KRAS4A and KRAS4B in liquid biopsy of metastatic lung adenocarcinoma patients treated with Pembrolizumab or chemotherapy plus Pembrolizumab.

KRAS is involved in the stability and expression of PD-L1. We investigated the expression of circulating mRNA (cmRNA) of KRAS4A and KRAS4B and the possible impact on progression-free survival (PFS) of patients with metastatic lung adenocarcinoma treated with immunotherapy. Patients without driver mutations undergoing Pembrolizumab (P) or P plus chemotherapy (PC) were prospectively accrued for liquid biopsy analysis of KRAS4A, KRAS4B, and PD-L1 cmRNA. Both KRAS isoforms were also studied for association with PD-L1 cmRNA. Of 56 patients, 28 received P and 28 PC. Patients with high levels of both KRAS isoforms showed significantly better PFS. The median PFS for KRAS4A was 29 months (95% CI 22-29 months) and KRAS4B 24 months (95% CI 13-29 months), respectively. The median PFS of patients with low levels of both isoforms was 12 months (95% CI 6-15 months for KRAS4A and 95% CI 5-20 months for KRAS4B). High KRAS4A retained a significant positive association with PFS in the multivariate model. An exploratory analysis in treatment subgroups found a positive association between high KRAS4A and KRAS4B with PFS in patients treated with P. PD-L1 cmRNA was significantly higher in patients with high KRAS isoforms levels and this effect was pronounced for high KRAS4A carriers. KRAS4A deserves further investigation as a potential marker for defining patients who may benefit the most from immune checkpoint inhibitors therapy and improving personalized cancer immunotherapeutic strategies.

Epidemiology of listeriosis in a region in central Italy from 2010 to 2019: Estimating the real incidence and space-time analysis for detecting cluster of cases.

BACKGROUND: Contamination and transmission of different Listeria monocytogenes strains along food chain are a serious threat to public health and food safety. Understanding the distribution of diseases in time and space-time is fundamental in the epidemiological study and in preventive medicine programs. The aim of this study is to estimate listeriosis incidence along 10-years period and to perform space-time cluster analysis of listeriosis cases in Marche Region, Italy. METHODS: The number of observed listeriosis cases/year was derived from regional data of surveillance of notifiable diseases and hospital discharge form. The capture and recapture method (C-R method) was applied to estimate the real incidence of listeriosis cases in Marche Region and the space-time scan statistics analysis was performed to detect clusters of space-time of listeriosis cases and add precision to the conventional epidemiological analysis. RESULTS: The C-R method estimation of listeriosis cases was 119 in the 10- year period (2010-2019), with an average of 31.93 % of unobserved cases (lost cases). The estimated mean annual incidence of listeriosis was 0.77 per 100,000 inhabitants (95 %CI 0.65-0.92), accounting for 6.07 % of additional listeriosis cases per year than observed cases. Using the scan statistic, the two most likely clusters were identified, one of these was statistically significant (p < 0.05). The underdiagnosis and under-reporting in addition to listeriosis incidence variability suggested that the surveillance system of Marche Region should be improved. CONCLUSIONS: This study provides evidence of the ability of space-time cluster analysis to complement traditional surveillance of food-borne diseases and to understand the local risk factors by implementing timely targeted interventions.

Hyperthermia combined with chemotherapy vs chemotherapy in patients with advanced pancreatic cancer: A multicenter retrospective observational comparative study.

BACKGROUND: Several studies report the useful therapeutic results of regional hyperthermia in association with chemotherapy (CHT) and radiotherapy for the treatment of pancreatic cancer. Modulated electro-hyperthermia (mEHT) is a new hyperthermia technique that induces immunogenic death or apoptosis of pancreatic cancer cells in laboratory experiments and increases tumor response rate and survival in pancreatic cancer patients, offering beneficial therapeutic effects against this severe type of cancer. AIM: To assess survival, tumor response and toxicity of mEHT alone or combined with CHT compared with CHT for the treatment of locally advanced or metastatic pancreatic cancer. METHODS: This was a retrospective data collection on patients affected by locally advanced or metastatic pancreatic cancer (stage III and IV) performed in 9 Italian centers, members of International Clinical Hyperthermia Society-Italian Network. This study included 217 patients, 128 (59%) of them were treated with CHT (no-mEHT) and 89 (41%) patients received mEHT alone or in association with CHT. mEHT treatments were performed applying a power of 60-150 watts for 40-90 min, simultaneously or within 72 h of administration of CHT. RESULTS: Median patients' age was 67 years (range 31-92 years). mEHT group had a median overall survival greater than non-mEHT group (20 mo, range 1.6-24, vs 9 mo, range 0.4-56.25, P < 0.001). mEHT group showed a higher number of partial responses (45% vs 24%, P = 0.0018) and a lower number of progressions (4% vs 31%, P < 0.001) than the no-mEHT group, at the three months follow-up. Adverse events were observed as mild skin burns in 2.6% of mEHT sessions. CONCLUSION: mEHT seems safe and has beneficial effects on survival and tumor response of stage III-IV pancreatic tumor treatment. Further randomized studies are warranted to confirm or not these results.

Movement and health beyond care, MoviS: study protocol for a randomized clinical trial on nutrition and exercise educational programs for breast cancer survivors.

BACKGROUND: Breast cancer (BC) is the most common invasive cancer in women, and exercise can significantly improve the outcomes of BC survivors. MoviS (Movement and Health Beyond Care) is a randomized controlled trial aimed to evaluate the potential health benefits of exercise and proper nutritional habits. This study aims to assess the efficacy of aerobic exercise training in improving quality of life (QoL) and health-related factors in high-risk BC. METHODS: One hundred seventy-two BC survivor women, aged 30-70 years, non-metastatic, stage 0-III, non-physically active, 6-12 months post-surgery, and post chemo- or radiotherapy, will be recruited in this study. Women will be randomly allocated to the intervention arm (lifestyle recommendations and MoviS Training) or control arm (lifestyle recommendations). The MoviS training consists of 12 weeks of aerobic exercise training (2 days/week of supervised and 1 day/week of unsupervised exercise) with a progressive increase in exercise intensity (40-70% of heart rate reserve) and duration (20-60 min). Both arms will receive counseling on healthy lifestyle habits (nutrition and exercise) based on the World Cancer Research Fund International (WCRF) 2018 guidelines. The primary outcome is the improvement of the QoL. The secondary outcomes are improvement of health-related parameters such as Mediterranean diet adherence, physical activity level, flexibility, muscular fitness, fatigue, cardiorespiratory fitness (estimated maximal oxygen uptake), echocardiographic parameters, heart rate variability (average of the standard deviations of all 5 min normal to normal intervals (ASDNN/5 min) and 24 h very low and low frequency), and metabolic, endocrine, and inflammatory serum biomarkers (glycemia, insulin resistance, progesterone, testosterone, and high-sensitivity C-reactive protein). DISCUSSION: This trial aims to evaluate if supervised exercise may improve QoL and health-related factors of BC survivors with a high risk of recurrence. Findings from this project could provide knowledge improvement in the field of exercise oncology through the participation of a multidisciplinary team that will provide a coordinated program of cancer care to improve healthcare quality, improve prognosis, increase survival times and QoL, and reduce the risk of BC recurrence. TRIAL REGISTRATION: ClinicalTrials.gov  NCT04818359 . Retrospectively registered on March 26, 2021.

Meta-Analysis of Modulated Electro-Hyperthermia and Tumor Treating Fields in the Treatment of Glioblastomas.

BACKGROUND: Glioblastoma is one of the most difficult to treat and most aggressive brain tumors, having a poor survival rate. The use of non-invasive modulated electro-hyperthermia (mEHT) and Tumor Treating Fields (TTF) devices has been introduced in the last few decades, both of which having proven anti-tumor effects. METHODS: A meta-analysis of randomized and observational studies about mEHT and TTF was conducted. RESULTS: A total of seven and fourteen studies about mEHT and TTF were included, with a total number of 450 and 1309 cases, respectively. A 42% [95% confidence interval (95% CI): 25-59%] 1-year survival rate was found for mEHT, which was raised to 61% (95% CI: 32-89%) if only the studies conducted after 2008 were investigated. In the case of TTF, 1-year survival was 67% (95% CI: 53-81%). Subgroup analyses revealed that newly diagnosed patients might get extra benefits from the early introduction of the devices (mEHT all studies: 73% vs. 37%, p = 0.0021; mEHT studies after 2008: 73% vs. 54%, p = 0.4214; TTF studies: 83% vs. 52%, p = 0.0083), compared with recurrent glioblastoma. CONCLUSIONS: Our meta-analysis showed that both mEHT and TTF can improve glioblastoma survival, and the most benefit may be achieved in newly diagnosed cases.

COVID-19 isolation/quarantine rules in home care patients.

The spread of Severe Acute Respiratory Syndrome Coronavirus 2 new variants increased the number of subjects in home isolation and quarantine. The aim of this study was to assess the compliance with coronavirus disease 2019 home isolation rules for 32 subjects in home care in Marche Region, Italy. The results showed that subjects in home isolation were better informed about isolation rules (P = 0.007) than those who were in quarantine. They had lower educational level (P < 0.001) and none/single income (P < 0.001) and higher rate of clinical manifestation. The education for a safe quarantine should be strengthened widely, especially among disadvantaged subjects.

Immune response and locoregional treatments for peritoneal carcinomatosis.

Peritoneal Carcinomatosis (PC) is considered as a terminal disease with short survival. It is treated with palliative therapies, consisting of repeated drainages and sometimes instillation of chemotherapy. Since the nineties, surgery has been combined with more effective systemic chemotherapy, intraperitoneal chemotherapy and hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of PC. This combination therapy significantly increases the overall survival of selected PC patients. The understanding of how intraperitoneal chemotherapy and HIPEC can cure patients is still unclear. Experts hypothesized that the efficacy is obtained by the ability of high peritoneal drug exposure and hyperthermia to directly kill cancer cells. Several studies indicate that cancer cells death directly influences the response of the immune system. For this reason, the protective effect of intraperitoneal chemotherapy and HIPEC could be mediated by its ability to kill cancer cells in an immuno-genic way, causing an efficient anticancer immune response. In this review, we investigate the role of the innate peritoneal or locoregional therapy-induced immune response in PC therapy.

Attitudes of Healthcare Workers toward Influenza Vaccination in the COVID-19 Era.

Healthcare workers (HCWs) are reluctant to participate in the influenza vaccination program, despite their high risk to contract and diffuse influenza due to professional exposure. The onset of the COVID-19 pandemic could raise HCW flu vaccination adherence. The aim of this study was to assess HCW attitudes toward influenza vaccination in the COVID-19 era. A multicenter observational study was carried out in three Italian hospitals (two in Pesaro and one in Fano, Marche region, Italy). Data about HCW influenza vaccination between 2013 and 2021 were extracted from the vaccination registers. An online questionnaire was sent to HCWs from July to October 2020 to assess their opinion about influenza vaccination in terms of knowledge, attitude, and practice during the COVID-19 pandemic. The number of flu-vaccinated HCWs increased from 3.7% in the 2013−2014 flu season to 53.6% in the 2020−2021 flu season (p < 0.001). About 15% (n = 324) of HCWs responded to the online questionnaire, and 30.5% of them declared that they had changed their minds on flu vaccination after the COVID-19 pandemic, deciding to get vaccinated. The COVID-19 pandemic significantly increased HCWs' attitudes toward flu vaccination. However, flu vaccination adherence remained low and should be improved.

Circulating tumour cell gene expression and chemosensitivity analyses: predictive accuracy for response to multidisciplinary treatment of patients with unresectable refractory recurrent rectal cancer or unresectable refractory colorectal cancer liver metastases.

BACKGROUND: Patients with unresectable recurrent rectal cancer (RRC) or colorectal cancer (CRC) with liver metastases, refractory to at least two lines of traditional systemic therapy, may receive third line intraarterial chemotherapy (IC) and targeted therapy (TT) using drugs selected by chemosensitivity and tumor gene expression analyses of liquid biopsy-derived circulating tumor cells (CTCs). METHODS: In this retrospective study, 36 patients with refractory unresectable RRC or refractory unresectable CRC liver metastases were submitted for IC and TT with agents selected by precision oncotherapy chemosensitivity assays performed on liquid biopsy-derived CTCs, transiently cultured in vitro, and by tumor gene expression in the same CTC population, as a ratio to tumor gene expression in peripheral mononuclear blood cells (PMBCs) from the same individual. The endpoint was to evaluate the predictive accuracy of a specific liquid biopsy precision oncotherapy CTC purification and in vitro culture methodology for a positive RECIST 1.1 response to the therapy selected. RESULTS: Our analyses resulted in evaluations of 94.12% (95% CI 0.71-0.99) for sensitivity, 5.26% (95% CI 0.01-0.26) for specificity, a predictive value of 47.06% (95% CI 0.29-0.65) for a positive response, a predictive value of 50% (95% CI 0.01-0.98) for a negative response, with an overall calculated predictive accuracy of 47.22% (95% CI 0.30-0.64). CONCLUSIONS: This is the first reported estimation of predictive accuracy derived from combining chemosensitivity and tumor gene expression analyses on liquid biopsy-derived CTCs, transiently cultured in vitro which, despite limitations, represents a baseline and benchmark which we envisage will be improve upon by methodological and technological advances and future clinical trials.

Atmospheric particulate matter effects on SARS-CoV-2 infection and spreading dynamics: A spatio-temporal point process model.

Particulate matter (PM) may play a role in differential distribution and transmission rates of SARS-CoV-2. For public health surveillance, identification of factors affecting the transmission dynamics concerning the endemic (persistent sporadic) and epidemic (rapidly clustered) component of infection can help to implement intervention strategies to reduce the disease burden. The aim of this study is to assess the effect of long-term residential exposure to outdoor PM ≤ 10 µm (PM10) concentrations on SARS-CoV-2 incidence and on its spreading dynamics in Marche region (Central Italy) during the first wave of the COVID-19 pandemic (February to May 2020), using the endemic-epidemic spatio-temporal regression model for individual-level data. Environmental and climatic factors were estimated at 10 km2 grid cells. 10-years average exposure to PM10 was associated with an increased risk of new endemic (Rate Ratio for 10 µg/m3 increase 1.14, 95%CI 1.04-1.24) and epidemic (Rate Ratio 1.15, 95%CI 1.08-1.22) infection. Male gender, older age, living in Nursing Homes and Long-Term Care Facilities residence and socio-economic deprivation index increased Rate Ratio (RR) in epidemic component. Lockdown increased the risk of becoming positive to SARS-CoV-2 as concerning endemic component while it reduced virus spreading in epidemic one. Increased temperature was associated with a reduction of endemic and epidemic infection. Results showed an increment of RR for exposure to increased levels of PM10 both in endemic and epidemic components. Targeted interventions are necessary to improve air quality in most polluted areas, where deprived populations are more likely to live, to minimize the burden of endemic and epidemic COVID-19 disease and to reduce unequal distribution of health risk.

Recognising undernutrition in a community hospital: the nursing judgement is insufficient.

INTRODUCTION: Standardised nutritional screening methods improve the rate of recognising older patients with undernutrition, which is strongly encouraged in hospitals and residential settings. Therefore, our study compared the rates of identifying undernutrition before and after introducing the Mini Nutritional Assessment (MNA®) in a community hospital. METHODS: This was a single-centre, retrospective, observational before-after study. Participants were subjects aged 65 years or older, admitted to a community hospital from May 2018 to December 2020. The nursing assessment at admission included the MNA® from January 2020. The prevalence of undernutrition gathered by nursing diagnoses from 2018 to 2019 was compared with data obtained using the MNA® in 2020. Then, a confirmatory analysis was conducted to compare the prevalence of undernutrition in 2020 when both nursing diagnoses and the MNA® were used. RESULTS: We analysed data of approximately 316 patients (238 before and 78 after introducing the MNA®). Overall, results showed that 47.1% (n = 149) of the patients were undernourished. As observed, the prevalence of undernutrition was 38.6% (n = 92) in 2018-2019 and 73.1% (n = 57) in 2020 (p < 0.001). In 2020, however, 38.5% of patients (n = 30) were identified as undernourished using the MNA® but not using nursing diagnoses. Therefore, the correlation between these two methods was poor (Pearson's correlation 0.169, p = 0.14). CONCLUSION: Identifying elderly patients with undernutrition significantly increased after introducing the MNA®. Undernutrition is a common condition that should be systematically screened using a validated tool to activate personalised nutritional interventions promptly.

Transarterial chemoembolization alone or followed by bevacizumab for treatment of colorectal liver metastases.

AIMS: Bevacizumab (B) in association with systemic chemotherapy is commonly used for the treatment of colorectal cancer liver metastases. The aim of this study was to monitor tumor response, overall survival (OS) and progression-free survival (PFS) of patients with colorectal cancer liver metastases treated with transarterial chemoembolization (TACE) + B compared with TACE alone and to correlate the results with KRAS mutational status. PATIENTS & METHODS: This was an observational multicentric case-control study (NCT03732235) on the efficacy and safety of B administered after TACE. RESULTS: The disease control rate was significantly higher for the TACE + B than the TACE alone group (p < 0.001). KRAS wild-type patients had a significantly better disease control rate than those with KRAS mutations in the TACE + B group. Median OS and PFS were similar for the TACE + B and TACE groups, whereas median time to progression was significantly higher for the TACE + B group (p < 0.01). CONCLUSION: The combination of TACE with B may improve tumor response and delay disease progression.

Modulated electro-hyperthermia in stage III and IV pancreatic cancer: Results of an observational study on 158 patients.

BACKGROUND: An increasing number of studies report the beneficial effects of regional hyperthermia in association with chemotherapy (CHT) and radiotherapy for the treatment of pancreatic cancer; in particular, the use of modulated electro-hyperthermia (mEHT) results in increased survival and tumor response. AIM: To compare outcomes of CHT alone or in association with mEHT for the treatment of stage III and IV pancreatic cancer. METHODS: This was an observational retrospective study; data were collected for patients with stage III-IV pancreatic cancer that were treated with CHT alone or in combination with mEHT from 2003 to 2019. A total of 158 patients were included in the study out 270 patients screened in four Italian hospitals; 58 (37%) of these received CHT + mEHT and 100 (63%) CHT. CHT was mainly gemcitabine-based regimens in both groups. RESULTS: Overall (19.5 mo vs 11.02 mo, P < 0.001) and progression-free (12 mo vs 3 mo, P < 0.001) survival were better for the CHT + mEHT group compared to the CHT group. The association of mEHT resulted also in an improvement of tumor response with disease control rate 95% vs 58% (P < 0.001) at 3 mo. Toxicity was comparable in the two study groups, and mEHT related adverse events were limited in 8 patients presenting G1-2 skin burns. CONCLUSION: The addition of mEHT to systemic CHT improved overall and progression-free survival and local tumor control with comparable toxicity.

COVID-19 in Workplaces: Secondary Transmission.

OBJECTIVES: Coronavirus disease (COVID-19) contagion at work is well studied for healthcare workers, however it is not enough assessed in other working settings. Very little is known, indeed, about the risk of COVID-19 transmission through occupational exposure in non-health working places. This study aims to describe a COVID-19 cluster among workers in an office in Italy. METHODS: This was a retrospective observational study on a cluster of COVID-19 that occurred from 20 November through 3 December 2020 in a group of six colleagues (A-F) working in the same office full time 5 days a week, 8 h a day. The workers used the following prevention measures: social distancing (desks were >1 m, 1.76-5.01 m range), plexiglas panels, hands disinfection, and use of face mask. However, they did not wear face mask when in static position sitting at their desk and they did not aerate the place frequently. RESULTS: The disease spread from one worker (subject A) to four (80%) of the five colleagues (subjects B-F). Only subject D was negative to COVID-19 on 14 days after last contact with subject A (20 November 2020) as confirmed by nasopharyngeal swab testing. Subject D, in particular, did not contact subject A in the 48 h before symptoms onset. COVID-19 positivity of subject A was promptly communicated to the colleagues, who started self-isolation from their relatives and none of their households were infected. COVID-19 transmission was observed only in households of subject A. CONCLUSIONS: The rapid communication of COVID-19 positivity to the colleagues and the prompt isolation of index case's close contacts allowed to eliminate the secondary transmission to their households. The contagion of index case's colleagues occurred from second day before symptoms onset. Distancing of >1 m, use of plexiglass panels, sanitizing hand gel, and inconstant use of face mask may not be enough for infection prevention in closed places with poor ventilation and high occupancy.

A Prospective Study of Intraarterial Infusion Chemotherapy in Advanced Wild-Type BRAF Melanoma Patients.

BACKGROUND: Treatment strategies for advanced cutaneous melanoma (CM) patients, resistant or not treatable with novel target and immunotherapeutic drugs, remain a significant challenge, particularly for patients with unresectable stage IIIC/D disease localized to inferior limbs and pelvis, for whom specific outcomes are rarely considered. MATERIALS AND METHODS: This is a prospective study of multidisciplinary treatments, including locoregional melphalan chemotherapy, in 62 BRAF wild-type CM patients with locoregional metastases in the inferior limbs and pelvis, including inguinal regions. Patients were either in progression following or ineligible for, or not treatable with novel immunotherapy. For exclusively inferior limb-localised disease, patients received locoregional melphalan chemotherapy performed by hyperthermic isolated limb perfusion (n = 19) or isolated limb infusion (n = 19), and for synchronous lesions localised to inferior limbs and pelvis, received hypoxic pelvic and limb perfusion (n = 24). Additional multidisciplinary therapy included local, locoregional and systemic treatments and the primary endpoint was tumour response. RESULTS: The objective response rate following first cycle of locoregional chemotherapy was 37.1% at 3 mo and median progression-free survival was 4-mo, with 12.9% procedure-related complications, 30.6% low-grade haematological toxicity and 11.3% severe limb toxic tissue reactions. Multivariate logistic regression showed that the odds of response were significantly higher for patients ≤ 75 y of age and for patients with locoregional metastases exclusively located in the inferior limbs. CONCLUSION: In this subgroup of CM patients with BRAF wild-type status, locoregional metastases localized to inferior limbs and pelvis, in progression following or ineligible for immunotherapy, melphalan locoregional chemotherapy demonstrated a safe and effective profile. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01920516; date of trial registration: August 6, 2013.

Predictors of adverse outcomes using a multidimensional nursing assessment in an Italian community hospital.

BACKGROUND: There is growing evidence about the role of nurses in patient outcomes in several healthcare settings. However, there is still a lack of evidence about the transitional care setting. We aimed to assess the association between patient characteristics identified in a multidimensional nursing assessment and outcomes of mortality and acute hospitalization during community hospital stay. METHODS: A retrospective observational study was performed on patients consecutively admitted to a community hospital (CH) in Loreto (Ancona, Italy) between January 1st, 2018 and May 31st, 2019. The nursing assessment included sociodemographic characteristics, functional status, risk of falls (Conley Score) and pressure damage (Norton scale), nursing diagnoses, presence of pressure sores, feeding tubes, urinary catheters or vascular access devices and comorbidities. Two logistic regression models were developed to assess the association between patient characteristics identified in a multidimensional nursing assessment and outcomes of mortality and acute hospitalization during CH stay. RESULTS: We analyzed data from 298 patients. The mean age was 83 ± 9.9 years; 60.4% (n = 180) were female. The overall mean length of stay was 42.8 ± 36 days (32 ± 32 days for patients who died and 33.9 ± 35 days for patients who had an acute hospitalization, respectively). An acute hospitalization was reported for 13.4% (n = 40) of patients and 21.8% (n = 65) died. An increased risk of death was related to female sex (OR 2.25, 95% CI 1.10-4.62), higher Conley Score (OR 1.19; 95% CI 1.03-1.37) and having a vascular access device (OR 3.64, 95% CI 1.82-7.27). A higher Norton score was associated with a decreased risk of death (OR 0.71, 95% CI 0.62-0.81). The risk for acute hospitalization was correlated with younger age (OR 0.94, 95% CI 0.91-0.97), having a vascular access device (OR 2.33, 95% CI 1.02-5.36), impaired walking (OR 2.50, 95% CI 1.03-6.06) and it is inversely correlated with a higher Conley score (OR 0.84, 95% CI 0.77-0.98). CONCLUSION: Using a multidimensional nursing assessment enables identification of risk of nearness of end of life and acute hospitalization to target care and treatment. The present study adds further knowledge on this topic and confirms the importance of nursing assessment to evaluate the risk of patients' adverse outcome development.

Multidisciplinary Treatment, Including Locoregional Chemotherapy, for Merkel-Polyomavirus-Positive Merkel Cell Carcinomas: Perspectives for Patients Exhibiting Oncogenic Alternative Δ exon 6-7 TrkAIII Splicing of Neurotrophin Receptor Tropomyosin-Related Kinase A.

Merkel cell carcinomas (MCCs) are rare, aggressive, cutaneous neuroendocrine tumours, approximately 80% of which are caused by the genomic integration of Merkel cell polyomavirus (MCPyV). MCPyV-positive MCCs carry poor prognosis in approximately 70% of cases, highlighting the need for greater understanding of the oncogenic mechanisms involved in pathogenesis, progression and post-therapeutic relapse, and translation into novel therapeutic strategies. In a previous pilot study, we reported a potential relationship between MCPyV gene expression and oncogenic alternative Δ exon 6-7 TrkAIII splicing in formalin-fixed paraffin-embedded (FFPE) MCC tissues from a 12-patient cohort of >90% MCPyV-positive MCCs, diagnosed at San Salvatore Hospital, L'Aquila, Italy, characterising a new MCC subgroup and unveiling a novel potential MCPyV oncogenic mechanism and therapeutic target. This, however, could not be fully verified due to poor RNA quality and difficulty in protein extraction from FFPE tissues. Here, therefore, we extend our previous observations to confirm the relationship between MCPyV and oncogenic alternative Δ exon 6-7 TrkAIII splicing in fresh, nonfixed, MCPyV-positive MCC metastasis by detecting sequence-verified RT-PCR products, including full-length Δ exon 6-7 TrkAIII, and by Western blot detection of a 100 kDa TrkA protein isoform of identical size to 100 kDa Δ exon 6-7 TrkAIII expressed by stable transfected SH-SY5Y cells. We also report that in three MCC patients submitted for multidisciplinary treatment, including locoregional chemotherapy, MCPyV large T-antigen mRNA expression, Δ exon 6-7 TrkAIII mRNA expression and intracellular indirect immunofluorescence (IF) TrkA and phosphorylation protein isoform(s) immunoreactivity in FFPE tissues were not reduced in postchemotherapeutic-relapsed MCCs compared to pretherapeutic MCCs, extending the possible roles of this novel potential MCPyV oncogenic mechanism from MCC pathogenesis to post-therapeutic relapse and progression. Detection of alternative Δ exon 6-7 TrkAIII splicing in MCC, therefore, not only characterises a new MCPyV-positive MCC subgroup and unveils a novel potential MCPyV oncogenic mechanism but also identifies patients who may benefit from inhibitors of MCPyV T-antigen and/or TrkAIII expression or clinically approved Trk kinase inhibitors such as larotrectinib or entrectinib, which are known to inhibit activated TrkA oncogenes and to elicit durable responses in TrkA-fusion oncogene-driven cancers, supporting the call for a large-scale multicentre clinical study.

A Narrative Review of Regional Hyperthermia: Updates From 2010 to 2019.

The role of hyperthermia (HT) in cancer therapy and palliative care has been discussed for years in the literature. There are plenty of articles that show good feasibility of HT and its efficacy in terms of tumor response and survival improvements. Nevertheless, HT has never gained enough interest among oncologists to become a standard therapy in clinical practice. The main advantage of HT is the enhancement of chemotherapy (CHT), radiotherapy (RT), chemoradiotherapy (CRT), and immunotherapy benefits. This effect has been confirmed in several types of tumors: esophageal, gastrointestinal, pancreas, breast, cervix, head and neck, and bladder cancers, and soft tissue sarcoma. HT effects include oxygenation and perfusion changes, DNA repair inhibition and immune system activation as a consequence of new antigen exposure. The literature shows a wide variety of randomized, nonrandomized, and observational studies and both prospective and retrospective data to confirm the advantage of HT association to CHT and RT. There are still many ongoing trials on this subject. This article summarizes the available literature on HT in order to update the current knowledge on HT use in association with RT and/or CHT from 2010 up to 2019.

Immune response activation following hyperthermic intraperitoneal chemotherapy for peritoneal metastases: A pilot study.

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal metastases (PM) is considered to be feasible, safe and to improve survival. AIM: To investigate whether an immune response is activated following HIPEC for PM. METHODS: Six patients were enrolled in this study. Peripheral blood samples were obtained from each patient prior to (day 0) and post-procedure (day 30), and used to evaluate the number of CD3+ total, CD3+/CD4+ T-Helper, CD3+/CD8+ cytotoxic T, CD3+/CD56+ natural killer and CD19+ B lymphocyte numbers, and CD4+: CD8+ T lymphocyte ratios. RESULTS: The total numbers of CD3+, CD3+/CD4+ T-Helper, CD3+/CD8+ cytotoxic T, CD3+/CD56+ natural killer and CD19+ B lymphocytes, and CD4+: CD8+ lymphocyte ratios were increased in all but one patient 30 d following the cytoreductive surgery-HIPEC procedure, and these increases were significant (P ≤ 0.05) for CD3+/CD4+ T Helper and CD3+/CD8+ cytotoxic T lymphocyte numbers. CONCLUSION: This report provides the first evidence that HIPEC exhibits immunomodulating activity in PM patients, resulting in generalized activation of the adaptive immune response. Moreover, the majority of lymphocyte populations increased following HIPEC and continued to be elevated several weeks following the procedure, consistent with a potential authentic immunomodulating effect rather than a normal inflammatory response, to be fully characterised in future studies.