Lung cancer after kidney transplantation: a 50-year experience at a single institution.

PURPOSE: To investigate the clinical characteristics of lung cancer that develops after kidney transplantation. METHODS: The clinical data of patients with lung cancer diagnosed after kidney transplantation were collected retrospectively. The medical records were extracted from our database. All patients underwent routine chest examination after kidney transplantation. RESULTS: In total, 17 lung tumors were detected in 15 (0.6%) of 2593 patients who underwent kidney transplantation at our institution. Eleven lung tumors were completely resected from a collective 10 patients (surgical group). The remaining five patients did not receive surgical treatment (nonsurgical group). The surgical group underwent wedge resection (n = 5), segmentectomy (n = 1), lobectomy (n = 3), and bilobectomy (n = 1). The pathological stages were 0 (n = 1), IA1 (n = 2), IA2 (n = 4), IA3 (n = 2), and IB (n = 1). The surgical group had a significantly better prognosis than the nonsurgical group. There were no perioperative complications related to kidney transplantation in either group. CONCLUSIONS: Routine chest examination would be useful for the early diagnosis and treatment of lung cancer after kidney transplantation. Moreover, surgical resection for early-stage lung cancer was associated with a better prognosis for kidney transplantation patients.

Prospective Observational Study of COVID-19 Vaccination in Patients with Thoracic Malignancies: Adverse Events, Breakthrough Infections and Survival Outcomes.

Due to the devastating COVID-19 pandemic, a preventive tool in the form of vaccination was introduced. Thoracic cancer patients had one of the highest rates of morbidity and mortality due to COVID-19 disease, but the lack of data about the safety and effectiveness of vaccines in this population triggered studies like ours to explore these parameters in a cancer population. Out of 98 patients with thoracic malignancies vaccinated per protocol, 60-75% experienced some adverse events (AE) after their first or second vaccination, most of them were mild and did not interfere with their daily activities. Out of 17 severe AEs reported, all but one were resolved shortly after vaccination. No significant differences were noted considering AE occurrence between different cancer therapies received after the first or second vaccination dose, p = 0.767 and p = 0.441, respectively. There were 37 breakthrough infections either after the first (1), second (13) or third (23) vaccine dose. One patient died as a direct consequence of COVID-19 infection and respiratory failure, and another after disease progression with simultaneous severe infection. Eight patients had moderate disease courses, received antiviral therapies and survived without consequences. Vaccination did not affect the time to disease progression or death from underlying cancer.

Safety and efficacy of stereotactic body proton therapy for high-risk lung tumors.

Purpose: Stereotactic body proton therapy (SBPT) is an emerging treatment strategy for lung tumors that aims to combine the excellent local control benefits of ultra-hypofractionation with the physical advantages of protons, which reduce the integral dose to organs at risk (OARs) compared to photons. To date, however, very little data delivering SBPT in 5 or fewer fractions to lung tumors have been reported. Given that photon stereotactic body radiation therapy can struggle to deliver ablative doses to high-risk tumors (i.e., central/ultra-central location, prior in-field radiation, tumor size >5 cm, or the presence of severe pulmonary comorbidities) while adhering to OAR dose constraints, we hypothesized that SBPT would be an effective alternative for patients with high-risk tumors. Methods and Materials: Twenty-seven high-risk patients with 29 lung tumors treated with SBPT at the New York Proton Center between December 2019 and November 2022 were retrospectively identified. Patients were divided into three major subgroups: early-stage non-small cell lung cancer (NSCLC), locally recurrent NSCLC, and metastatic cancer from lung cancer or other histologies. Patient characteristics were reported using descriptive statistics, actuarial methods were used to quantify disease control rates, and toxicities were scored using CTCAE v 5.0. Results: The most common high-risk indications for SBPT were central/ultra-central tumor location (69.0%), severe COPD (48.1%), reirradiation (44.4%), significant pulmonary fibrosis (22.2%), and large tumor size > 5 cm (18.5%). In total, 96.6% of tumors were fully covered by the prescription dose without compromising target coverage. Three-year actuarial rates of local control for early-stage NSCLC, locally recurrent NSCLC, and metastatic patients were 89%, 100%, and 43%, respectively. Three-year actuarial rates of regional control were 89%, 67%, and 86%. Three-year actuarial rates of distant metastasis-free survival were 79%, 100%, and 0%. Two patients (7.4%), both of whom had clinically significant baseline interstitial lung disease and pre-treatment continuous oxygen demand, experienced grade ≥2 pulmonary toxicity (1 grade 3, 1 grade 5). There were no acute or late grade ≥2 toxicities related to esophagitis, cardiac injury, airway injury, pulmonary fibrosis, bronchopulmonary hemorrhage or brachial plexopathy. Conclusions: In the largest study of proton SBRT reported to date, SBPT has a favorable toxicity profile while being an effective approach for treating most high-risk tumors without requiring dose de-escalation or compromising tumor coverage and warrants further investigation.

Stereotactic body proton therapy for non-small cell lung cancer: Clinical indications and recommendations.

Stereotactic body radiation therapy (SBRT) has emerged as a standard treatment approach for early-stage lung cancer and intrathoracic oligometastatic or oligoprogressive disease. While local control is often excellent with this modality when delivered with photon therapy, toxicities for select patients can be significant. Proton therapy offers a unique opportunity to widen the therapeutic window when treating patients with thoracic malignancies requiring or benefitting from ultra-high doses per fraction. Thoracic proton SBRT may be particularly beneficial in cases requiring dose escalation, for tumors >5 cm, for central or ultra-central tumors, for reirradiation, in patients with interstitial lung diseases, and when combining radiation with immunotherapy. These clinical indications are detailed, along with supporting literature and clinical recommendations. Other considerations, future directions and potential benefits of proton SBRT, including sparing lymphocytes, when delivered as intensity-modulated proton therapy or as FLASH, and for the treatment of locally advanced non-small cell lung cancer or in patients with homologous recombination repair deficiencies, are also discussed.

Guideline adherence of tumor board recommendations in lung cancer and transfer into clinical practice.

PURPOSE: Evaluating patients and treatment decisions in a multidisciplinary tumor board has led to better quality of care and longer survival in cancer patients. The aim of this study was to evaluate tumor board recommendations for thoracic oncology patients regarding guideline adherence and transferal of recommendations into clinical practice. METHODS: We evaluated tumor board recommendations of the thoracic oncology tumor board at Ludwig-Maximilians University (LMU) Hospital Munich between 2014 and 2016. We compared patient characteristics between guideline-adherent and non-guideline-adherent recommendations, as well as between transferred and non-transferred recommendations. We used multivariate logistic regression models to evaluate factors associated with guideline adherence. RESULTS: Over 90% of recommendations by the tumor board were either adherent to the guidelines (75.5%) or over fulfilling guidelines (15.6%). Almost 90% of recommendations were transferred to clinical practice. If a recommendation was not according to the guidelines, the reason was mostly associated with the general condition (age, Charlson comorbidity index, ECOG) of the patient or due to the patients' request. Surprisingly, sex also had a significant influence on the guideline adherence of recommendations, with females being more likely to get recommendations not according to the guidelines. CONCLUSION: In conclusion, the results of this study are promising, as the guideline adherence of recommendations as well as the transferal of recommendations into clinical practice were high. In the future, a special focus should be put on fragile patients as well as female patients.

The Role of Germline Mutations in Thoracic Malignancies: Between Myth and Reality.

Considering the established contribution of environmental factors to the development of thoracic malignancies, the inherited susceptibility of these tumors has rarely been explored. However, the recent introduction of next-generation sequencing-based tumor molecular profiling in the real-word setting enabled us to deeply characterize the genomic background of patients with lung cancer with or without smoking-related history, increasing the likelihood of detecting germline mutations with potential prevention and treatment implications. Pathogenic germline variants have been detected in 2% to 3% of patients with NSCLC undergoing next-generation sequencing analysis, whereas the proportion of germline mutations associated with the development of pleural mesothelioma widely varies across different studies, ranging between 5% and 10%. This review provides an updated summary of emerging evidence about germline mutations in thoracic malignancies, focusing on pathogenetic mechanisms, clinical features, therapeutic implications, and screening recommendations for high-risk individuals.

Uso de eSalud para promover la actividad física en los supervivientes de neoplasias torácicas: revisión sistemática y metaanálisis / The use of eHealth to promote physical activity in thoracic malignancies survivors: A systematic review and meta-analysis

Antecedentes: Las tasas de supervivencia para muchas formas de neoplasias torácicas han mejorado durante las últimas décadas. Sin embargo, muchos supervivientes tienen que hacer frente a los efectos secundarios del tratamiento del cáncer durante un tiempo prolongado. La actividad física (AF) ha sido propuesta como estrategia terapéutica para combatir los efectos del tratamiento del cáncer, pudiendo ser eSalud una buena manera de animar a los pacientes a practicarla. Objetivo: Explorar los efectos de eSalud en la promoción de la AF entre las neoplasias torácicas. Métodos: Se realizó una búsqueda de los artículos adecuados utilizando las bases de datos de PubMed, Web of Science y Scopus, mediante una combinación de títulos de temas médicos. Resultados: Se identificaron 4.781 artículos en total, de los cuales 10 cumplieron los criterios de elegibilidad. Se describieron diferentes intervenciones de eSalud en estos estudios: aplicación para móviles (app) (n = 3), sitio web (n = 2), correo electrónico (n = 2), aplicación para web y móvil (n = 1), asesoramiento telefónico (n = 1) y página online (n = 1). Todos los estudios reportaron mejoras en cuanto a AF y 8/10 estudios reportaron cambios estadísticamente significativos. Conclusión: Nuestros resultados muestran que los programas de eSalud son útiles para promover la AF en los supervivientes de neoplasias torácicas, en comparación con la no intervención, el tratamiento convencional o el enfoque dietético. Además, este metaanálisis reveló también que eSalud es un buen modo de mejorar el nivel de AF en los supervivientes de neoplasias torácicas.(AU)

Background: Survival rates for many forms of thoracic malignancies have improved over the past few decades, however, many survivors are coping with the side effects of cancer treatment for longer. Physical activity (PA) has been proposed as a therapeutic strategy to combat the effects of treatment in cancer survivors and eHealth could be a good way to encourage patients to practice it. Objective: To explore the effects of eHealth in the promotion of PA among thoracic malignancies. Methods: Suitable articles were searched using PubMed, Web of Science and Scopus databases using a combination of medical subject headings. Results: In total, 4781 articles were identified, of which ten met eligibility criteria. Different eHealth interventions were described in these studies: mobile application (app) (n = 3), website (n = 2), email (n = 2), web and mobile application (n = 1), telephone counseling (n = 1) and online sheet (n = 1). All studies reported improvements in PA, with 8/10 studies reporting statistically significant changes. Conclusion: Our results show that eHealth programs are useful to promote PA in malignancy thoracic survivors, compared to no intervention, conventional treatment or a dietary approach. Moreover, the meta-analysis also revealed eHealth is a good way to improve the level of PA in thoracic malignancies survivors.(AU)

Cardiotoxicity of Anti-Cancer Radiation Therapy: a Focus on Heart Failure.

PURPOSE OF REVIEW: As the percentage of patients achieving long-term survival following treatment of their cancer grows, it is increasingly important to understand the long-term toxicities of cancer-directed treatment. In this review, we highlight the recent findings regarding radiation-induced cardiotoxicity across multiple disease sites, with a particular focus on heart failure. RECENT FINDINGS: Despite its relative lack of study historically, radiation-induced heart failure has now recently been implicated in several studies of breast cancer, lung cancer, esophageal cancer, and lymphoma as a non-trivial potential consequence of thoracic radiotherapy. Data regarding specific cardiac dosimetric endpoints relevant to cardiotoxicity continue to accumulate. Radiation-induced heart failure is a rare but significant toxicity of thoracic radiotherapy, that is likely underreported. Important areas for future focus include understanding the interplay between thoracic radiotherapy and concurrent cardiotoxic systemic therapy as well as development of potential mitigation strategies and novel therapeutics.

Short-Term Safety and Psychosocial Impact of the BNT162b2 mRNA COVID-19 Vaccine in Cancer Patients-An Italian Single-Center Experience.

Safety data regarding BNT162b2 in cancer patients (CPs) are scarce. Herein we report the side effects (SEs), the adverse events (AEs), and the patient-reported outcomes (PROs) following BNT162b2 administration in CPs treated at the San Luigi Gonzaga University Hospital. All CPs who agreed to participate in our vaccination campaign received BNT162b2 and were included in the descriptive analysis. An anonymous questionnaire investigating the occurrence of SEs/AEs and PROs was administered to the study population 21 days after the first dose. Pearson's chi-squared test was used to estimate the risk of experiencing SEs/AEs according to selected variables. A total of 997 patients were included in the study: 62.0% had stage IV cancer, and 68.8% were receiving an active treatment, of whom 15.9% were receiving immunotherapy. SEs/AEs were recorded in 37.1% of cases after the first dose and in 48.5% of cases after the second dose. The most common SEs were muscle pain/local rash (27.9% and 28%, after the first and second dose, respectively). Patients older than 70 years showed lower risk of SEs/AEs, while women showed a higher risk. Before receiving the vaccine, 18.2% of patients felt fearful and/or insecure about the vaccination. After the first dose, 57.5% of patients changed their feelings positively. Our data support the short-term safety of BNT162b2 in CPs, regardless of disease stage and concurrent treatments. Overall, the vaccination showed a positive impact on quality of life.

The use of eHealth to promote physical activity in thoracic malignancies survivors: A systematic review and meta-analysis.

BACKGROUND: Survival rates for many forms of thoracic malignancies have improved over the past few decades, however, many survivors are coping with the side effects of cancer treatment for longer. Physical activity (PA) has been proposed as a therapeutic strategy to combat the effects of treatment in cancer survivors and eHealth could be a good way to encourage patients to practice it. OBJECTIVE: To explore the effects of eHealth in the promotion of PA among thoracic malignancies. METHODS: Suitable articles were searched using PubMed, Web of Science and Scopus databases using a combination of medical subject headings. RESULTS: In total, 4781 articles were identified, of which ten met eligibility criteria. Different eHealth interventions were described in these studies: mobile application (app) (n = 3), website (n = 2), email (n = 2), web and mobile application (n = 1), telephone counseling (n = 1) and online sheet (n = 1). All studies reported improvements in PA, with 8/10 studies reporting statistically significant changes. CONCLUSION: Our results show that eHealth programs are useful to promote PA in malignancy thoracic survivors, compared to no intervention, conventional treatment or a dietary approach. Moreover, the meta-analysis also revealed eHealth is a good way to improve the level of PA in thoracic malignancies survivors.

Progress of Chimeric Antigen Receptor Gene Modified-T Cell Immunotherapy for Thoracic Malignancies / 肿瘤防治研究

With a deepened understanding of the pathophysiology and pathogenesis of thoracic malignancies, the treatment has been transited from traditional treatment on the basis of surgery, radiotherapy, and chemotherapy to individualized and precise targeted therapy and immunotherapy. As an antitumor immunotherapy, chimeric antigen receptor gene-modified T (CAR-T) cells have been approved by the FDA for the treatment of hematological malignancies in five CAR-T products. They have also achieved good therapeutic effects in solid tumors. However, significant challenges remain in the clinical application of CAR-T cell immunotherapy in thoracic malignancies. In this review, the latest research progress of CAR-T cell immunotherapy in the treatment of thoracic malignancies were summarized, including the basic characteristics of CAR-T cells, the popular target antigens, and the existing problems and challenges, to provide new ideas and strategies for clinical immunotherapy of thoracic malignancies.

The impact of frailty on health outcomes in older adults with lung cancer: A systematic review.

BACKGROUND: Frailty is prevalent in older adults with lung cancer, however the impact of frailty in this population is not well understood. The aim of this review was to evaluate the outcomes that are measured in frail older adults with lung cancer, and to determine the associations between frailty and these outcomes. METHODS: A systematic online search of PubMed, EMBASE, and Cochrane databases was conducted to identify all English-language studies between January 2015 and May 2022 prospectively evaluating frailty and outcomes in older adults (median age > 65 years) with lung cancer. Studies were excluded if frailty was defined by a single domain assessment or not clearly defined. Quality was assessed using the Newcastle-Ottawa Scale. RESULTS: Of 1891 studies screened, 16 met inclusion criteria. The median number of patients was 96 (range 26-494) and the mean age was 76.6 years. Eight different frailty assessments were used, and frailty definitions varied widely. The most frequently assessed outcomes were overall survival (n = 13,81%), treatment-related toxicity (n = 8,50%), hospitalisation (n = 5,31%), and treatment completion/discontinuation (n = 4,25%). Quality of life (n = 3,19%), function (n = 1,6%), frailty trajectory (n = 1,6%), and emergency visits (n = 1,6%) were infrequently assessed. Frailty had a strong and consistent association with mortality (Hazard Ratio range: 3.5-11.91). It was also associated with treatment-related toxicity and treatment selection. The remaining outcomes were not statistically significant. CONCLUSION: These data support frailty as an important predictor of mortality in older adults with lung cancer, however further research is warranted to determine the association between frailty and other meaningful endpoints for this vulnerable population.

Safety of image guided research biopsies in patients with thoracic malignancies.

OBJECTIVE: A common opportunity to collect research samples is during image-guided percutaneous core needle biopsies (CNBs) performed when clinically indicated or for assessing clinical trial eligibility. The relative safety of extra CNBs collected for research is undefined. MATERIALS AND METHODS: Patients who underwent CNB for research purposes only [RO], as clinically indicated [CI], or as part of a clinical trial [CT] were identified. 30-day post-procedure adverse events (AEs) among the cohorts were examined and compared to the 2020 Society of Interventional Radiology QI guidelines. RESULTS: 236 patients with thoracic cancers (90 % NSCLC, 5 % SCLC, 4 % mesothelioma, and 1 % thymic) had 292 CNBs (63 RO, 229 CI + CT). AEs occurred in 13 % of both the RO and CI + CT groups. Compared to the CI + CT group, the RO group did not have a higher pneumothorax incidence (RO: 5/29 [17 %], CI + CT: 18/114 [16 %], p = 0.79); both were below the suggested QI threshold of 45 % for pneumothorax. There was a negative association between number of cores obtained and risk of AE (AE vs no AE mean cores = 3.5 vs 4.8). After adjusting for the number of cores and smoking history, RO vs CI + CT lung biopsies had a higher risk of AEs (adjusted relative risk [aRR] = 2.44, 1.08-5.55, p = 0.03 vs non-lung aRR = 0.86, 0.10-7.09, p = 0.89). CONCLUSION: CNBs performed for research purposes do not have a significantly increased risk of AEs when compared to those performed for clinical trials and/or when clinically indicated. However, AEs were most frequent in lung biopsies. When performing research biopsies, a target other than lung may be preferred when clinically appropriate.

Changes in Behavior After Vaccination and Opinions Toward Mask Wearing: Thoracic Oncology Patient-Reported Experiences During the COVID-19 Pandemic.

Background: The COVID-19 vaccines, face masks, and social distancing are effective interventions to prevent SARS-CoV-2 infections. In this study, we aimed to determine lung cancer patients' attitudes toward vaccination, changes in behavior after vaccination, and willingness to continue mask wearing after the pandemic. Methods: We sent out questionnaires to 220 thoracic oncology patients treated at our lung cancer center in May 2021. The questionnaire focused on patients' vaccination status, self-reported experiences surrounding vaccination, and assessed changes in behaviors before and after vaccination as well as opinions toward mask wearing after the pandemic. Results are presented as absolute and relative frequencies and means with standard deviation and compared using t test, paired t test, and analysis of variance test as well as chi2 test, and Fisher exact text. Results: About 91.0% of patients reported having received at least 1 vaccination. About 73.3% of patients reported having at least 1 reaction to the vaccination. The most common reactions were pain at the injection site, fatigue, and headache. After vaccination, patients increased contact with family and friends, use of public transport, and grocery shopping. Overall, the level of willingness to wear masks beyond the end of the pandemic differed according to vaccination status. Conclusions: Acceptance of the COVID-19 vaccination among thoracic oncology patients in Germany was high. Overall, patients with thoracic malignancies tolerated the COVID-19 vaccination well. Rate of adverse reaction was not higher compared with the general population. After the vaccination, patients increased social contacts and usage of public transport. These changes suggest positive psychological effects on quality of life. While reducing social distancing can increase the risk of infection, our results indicate that an extension of mask mandates after the pandemic would likely be accepted by a majority of thoracic oncology patients, suggesting that our cohort was still aware and in support of other measure of protection.

Chimeric Antigen Receptor (CAR)-T Cell Immunotherapy Against Thoracic Malignancies: Challenges and Opportunities.

Different from surgery, chemical therapy, radio-therapy and target therapy, Chimeric antigen receptor-modified T (CAR-T) cells, a novel adoptive immunotherapy strategy, have been used successfully against both hematological tumors and solid tumors. Although several problems have reduced engineered CAR-T cell therapeutic outcomes in clinical trials for the treatment of thoracic malignancies, including the lack of specific antigens, an immunosuppressive tumor microenvironment, a low level of CAR-T cell infiltration into tumor tissues, off-target toxicity, and other safety issues, CAR-T cell treatment is still full of bright future. In this review, we outline the basic structure and characteristics of CAR-T cells among different period, summarize the common tumor-associated antigens in clinical trials of CAR-T cell therapy for thoracic malignancies, and point out the current challenges and new strategies, aiming to provide new ideas and approaches for preclinical experiments and clinical trials of CAR-T cell therapy for thoracic malignancies.

Adoptive cell therapies in thoracic malignancies.

Immunotherapy has gained great interest in thoracic malignancies in the last decade, first in non-small cell lung cancer (NSCLC), but also more recently in small-cell lung cancer (SCLC) and malignant pleural mesothelioma (MPM). However, while 15-20% of patients will greatly benefit from immune checkpoint blockers (ICBs), a vast majority will rapidly exhibit resistance. Reasons for this are multiple: non-immunogenic tumors, immunosuppressive tumor microenvironment or defects in immune cells trafficking to the tumor sites being some of the most frequent. Current progress in adoptive cell therapies could offer a way to overcome these hurdles and bring effective immune cells to the tumor site. In this review, we discuss advantages, limits and future perspectives of adoptive cell therapy (ACT) in thoracic malignancies from lymphokine-activated killer cells (LAK), cytokine-induced killer cells (CIK), natural killer cells (NK), dendritic cells (DC) vaccines and tumor-infiltrating lymphocytes (TILs) to TCR engineering and CARs. Trials are still in their early phases, and while there may still be many limitations to overcome, a combination of these different approaches with ICBs, chemotherapy and/or radiotherapy could vastly improve the way we treat thoracic cancers.

Consequences of the COVID-19 pandemic on lung cancer care and patient health in a German lung cancer center: results from a cross-sectional questionnaire.

BACKGROUND: The novel coronavirus SARS-CoV-2 has caused a global COVID-19 pandemic, leading to worldwide changes in public health measures. In addition to changes in the public sector (lockdowns, contact restrictions), hospitals modified care to minimize risk of infection and to mobilize resources for COVID-19 patients. Our study aimed to assess the impact of these measures on access to care and behaviour of patients with thoracic malignancies. METHODS: Thoracic oncology patients were surveyed in October 2020 using paper-based questionnaires to assess access to ambulatory care services and tumor-directed therapy during the COVID-19 pandemic. Additionally, behaviour regarding social distancing and wearing of face masks were assessed, as well as COVID-19 exposure, testing and vaccination. Results are presented as absolute and relative frequencies for categorical variables and means with standard deviation for numerical variables. We used t-test, and ANOVA to compare differences in metric variables and Chi2-test to compare proportions between groups. RESULTS: 93 of 245 (38%) patients surveyed completed the questionnaire. Respiration therapy and physical therapy were unavailable for 57% to 70% of patients during March/April. Appointments for tumor-directed therapy, tumor imaging, and follow-up care were postponed or cancelled for 18.9%, 13.6%, and 14.8% of patients, respectively. Patients reported their general health as mostly unaffected. The majority of patients surveyed did not report reducing their contacts with family. The majority reduced contact with friends. Most patients wore community masks, although a significant proportion reported respiratory difficulties during prolonged mask-wearing. 74 patients (80%) reported willingness to be vaccinated against SARS-CoV-2. CONCLUSIONS: This survey provides insights into the patient experience during the second wave of the COVID-19 pandemic in Munich, Germany. Most patients reported no negative changes to cancer treatments or general health; however, allied health services were greatly impacted. Patients reported gaps in social distancing, but were prepared to wear community masks. The willingness to get vaccinated against SARS-CoV-2 was high. This information is not only of high relevance to policy makers, but also to health care providers.

How to Better Understand the Influence of Host Genetics on Developing an Effective Immune Response to Thoracic Cancers.

Thoracic cancers pose a significant global health burden. Immune checkpoint blockade therapies have improved treatment outcomes, but durable responses remain limited. Understanding how the host immune system interacts with a developing tumor is essential for the rational development of improved treatments for thoracic malignancies. Recent technical advances have improved our understanding of the mutational burden of cancer cells and changes in cancer-specific gene expression, providing a detailed understanding of the complex biology underpinning tumor-host interactions. While there has been much focus on the genetic alterations associated with cancer cells and how they may impact treatment outcomes, how host genetics affects cancer development is also critical and will greatly determine treatment response. Genome-wide association studies (GWAS) have identified genetic variants associated with cancer predisposition. This approach has successfully identified host genetic risk factors associated with common thoracic cancers like lung cancer, but is less effective for rare cancers like malignant mesothelioma. To assess how host genetics impacts rare thoracic cancers, we used the Collaborative Cross (CC); a powerful murine genetic resource designed to maximize genetic diversity and rapidly identify genes associated with any biological trait. We are using the CC in conjunction with our asbestos-induced MexTAg mouse model, to identify host genes associated with mesothelioma development. Once genes that moderate tumor development and progression are known, human homologues can be identified and human datasets interrogated to validate their association with disease outcome. Furthermore, our CC-MexTAg animal model enables in-depth study of the tumor microenvironment, allowing the correlation of immune cell infiltration and gene expression signatures with disease development. This strategy provides a detailed picture of the underlying biological pathways associated with mesothelioma susceptibility and progression; knowledge that is crucial for the rational development of new diagnostic and therapeutic strategies. Here we discuss the influence of host genetics on developing an effective immune response to thoracic cancers. We highlight current knowledge gaps, and with a focus on mesothelioma, describe the development and application of the CC-MexTAg to overcome limitations and illustrate how the knowledge gained from this unique study will inform the rational design of future treatments of mesothelioma.

Novel patterns of progression upon immunotherapy in other thoracic malignancies and uncommon populations.

In the immunotherapy era, considering the prolonged survival benefit and responses observed with immunecheckpoint inhibitors (ICI) in many cancer types, the identification of patients with rapid progression (PD) and deaths upon ICI has found some skepticism and resistance among the scientific community. Nevertheless, an acceleration of tumour during ICI, defined as hyperprogressive disease (HPD), has been recognized across different cancer types and evidence regarding rapid PDs and deaths are emerging in patients with malignant pleural mesothelioma (MPM), small cell lung cancer (SCLC) and thymic malignancies and in uncommon non-small cell lung cancer (NSCLC) populations. Of note, PD and early deaths (ED) rates upon single agent ICI were up to 60% and 30% in MPM and 70% and 38% in SCLC patients, respectively. Similarly, rapid PDs and deaths were observed in clinical trials and retrospective studies including patients with poor performance status (PS), HIV infection and rare NSCLC histologies. Atypical patterns of response, such as pseudoprogression (PsPD) may also occur in other thoracic malignancies (MPM) and in some uncommon populations (i.e., HIV patients), however probably at lower rate compared to HPD. The characterizations of HPD and PsPD mechanisms and the identification of common definition criteria are the next future challenges in this area of cancer research.