The full cohort of 512 patients and the nested controlled trial in 93 patients in the Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) study raise doubts about the effective size at present claimed

A comparison of the relative merits of video-assisted pulmonary metastasectomy versus thoracotomy is predicated on the assumption that removal of asymptomatic lung metastases favourably influences survival and that it does so by a large degree. Recently published but long-awaited evidence from a prospective cohort study and a randomised trial of Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) challenges that assumption.

Diagnostic Value of Bronchoscopy for Peripheral Metastatic Lung Tumors

Although lungs are one of the most frequent sites of metastasis for malignant tumors, little has been reported about the value of bronchoscopy for lung metastases presenting with peripheral pulmonary lesions (PPLs). This retrospective cohort study investigated the diagnostic value of bronchoscopy for peripheral metastatic lung tumors. Consecutive patients who underwent diagnostic bronchoscopy with radial endobronchial ultrasound for PPLs and were finally diagnosed with metastatic lung tumors from April 2012 to March 2019 were included. We analyzed 235 PPLs, with a median size of 18.8 mm. The overall diagnostic yield was 76.6%. In a multivariable analysis, large lesion size (>20.0 mm vs. <20.0 mm: 87.6% vs. 67.7%, p = 0.043, OR = 2.26), inner location (inner 2/3 vs. outer 1/3: 84.8% vs. 69.1%, p = 0.004, OR = 2.79), and visibility on radiography (visible vs. invisible: 83.2% vs. 56.1%, p = 0.015, OR = 3.29) significantly affected the diagnostic yield. Although a positive bronchus sign tended to have a higher yield, no significant difference was observed (81.8% vs. 70.6%, p = 0.063). Only one case of lung abscess was observed, with no serious complications. In conclusion, bronchoscopy is a valuable technique for peripheral metastatic lung tumors, with good diagnostic accuracy and safety.

Image-Guided Robotic Radiosurgery for the Treatment of Lung Metastases of Renal Cell Carcinoma—A Retrospective, Single Center Analysis

Pulmonary metastases are the most frequent site of metastases in renal cell carcinoma (RCC). Metastases directed treatment remains an important treatment option despite advances in systemic therapies. However, the safety and efficacy of robotic radiosurgery (RRS) for the treatment of lung metastases of RCC remains unclear. Patients with metastatic RCC and lung metastases treated by RRS were retrospectively analyzed for overall survival (OS), progression-free survival (PFS), local recurrence free survival (LRFS) and adverse events. The Kaplan–Meier method was used for survival analysis and the common terminology criteria for adverse events (CTCAE; Version 5.0) classification for assessment of adverse events. A total of 50 patients were included in this study. Median age was 64 (range 45–92) years at the time of RRS. Prior to RRS, 20 patients (40.0%) had received either tyrosine kinase inhibitors or immunotherapy and 27 patients (54.0%) were treatment naïve. In our patient cohort, the median PFS was 13 months (range: 2–93). LRFS was 96.7% after two years with only one patient revealing progressive disease of the treated metastases 13 months after RRS. Median OS was 35 months (range 2–94). Adverse events were documented in six patients (12%) and were limited to grade 2. Fatigue (n = 4) and pneumonitis (n = 2) were observed within 3 months after RRS. In conclusion, RRS is safe and effective for patients with metastatic RCC and pulmonary metastases. Radiation induced pneumonitis is specific in the treatment of pulmonary lesions, but not clinically relevant and survival rates seem favorable in this highly selected patient cohort. Future directions are the implementation of RRS in multimodal treatment approaches for oligometastatic or oligoprogressive disease.

Systemic Delivery of mLIGHT-Armed Myxoma Virus Is Therapeutic for Later-Stage Syngeneic Murine Lung Metastatic Osteosarcoma

Cancers that metastasize to the lungs represent a major challenge in both basic and clinical cancer research. Oncolytic viruses are newly emerging options but successful delivery and choice of appropriate therapeutic armings are two critical issues. Using an immunocompetent murine K7M2-luc lung metastases model, the efficacy of MYXV armed with murine LIGHT (TNFSF14/CD258) expressed under virus-specific early/late promoter was tested in an advanced later-stage disease K7M2-luc model. Results in this model show that mLIGHT-armed MYXV, delivered systemically using ex vivo pre-loaded PBMCs as carrier cells, reduced tumor burden and increased median survival time. In vitro, when comparing direct infection of K7M2-luc cancer cells with free MYXV vs. PBMC-loaded virus, vMyx-mLIGHT/PBMCs also demonstrated greater cytotoxic capacity against the K7M2 cancer cell targets. In vivo, systemically delivered vMyx-mLIGHT/PBMCs increased viral reporter transgene expression levels both in the periphery and in lung tumors compared to unarmed MYXV, in a tumor- and transgene-dependent fashion. We conclude that vMyx-mLIGHT, especially when delivered using PBMC carrier cells, represents a new potential therapeutic strategy for solid cancers that metastasize to the lung.

Exercise-Induced Extracellular Vesicles Delay the Progression of Prostate Cancer

Increasing evidence suggests that regular physical exercise not only reduces the risk of cancer but also improves functional capacity, treatment efficacy and disease outcome in cancer patients. At least partially, these effects are mediated by the secretome of the tissues responding to exercise. The secreted molecules can be released in a carrier-free form or enclosed into extracellular vesicles (EVs). Several recent studies have shown that EVs are actively released into circulation during physical exercise. Here, we for the first time investigated the effects of exercise-induced EVs on the progression of cancer in an F344 rat model of metastatic prostate cancer. Although we did not observe a consistent increase in the circulating EV levels, RNA sequencing analysis demonstrated substantial changes in the RNA content of EVs collected before and immediately after forced wheel running exercise as well as differences between EVs from runners at resting state and sedentary rats. The major RNA biotype in EVs was mRNA, followed by miRNA and rRNA. Molecular functions of differentially expressed RNAs reflected various physiological processes including protein folding, metabolism and regulation of immune responses triggered by the exercise in the parental cells. Intravenous administration of exercise-induced EVs into F344 rats with orthotopically injected syngeneic prostate cancer cells PLS10, demonstrated reduction of the primary tumor volume by 35% and possibly—attenuation of lung metastases. Hence, our data provide the first evidence that exercise-induced EVs may modulate tumor physiology and delay the progression of cancer.

A phase I dose-escalation, safety/tolerability, and preliminary efficacy study of the intratumoral administration of GEN0101 in patients with advanced melanoma

Despite recent advance in immunotherapy agents, safe new therapies that enhance the effects of immune checkpoint inhibitors are still required to develop. We previously demonstrated that hemagglutinating virus of Japan-envelope (HVJ-E) induced not only direct tumor cell death but also antitumor immunity through the activation of T and natural killer (NK) cells, thereafter, developed a manufacturing process of HVJ-E (GEN0101) for clinical use. We here performed a phase Ia clinical trial of intratumoral GEN0101 administration in six patients with stage IIIC or IV malignant melanoma. The primary aim was to evaluate the safety and tolerability of GEN0101, and the secondary aim was to examine the objective tumor response. Patients were separated into two groups (n = 3 each) and received a low dose of 30,000 and high dose of 60,000 mNAU of GEN0101. All patients completed a two-week follow-up evaluation without severe adverse events. The overall response rate was 33% (2 of 6), with 2 partial responses in the high-dose group and 2 with stable disease, and 2 with progressive disease in the low-dose group. Local complete or partial responses were observed in 11 of 18 (61%) target lesions. One patient demonstrated shrinkage of lung metastases after the treatment. The activity of NK cells and interferon-γ levels were increased in the circulation, indicating augmentation of antitumor immunity by GEN0101. This trial showed not only the safety and tolerability but also the significant antitumor effect of GEN0101, suggesting that GEN0101 might be a promising new drug for patients with advanced melanoma.

Unusual increase in carcinoembryonic antigen despite response to selpercatinib in two patients with medullary thyroid cancer

Introduction: Serum calcitonin (CT) and carcinoembryonic antigen (CEA) are valuable tumour markers in patients with medullary thyroid carcinoma (MTC). Both markers most often evolve in parallel after treatment. Selpercatinib (LOXO-292) is a highly selective RET kinase inhibitor indicated in advanced RET-mutant MTC patients. Case presentation: We report two observations of RET-mutant progressive metastatic and symptomatic MTC patients who were treated with selpercatinib. Patient 1, a 61-year-old man, presented dyspnoea and diarrhoea at selpercatinib initiation with large neck lymph nodes and lung metastases. Patient 2, a 76-year-old man, had acute discomfort with flush and diarrhoea, with small but diffuse bone and liver disease. Both patients had an objective response with rapid clinical improvement and RECIST 1.1 response (-90%) in patient 1. A rapid dramatic decrease in CT level was observed in both patients (-99% in both patients) while CEA levels gradually and sustainably increased after selpercatinib initiation (+207% at cycle 15 in patient 1 and + 835% at cycle 14 in patient 2). In both patients, FDG PET/CT did not show any abnormal uptake that could explain the CEA increase. Colonoscopy and oesogastric fibroscopy showed colonic polyposis with mild oesophagitis and gastritis in patient 1 and were normal in patient 2. Conclusion: These observations show an unusual and lasting increase in serum CEA in two MTC patients who exhibited an objective tumour response to selpercatinib. The mechanism behind this unexpected rise in CEA level remains unknown. The frequency of this evolving profile will be determined in further phase III studies.

Interleukin 4 controls the role of macrophages in pulmonary metastatic tumor cell seeding and growth

Metastasis is the systemic manifestation of cancer and the main cause of death from breast cancer. In mouse models of lung metastases, recruitment of classical monocytes from blood to the lung and their differentiation to metastasis-associated macrophages (MAMs) facilitate cancer cell extravasation, survival, and growth. Ablation of MAMs or their monocytic progenitors inhibits metastasis. We hypothesized that factors controlling macrophage polarization modulate tumor cell extravasation in the lung. We evaluated whether signaling by Th1 or Th2 cytokines in macrophages affected trans-endothelial migration of tumor cells in vitro. Interferon γ and LPS inhibited macrophage-dependent tumor cell extravasation while the Th2 cytokine interleukin-4 (IL4) enhanced this process. We demonstrated that IL4 receptor (IL4rα) null mice develop fewer and smaller lung metastasis. Adoptive transfer of wild type monocytes to IL4rα deficient mice rescued this phenotype. IL4 signaling in macrophages controls the expression of the chemokine receptor CXCR2, necessary for IL4-mediated tumor cell extravasation in vitro. Furthermore, IL4 signaling in macrophages transcriptionally regulates several other genes already causally associated with lung metastasis including CCL2, CSF1, CCR1, HGF and FLT1. The central role for IL4 signaling in MAMs was confirmed by high-resolution intravital imaging of the lung in mice at the time of metastatic seeding, which showed reduced physical interaction between tumor cells and IL4rα-deficient macrophages. This interaction enhances tumor cell survival. These data indicate that IL4 signaling in monocytes and macrophages is key during seeding and growth of breast metastasis in the lung as it regulates pro-tumoral paracrine signaling between cancer cells and macrophages.