. Although the first clinical data are encouraging, the treatment's stratification by molecular characteristics for mesothelioma is only at the beginning. Luckily, the rapid improvement of understanding the biology of mesothelioma is producing new opportunities in discovering new therapeutic targets to test in pre-clinical settings and to transfer in the clinical setting. In this evolving scenario, the future perspectives for mesothelioma patients seem really promising.

Hepatitis C virus infection and risk of liver-related and non-liver-related deaths: a population-based cohort study in Naples, southern Italy.

BACKGROUND: Hepatitis C virus (HCV) infection represents a global health issue with severe implications on morbidity and mortality. This study aimed to evaluate the impact of HCV infection on all-cause, liver-related, and non-liver-related mortality in a population living in an area with a high prevalence of HCV infection before the advent of Direct-Acting Antiviral (DAA) therapies, and to identify factors associated with cause-specific mortality among HCV-infected individuals. METHODS: We conducted a cohort study on 4492 individuals enrolled between 2003 and 2006 in a population-based seroprevalence survey on viral hepatitis infections in the province of Naples, southern Italy. Study participants provided serum for antibodies to HCV (anti-HCV) and HCV RNA testing. Information on vital status to December 2017 and cause of death were retrieved through record-linkage with the mortality database. Hazard ratios (HRs) for cause-specific mortality and 95% confidence intervals (CIs) were estimated using Fine-Grey regression models. RESULTS: Out of 626 deceased people, 20 (3.2%) died from non-natural causes, 56 (8.9%) from liver-related conditions, 550 (87.9%) from non-liver-related causes. Anti-HCV positive people were at higher risk of death from all causes (HR = 1.38, 95% CI: 1.12-1.70) and liver-related causes (HR = 5.90, 95% CI: 3.00-11.59) than anti-HCV negative ones. Individuals with chronic HCV infection reported an elevated risk of death due to liver-related conditions (HR = 6.61, 95% CI: 3.29-13.27) and to any cause (HR = 1.51, 95% CI: 1.18-1.94). The death risk of anti-HCV seropositive people with negative HCV RNA was similar to that of anti-HCV seronegative ones. Among anti-HCV positive people, liver-related mortality was associated with a high FIB-4 index score (HR = 39.96, 95% CI: 4.73-337.54). CONCLUSIONS: These findings show the detrimental impact of HCV infection on all-cause mortality and, particularly, liver-related mortality. This effect emerged among individuals with chronic infection while those with cleared infection had the same risk of uninfected ones. These results underline the need to identify through screening all people with chronic HCV infection notably in areas with a high prevalence of HCV infection, and promptly provide them with DAAs treatment to achieve progressive HCV elimination and reduce HCV-related mortality.

[Mortality Atlas of the Campania Region. All-cause and cause-specific mortality at municipal level, 2006-2014]. / Atlante di mortalità della regione Campania. Mortalità generale e specifica per causa, con dettaglio comunale, periodo 2006-2014.

OBJECTIVES: This Monograph aims to provide the scientific community and the Regional Healthcare Service an up-to-date Atlas of mortality for the Campania Region (Southern Italy). The Atlas shows an overview of mortality through comparisons with national data and with intraregional macroareas. Maps presenting risk measures with municipal details are also provided. MATERIALS AND METHODS: Both overall and cause-specific mortality data for the period 2006-2014 referred to people residing in Campania Region are analysed in this Atlas. Twenty-nine death causes (major causes and specific cancers) are studied; for each of them, it has been provided: • direct standardised rates (standard population EU 2013) referred to Italy, Campania Region, and the seven regional Local Health Units (LHUs); • standardised mortality ratios (SMRs), estimated on a regional basis, referred to every LHU; • years of life lost (number and rate) both on a regional and on LHU basis; • mortality rate trends for the period 2006-2014, including annual percentage changes (APCs) for Italy, Campania Region, and every LHU; • for every death cause, regional maps are provided also with municipal details for Relative Risks (RRs) and risk posterior probabilities (PPs) estimated through a Bayesian hierarchical model. Risk estimates are presented both crude and adjusted by socioeconomic deprivation index resulted from the 2011 Census of the Italian National Institute fo Statistics. RESULTS: In Campania Region, standardised mortality ratios (per 100,000; IC95%) higher than the national average have been recorded for the following causes: all causes of death: M: 1,233.3 (IC95% 1,227.9-1,238.9) vs 1,093.8 (IC95% 1,092.5-1,095.1); F: 826.1 (IC95% 822.6-829.7) vs 722.8 (IC95% 721.9-732.6); digestive system diseases: M: 51.2 (IC95% 50.2-52.3) vs 44.2 (IC95% 44.0-44.5); F: 35.8 (IC95% 35.1-36.6) vs 29,2 (IC95% 29.0-29.4); circulatory system diseases: M: 493.1 (IC95% 489.6-496.8) vs 404.3 (IC95% 403.5-405.1); F: 388.5 (IC95% 386.1-390.9) vs 296.5 (IC95% 295.9-297.0); genitourinary system diseases: M: 27.2 (IC95% 26.4-28.1) vs 21.9- (IC95% 21.7-22.1); F: 18.2 (IC95% 17.7-18.7) vs 13.7- (IC95% 13.5-13.8); endocrine and metabolic diseases: M: 60.0 (IC95% 58.8-61.2) vs 43.8 (IC95% 43.5-44.0); F: 60.7 (IC95% 59.8-61.7) vs 36.6 (IC95% 36.4-36.8); myocardial infarction: M: 71.1 (IC95% 69.8-72.4) vs 60.9 (IC95% 60.6-61.2); F: 38.2 (IC95% 37.4-39.0) vs 30.2-(IC95% 30.0-30.4); diabetes: M: 52.6 (IC95% 51.5-53.8) vs 35.1 (IC95% 34.9-35.3); F: 53.8 (IC95% 52.9-54.7) vs 28.6 (IC95% 28.4-28.8). On the other hand, mortality rates comparable to or lower than the national average are observed for the remaining causes of death, with different differences for gender. Mortality for cancer causes in Campania Region presents rates higher than the rates observed at national level in males for the following causes: all cancers: 380.4 (IC95% 377.5-383.3) vs 356.5 (IC95% 355.8-357.2); lung cancer: 112.5 (IC95% 110.9/114.0) vs 93.0 (IC95% 92.6-93.3);larynx cancer: 7.6 (IC95% 7.2-8.0) vs 5.5 (IC95% 5.4-5.6);bladder cancer: 25.1 (IC95% 24.4-25.9) vs 17.3 (IC95% 17.1-17.4); in females for the following causes: liver cancer: 3.8 (IC95% 3.6-4.1) vs 3.3 (IC95% 3.2-3.4);bladder cancer:: 3.5 (IC95% 3.3-3.7) vs 3.0 (IC95% 2.9-3.0). In Campania Region, mortality rates comparable to or lower than the national average are observed for the remaining cancer causes both in females and in males. For almost all the death causes, the highest mortality rates are observed in the three LHUs of Naples (Naples centre, Naples 2 North, Naples 3 South); for some death causes, also the Province of Caserta presents the highest mortality rates. It is worth noting that these areas are characterised by the highest urbanisation and regional population density, and by exposures to possible environmental risks. Time trend analyses highlight that regional and national trends are similar for almost all the examined death causes. In Campania Region, males present decreasing trends for all-cause mortality; for respiratory system, circulatory system, and digestive system diseases; for all malignant cancers; for lung, prostate, and stomach cancers; for leukaemias. On the other hand, an increasing trend is shown for liver cancer. Trends for genitourinary system and nervous system diseases are almost unchanged; the same is for blood diseases and haemolymphopoietic system cancers. In females, there is a decreasing mortality trend for all causes, for circulatory system and digestive system diseases; for haemolymphopoietic system and stomach cancers; on the contrary, an increasing trend is highlighted for communicable diseases and lung and liver cancer, mirroring the national situation. Trends for respiratory system, genitourinary system, nervous system diseases; blood diseases; all malignant cancers; kidney and breast cancers; leukaemias are almost unchanged. The analysis of mortality data on municipal basis reported that the most excesses in mortality risk occur in the municipalities included in the area with the highest urban development of Naples and, partly, in the municipalities of the Caserta Province. The distribution of the excesses at municipal level is not homogeneous in Campania Region, but there are relevant intermunicipal differences related to the considered causes of death. This heterogeneity in the distribution of excess risk is a characteristic also of the area called Terra di fuochi (Land of fires), both for overall mortality and for mortality by gender. CONCLUSIONS: Mortality data are a valuable support to the analysis of the population health conditions. Excesses in general mortality and for some specific causes found in Campania Region vs Italy in 2006-2014 suggest that in this region there is a need to implement more strict intervention in terms both of primary prevention (for individuals and the environment) and of management of the whole care and clinical pathway of some pathologies, bearing in mind the burden of regional structural and economic factors on these excesses. The highest excesses in mortality in Campania Region have been found in the areas with the highest degree of urbanisation: this confirms the national data of a different distribution of diseases - and mortality - in the areas characterised by high urban development compared to rural areas. Finally, cause-specific mortality maps at municipal level, extended to the whole region, could enable to identify possible critical issues which may need epidemiological studies focused on possible local factors of environmental pressure.

Occurrence of second primary malignancies in patients with neuroendocrine tumors of the digestive tract: A case report.

RATIONALE: There is an association between the presence of neuroendocrine neoplasms and incremented risk to develop second primary malignancies. This risk is estimated to be 17%. The most common secondary neoplasms were found in the Gastrointestinal and Genitourinary tracts. PATIENT CONCERNS: A 74-year-old Caucasian patient with melaena came to our observation in June 2015. The Esophago-gastro-duodenoscopy exam found a polypoid formation in the duodenal bulb. Histopathological examination showed a well-differentiated neuroendocrine neoplasm (G1). DIAGNOSIS: During the follow up for the neuroendocrine neoplasm, a CT scan was performed in August 2016 describing infiltration of the right renal sinus and the third proximal ureter segment with heterogeneous enhancement of vascular structure. An US-guided biopsy was conclusive for a Diffuse Large B Cell Lymphoma. In October 2016, a colonoscopy showed a neoplastic lesion at 20 cm from the anal orifice. The Histology exam was positive for an adenocarcinoma with a desmoplastic stroma infiltration. INTERVENTIONS: In November 2016, the patient underwent a left hemicolectomy: the pathologic staging described a G2 adenocarcinoma pT3N1b. In May 2018, the Octreotide scan was negative. In the same month, the patient started a treatment based on 6 cycles of Rituximab, Oxaliplatin, and Capecitabine due to the persistence of lymphomatous disease and hepatic metastases. In July 2018, other 3 cycles of the same treatment were scheduled. OUTCOMES: In January 2019, due to an increase in liver metastases' size, it was decided to start a new regimen for the colon cancer with FOLFIRI+Cetuximab. The patient is still in treatment with this regimen in April 2019. LESSONS: The risk of a second primary tumor is increased among patients older than 70. Therefore, it is necessary to follow them using total body CT scan and endoscopic techniques of gastrointestinal and genitourinary tracts, not only for the evaluation of the neuroendocrine tumor but also for the higher risk to develop other neoplastic diseases.

Incidental finding of non-Hodgkin's lymphoma in a patient affected by castration-sensitive prostate cancer: A case report.

RATIONALE: This article describes the case of a patient with 2 simultaneous malignant diseases: Follicular lymphoma and 'castration sensitive prostate cancer. Patients with multiple cancers are not easy to manage and it is difficult to find the appropriate approach and resources to use with them. We focused our attention on how to choose the correct strategy to face 2 different neoplasms and control the adverse reactions related to the corresponding treatments. PATIENT CONCERNS: We present a case of a 71-year-old man who came to us complaining about an abnormal difficulty in urinating associated with an interrupted flow and excessive urination at night. Clinical examination detected multiple enlarged superior and inferior diaphragmatic lymph nodes. DIAGNOSIS: Prostate biopsy revealed an acinar adenocarcinoma (Gleason 4+3, Grade group 3). Clinical staging by bone scan was negative but computed tomography scan (CT) detected multiple enlarged superior and inferior diaphragmatic, and inguinal lymph nodes. This type of lymph node involvement pattern is unusual for an acinar adenocarcinoma prostate cancer therefore we suspected the simultaneous presence of a lymphatic neoplasm. Fluorodeoxyglucose positron emission tomography scan. The exam showed one of the left inguinal lymph nodes had the highest standardized uptake value (13.0) so a biopsy was taken. The sample analysis confirmed the diagnosis of a follicular non-Hodgkin lymphoma of Grade 3a. INTERVENTIONS: We used a multidisciplinary clinical approach based on Rituximab+CHOP administered every 21 days. Simultaneously, the patient underwent androgen deprivation therapy with triptorelin monthly and bicalutamide administered just during the first month of treatment. When we obtained a complete response for the lymphoma, the patient continued the therapy with Rituximab once every 2 months for the next 2 years. Then we added volumetric modulated arc therapy (VMAT) radiotherapy with simultaneous integrated boost (SIB) to androgen deprivation therapy for the duration of 1 month. OUTCOMES: After 1 year and 6 months since the conclusion of therapy for prostate cancer and Follicular lymphoma, patient's conditions are good and he is in complete remission for both diseases. Gut toxicity is reduced with a mean number of 2 to 3 discharges daily and an increased body weight. LESSONS: The presence of diffuse lymphadenopathy and urinary symptoms in the same patients must induce the suspect of 2 contemporary cancer diseases. Parallel treatments of follicular lymphoma and prostate cancer should consider the increased risk of severe adverse effects related to the treatment and their management. We describe our therapeutic strategy to highlight the importance to balance benefits and disadvantages to get the best possible response and maintain a good quality of life in this complex setting.