Respiratory viral infection promotes the awakening and outgrowth of dormant metastatic breast cancer cells in lungs (preprint)

Breast cancer is the second most common cancer globally. Most deaths from breast cancer are due to metastatic disease which often follows long periods of clinical dormancy1. Understanding the mechanisms that disrupt the quiescence of dormant disseminated cancer cells (DCC) is crucial for addressing metastatic progression. Infection with respiratory viruses (e.g. influenza or SARS-CoV-2) is common and triggers an inflammatory response locally and systemically2,3. Here we show that influenza virus infection leads to loss of the pro-dormancy mesenchymal phenotype in breast DCC in the lung, causing DCC proliferation within days of infection, and a greater than 100-fold expansion of carcinoma cells into metastatic lesions within two weeks. Such DCC phenotypic change and expansion is interleukin-6 (IL-6)-dependent. We further show that CD4 T cells are required for the maintenance of pulmonary metastatic burden post-influenza virus infection, in part through attenuation of CD8 cell responses in the lungs. Single-cell RNA-seq analyses reveal DCC-dependent impairment of T-cell activation in the lungs of infected mice. SARS-CoV-2 infected mice also showed increased breast DCC expansion in lungs post-infection. Expanding our findings to human observational data, we observed that cancer survivors contracting a SARS-CoV-2 infection have substantially increased risks of lung metastatic progression and cancer-related death compared to cancer survivors who did not. These discoveries underscore the significant impact of respiratory viral infections on the resurgence of metastatic cancer, offering novel insights into the interconnection between infectious diseases and cancer metastasis.

A Systematic Review of Diffusion Microstructure Imaging (Dmi): Current and Future Applications in Neurology Research (preprint)

Background: Diffusion microstructure imaging (DMI) is a novel diffusion magnetic resonance imaging (MRI) technique that provides rich estimates of microscopic tissue properties, such as axon morphologies and fiber configurations. DMI has potential applications in neurology, where various diseases and disorders affect the brain tissue's microstructure and connectivity.Objectives: To investigate the current and future applications of DMI in neurology, covering various diseases and disorders such as brain tumors and metastases, Parkinson's syndromes, COVID-19-related neurological symptoms, temporal lobe epilepsy, and acute ischemic stroke.Methods: The PRISMA 2020 statement was followed. Four electronic databases were searched from inception to May the 5th 2023. Two reviewers independently screened, selected, and extracted data from the eligible studies.Results: Seven studies were included in the review. The studies showed that DMI can differentiate between various neurological diseases or disorders based on alterations in brain tissue microstructure and connectivity. The studies also showed that DMI can be superior to conventional diffusion imaging techniques, such as diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI), in detecting subtle differences between pathological conditions.Conclusions: DMI is a powerful diffusion imaging technique that can provide rich estimates of microscopic tissue properties and differentiate between various neurological diseases or disorders. However, more research is needed to compare DMI with other imaging modalities or clinical measures and to evaluate longitudinal changes or treatment effects using DMI in neurological diseases or disorders.

Migrasomes deliver messages from migrating cells (preprint)

Migrasomes are newly discovered extracellular vesicles that can mediate communication between cells. These unique vesicles form exclusively at the rear of migrating cells with the help of a protein called TSPAN4. After they’re left behind, the migrasomes and their contents can be captured by nearby cells and affect the recipient cells’ behavior. They can also serve as “breadcrumb trails” that mark the paths of their migrating parent cells. Migrasomes participate in both health and disease. For example, they can dispose of damaged mitochondria to maintain healthy cells and they help establish left–right patterning in zebrafish embryos by releasing the protein CXCL12 to recruit dorsal forerunner cells (DFCs). However, migrasomes can also deliver molecules that promote tumor growth and metastasis and migrasomes released from platelets promote blood clotting after SARS-CoV-2 infection. Furthermore, migrasomes can facilitate an eye condition called proliferative vitreoretinopathy that leads to retinal detachment and blindness. Better characterization of the contents and roles of migrasomes will help us understand these newly identified vesicles and reveal how they can be leveraged to diagnose and treat diseases.

Outpatient anti-spike monoclonal antibody administration is associated with decreased morbidity and mortality among patients with cancer and COVID-19 (preprint)

Background: Patients with cancer have many comorbidities that increase their risk of death from Coronavirus disease 2019 (COVID-19). Anti-spike monoclonal antibodies (mAbs) reduce the risk of hospitalization or death from COVID-19 in the general population. To our knowledge, no studies have focused on the clinical efficacy of mAbs compared to no outpatient treatment exclusively among patients with solid tumors and hematologic malignancies, who are often excluded from clinical trials.  Methods: We studied patients with cancer who had COVID-19 between 11.9.2020 and 7.21.2022 and received mAbs in an outpatient setting. We compared hospitalization and mortality rates to those of patients with cancer concurrently diagnosed with COVID-19, who were eligible for mAbs, but did not receive any outpatient treatment. Results: 63 patients received mAbs and 89 no outpatient treatment. Administration of mAbs was associated with lower 90-day hospitalization (20.6% vs. 60.7%, p<0.001), all-cause (6.3% vs. 19.1%, p=0.025) and COVID-19-attributed (3.2% vs. 14.6%, p=0.019) mortality rates, and lower peak O2 requirements (ordinal Odds Ratio [OR]=0.33, 95%Confidence Intervals [CI]=0.20-0.53). Administration of mAbs (aHR 0.21, p<0.001), age (≥ 60 years, adjusted Hazard Ratio [aHR] 1.86, p=0.033), and metastases (aHR 0.41, p=0.007) were independently associated with hospitalization. mAb treatment remained significantly associated with all-cause (aHR 0.27, p=0.019) and COVID-19-attributed (aHR 0.19, p=0.031) mortality, after adjustment for other factors.  Conclusions: mAb administration was associated with improved clinical outcomes among vulnerable patients with cancer and COVID-19. With no mAbs approved currently for treatment against the prevalent circulating variants, the development of new mAbs should be a research priority.

A potential alternative systemic treatment option for epithelioid sarcoma (preprint)

Background: Epithelioid sarcoma is a rare soft tissue sarcoma characterized by SMARCB1/INI1 deficiency. Much attention has been paid to the selective EZH2 inhibitor tazemetostat, where other systemic treatments are generally ignored. To explore alternative treatment options, we studied the effects of irinotecan-based chemotherapy in a series of epithelioid sarcoma patients. Methods: We retrospectively reviewed data from patients with metastatic or unresectable epithelioid sarcoma at the Peking University People’s Hospital treated with irinotecan (50 mg/m2/d d1-5 Q3W) in combination with Anlotinib (12 mg Qd, 2 weeks on and 1 week off) from July 2015 to November 2021. Results: A total of 54 courses were administered. With a median follow up of 21.2 months (95% CI, 12.2, 68.1), the 5-year overall survival rate was 83.3%. Five of eight (62.5%) patients presented with unresectable localized lesions, including local tumor thrombosis and lymphatic metastasis. The other patients had unresectable pulmonary metastases. Six of eight (75%) patients had progressed following two lines of systemic therapy. The objective response rate reached 37.5% (three of eight patients) while stabilized disease was observed in 62.5% (five of eight) of patients. No patient had progressed at initial evaluation. At the last follow up, two patients were still using the combination and three patients had ceased the therapy due to toxicities such as diarrhea, nausea, and emesis. One patient changed to tazemetostat for maintenance and one patient stopped treatment due to coronavirus disease 2019 (COVID-19). Another patient stopped therapy as residual lesions had been radiated. Conclusions: The combination of irinotecan and Anlotinib as a salvage regimen may be considered another effective treatment option for refractory epithelioid sarcoma. Trial registration: This trial was approved in the Medical Ethics Committee of Peking University People’s Hospital on October 28, 2022 (No.: 2022PHD015-002). The trial was registered in Clinicaltrials.gov with identifier no. NCT05656222.

R0 Surgical Resection of Giant Dedifferentiated Retroperitoneal Liposarcomas in the COVID era: Nephrectomy or Not Nephrectomy? (preprint)

Background: Retroperitoneal sarcomas (RPS) are rare findings that can grow into large masses without eliciting severe symptoms. Nowadays surgical resection is the only radical therapy, whenever possible. We present two consecutive cases of RPSs that resulted in dedifferentiated liposarcomas (DDLPS) and underwent R0 surgical resection with and without a nephron-sparing procedure. The diagnostic workup, the surgical approach, the impact of late surgical management due to the COVID pandemic, and the latest literature on the topic will be discussed and analyzed. Case Presentation: The patients, who refused to undergo any medical examination during the prior two years due to the COVID pandemic, were admitted to our Institution complaining about weight loss and general abdominal discomfort. In the first case, we observed a primitive giant abdominal right neoplasm of retroperitoneal origin enveloping and medializing the right kidney. The second patient had a similar primitive retroperitoneal giant left neoplasm which didn’t affect the kidney. Given the masses’ characteristics and the absence of distant metastases, after a multidisciplinary discussion, radical surgical removal was carried out for both patients. The lesions appeared well-defined from the surrounding tissues, and significantly compressed all the adjacent organs, without signs of infiltration. In the first patient, the right kidney was surrounded and undetachable from the tumor and it was removed en bloc with the mass. The second patient benefited from a nephron-sparing resection, thanks to the existence of a clear cleavage plane. The postoperative courses were uneventful. Both the histological examinations were oriented towards a DDLPS. And both patients were addressed with adjuvant chemotherapy. Conclusions: The treatment of giant RPS is still challenging and requires multidisciplinary treatment as well as, when possible, radical surgical removal. The lack of tissue infiltration and the avoidance of major organs’ excision or reconstruction (including the kidney) could lead to an easier postoperative course and a better prognosis. When possible, surgical management of recurrences or incompletely resected masses must be pursued. As the COVID pandemic caused limited medicalization of many population groups and delayed diagnosis of other oncologic diseases, an increased number of DDLPSs could be expected in the near future. 

A phase III, randomized, open-label study (CONTACT-02) of cabozantinib plus atezolizumab versus second novel hormone therapy in patients with metastatic castration-resistant prostate cancer.

Cabozantinib inhibits multiple receptor tyrosine kinases, including the TAM kinase family, and may enhance response to immune checkpoint inhibitors. One cohort of the ongoing phase Ib COSMIC-021 study (NCT03170960) evaluating cabozantinib plus the PD-L1 inhibitor atezolizumab in men with metastatic castration-resistant prostate cancer (mCRPC) that has progressed in soft tissue on/after enzalutamide and/or abiraterone treatment for metastatic disease has shown promising efficacy. Here, we describe the rationale and design of a phase III trial of cabozantinib plus atezolizumab versus a second novel hormone therapy (NHT) in patients who have previously received an NHT for mCRPC, metastatic castration-sensitive PC or nonmetastatic CRPC and have measurable visceral disease and/or extrapelvic adenopathy - a population with a significant unmet need for treatment options. Trial Registration Clinical Trial Registration: NCT04446117 (ClinicalTrials.gov) Registered on 24 June 2020.

Lipid nanoparticle-mediated lymph node-targeting delivery of mRNA cancer vaccine elicits robust CD8+ T cell response.

The targeted delivery of messenger RNA (mRNA) to desired organs remains a great challenge for in vivo applications of mRNA technology. For mRNA vaccines, the targeted delivery to the lymph node (LN) is predicted to reduce side effects and increase the immune response. In this study, we explored an endogenously LN-targeting lipid nanoparticle (LNP) without the modification of any active targeting ligands for developing an mRNA cancer vaccine. The LNP named 113-O12B showed increased and specific expression in the LN compared with LNP formulated with ALC-0315, a synthetic lipid used in the COVID-19 vaccine Comirnaty. The targeted delivery of mRNA to the LN increased the CD8+ T cell response to the encoded full-length ovalbumin (OVA) model antigen. As a result, the protective and therapeutic effect of the OVA-encoding mRNA vaccine on the OVA-antigen-bearing B16F10 melanoma model was also improved. Moreover, 113-O12B encapsulated with TRP-2 peptide (TRP2180-188)-encoding mRNA also exhibited excellent tumor inhibition, with the complete response of 40% in the regular B16F10 tumor model when combined with anti-programmed death-1 (PD-1) therapy, revealing broad application of 113-O12B from protein to peptide antigens. All the treated mice showed long-term immune memory, hindering the occurrence of tumor metastatic nodules in the lung in the rechallenging experiments that followed. The enhanced antitumor efficacy of the LN-targeting LNP system shows great potential as a universal platform for the next generation of mRNA vaccines.

Case Report: Clinical Management of a Patient With Metastatic Non-Small Cell Lung Cancer Newly Receiving Immune Checkpoint Inhibition During Symptomatic COVID-19.

Effects of initiation of programmed-death-protein 1 (PD1) blockade during active SARS-CoV-2 infection on antiviral immunity, COVID-19 course, and underlying malignancy are unclear. We report on the management of a male in his early 40s presenting with highly symptomatic metastatic lung cancer and active COVID-19 pneumonia. After treatment initiation with pembrolizumab, carboplatin, and pemetrexed, the respiratory situation initially worsened and high-dose corticosteroids were initiated due to suspected pneumonitis. After improvement and SARS-CoV-2 clearance, anti-cancer treatment was resumed without pembrolizumab. Immunological analyses with comparison to otherwise healthy SARS-CoV-2-infected ambulatory patients revealed a strong humoral immune response with higher levels of SARS-CoV-2-reactive IgG and neutralizing serum activity. Additionally, sustained increase of Tfh as well as activated CD4+ and CD8+ T cells was observed. Sequential CT scans showed regression of tumor lesions and marked improvement of the pulmonary situation, with no signs of pneumonitis after pembrolizumab re-challenge as maintenance. At the latest follow-up, the patient is ambulatory and in ongoing partial remission on pembrolizumab. In conclusion, anti-PD1 initiation during active COVID-19 pneumonia was feasible and cellular and humoral immune responses to SARS-CoV-2 appeared enhanced in our hospitalized patient. However, distinguishing COVID-19-associated changes from anti-PD1-associated immune-related pneumonitis posed a considerable clinical, radiographic, and immunologic challenge.

Feasibility, safety, and acceptability of a remotely monitored exercise pilot CHAMP: A Clinical trial of High-intensity Aerobic and resistance exercise for Metastatic castrate-resistant Prostate cancer.

BACKGROUND: Exercise may improve clinical and quality of life outcomes for men with prostate cancer. No randomized controlled trials (RCTs) have examined the feasibility, safety, and acceptability of remote exercise training in men with metastatic castrate-resistant prostate cancer (mCRPC). METHODS: We conducted a pilot RCT (1:1:1 aerobic or resistance exercise 3x/week or usual care) to determine the feasibility, safety, and acceptability of remotely monitored exercise over 12 weeks in 25 men with mCRPC. A prescribed exercise program was based on baseline testing including high- and moderate-intensity aerobic exercise or resistance exercise completed at a local exercise facility. Feasibility was based on attendance, adherence, and tolerance; safety on adverse events; and acceptability on participant interviews. RESULTS: Between March 2016 and March 2020, 25 patients were randomized (8 aerobic, 7 resistance, and 10 control). Twenty-three men (82%) completed the 12-week study. Men who completed the remote intervention attempted 90% and 96% of prescribed aerobic and resistance training sessions, respectively, and 86% and 88% of attempted sessions were completed as or more than prescribed. We observed changes in performance tests that corresponded with the exercise prescription. No safety concerns were identified. Ninety percent of participants interviewed were satisfied with the program and would recommend it to others. CONCLUSIONS: Remotely monitored exercise training is feasible, safe, and acceptable in men with mCRPC; there was no difference in these outcomes by mode of exercise. Through this research, we provide direction and rationale for future studies of exercise and clinical outcomes in patients with metastatic prostate cancer.

Neutrophil Extracellular Traps in Colorectal Cancer Progression and Metastasis.

Neutrophils form sticky web-like structures known as neutrophil extracellular traps (NETs) as part of innate immune response. NETs are decondensed extracellular chromatin filaments comprising nuclear and cytoplasmic proteins. NETs have been implicated in many gastrointestinal diseases including colorectal cancer (CRC). However, the regulatory mechanisms of NET formation and potential pharmacological inhibitors in the context of CRC have not been thoroughly discussed. In this review, we intend to highlight roles of NETs in CRC progression and metastasis as well as the potential of targeting NETs during colon cancer therapy.

Pembrolizumab-induced cytokine release syndrome in a patient with metastatic lung adenocarcinoma: a case report.

Cytokine release syndrome (CRS) is a well-described immune-related adverse event following chimeric antigen receptor T-cell therapy, but has rarely been reported following anti-programmed death ligand-1 therapy. We report the case of a 55-year-old man with metastatic lung adenocarcinoma who presented with fever, chills and hypotension. Initial labs were notable for highly elevated serum ferritin levels and mildly elevated triglyceride levels. He was ultimately diagnosed with pembrolizumab-induced CRS complicated by multiorgan failure. The patient was treated with steroids and tocilizumab with normalization of inflammatory markers and resolution of renal failure. This case not only highlights the importance of considering CRS in patients who have developed multiorgan failure after immune checkpoint inhibitor therapy, but also demonstrates clinical similarities between CRS and other hyperinflammatory states such as hemophagocytic lymphohistiocytosis.

Eicosanoid regulation of debris-stimulated metastasis.

Cancer therapy reduces tumor burden via tumor cell death ("debris"), which can accelerate tumor progression via the failure of inflammation resolution. Thus, there is an urgent need to develop treatment modalities that stimulate the clearance or resolution of inflammation-associated debris. Here, we demonstrate that chemotherapy-generated debris stimulates metastasis by up-regulating soluble epoxide hydrolase (sEH) and the prostaglandin E2 receptor 4 (EP4). Therapy-induced tumor cell debris triggers a storm of proinflammatory and proangiogenic eicosanoid-driven cytokines. Thus, targeting a single eicosanoid or cytokine is unlikely to prevent chemotherapy-induced metastasis. Pharmacological abrogation of both sEH and EP4 eicosanoid pathways prevents hepato-pancreatic tumor growth and liver metastasis by promoting macrophage phagocytosis of debris and counterregulating a protumorigenic eicosanoid and cytokine storm. Therefore, stimulating the clearance of tumor cell debris via combined sEH and EP4 inhibition is an approach to prevent debris-stimulated metastasis and tumor growth.

Knowledge and Attitudes Regarding Surgical Castration in Men Receiving Androgen Deprivation Therapy for Metastatic Prostate Cancer and Their Relationship to Health-Related Quality of Life.

OBJECTIVE: To determine the attitudes and education regarding surgical castration in men receiving androgen deprivation therapy (ADT) for metastatic prostate cancer (mCaP). METHODS: We identified 142 patients receiving ADT for mCaP at our institution without prior orchiectomy who were then sent 2 surveys via mail: (1) A questionnaire to assess knowledge and understanding of ADT treatment alternatives and (2) the functional assessment of cancer therapy - prostate (FACT-P) questionnaire which determines health-related quality of life (HRQOL). Two cohorts were created based on the answer to "would you be interested in surgical orchiectomy?" and demographic, CaP and HRQOL were compared between the surgical castration yes (SC+) and surgical castration no (SC-) cohorts. A second analysis identified predictors of worse HRQOL. RESULTS: Of 68 (47.9%) patients that responded to the survey, only 39 (59.1%) recalled a discussion regarding treatment alternatives to ADT and only 22 (33.3%) recalled a discussion regarding orchiectomy. There were 24 (40.0%) patients that stated interest in undergoing orchiectomy (SC+) as an alternative to ADT with the only independent risk factor being "…bother from the number of clinical appointments required for ADT…" Patients most bothered by side effects and cosmetic changes associated with ADT reported lower HRQOL scores on the FACT-P. CONCLUSIONS: Few men on ADT knew about surgical alternatives, implying that educational deficits may be a significant factor in the decline in the utilization of orchiectomy. Changes in healthcare economics, utilization and delivery brought on by a global pandemic should warrant a fresh look at the use of surgical castration.

Twelfth Annual ENBDC Workshop: Methods in Mammary Gland Biology and Breast Cancer.

The twelfth annual workshop of the European Network for Breast Development and Cancer focused on methods in mammary gland biology and breast cancer, was scheduled to take place on March 26-28, 2020, in Weggis, Switzerland. Due to the COVID-19 pandemic, the meeting was rescheduled twice and eventually happened as a virtual meeting on April 22 and 23, 2021. The main topics of the meeting were branching and development of the mammary gland, tumor microenvironment, circulating tumor cells, tumor dormancy and breast cancer metastasis. Novel and unpublished findings related to these topics were presented, with a particular focus on the methods used to obtain them. Virtual poster sessions were a success, with many constructive and fruitful interactions between researchers and covered many areas of mammary gland biology and breast cancer.

Safety, Efficacy, and Patterns of Failure After Single-Fraction Stereotactic Body Radiation Therapy (SBRT) for Oligometastases.

PURPOSE: Fewer attendances for radiation therapy results in increased efficiency and less foot traffic within a radiation therapy department. We investigated outcomes after single-fraction (SF) stereotactic body radiation therapy (SBRT) in patients with oligometastatic disease. METHODS AND MATERIALS: Between February 2010 and June 2019, patients who received SF SBRT to 1 to 5 sites of oligometastatic disease were included in this retrospective study. The primary objective was to describe patterns of first failure after SBRT. Secondary objectives included overall survival (OS), progression-free survival (PFS), high-grade treatment-related toxicity (Common Terminology Criteria for Adverse Events grade ≥3), and freedom from systemic therapy (FFST). RESULTS: In total, 371 patients with 494 extracranial oligometastases received SF SBRT ranging from 16 Gy to 28 Gy. The most common primary malignancies were prostate (n = 107), lung (n = 63), kidney (n = 52), gastrointestinal (n = 51), and breast cancers (n = 42). The median follow-up was 3.1 years. The 1-, 3-, and 5-year OS was 93%, 69%, and 55%, respectively; PFS was 48%, 19%, and 14%, respectively; and FFST was 70%, 43%, and 35%, respectively. Twelve patients (3%) developed grade 3 to 4 treatment-related toxicity, with no grade 5 toxicity. As the first site of failure, the cumulative incidence of local failure (irrespective of other failures) at 1, 3 and 5 years was 4%, 8%, and 8%, respectively; locoregional relapse at the primary was 10%, 18%, and 18%, respectively; and distant failure was 45%, 66%, and 70%, respectively. CONCLUSIONS: SF SBRT is safe and effective, and a significant proportion of patients remain FFST for several years after therapy. This approach could be considered in resource-constrained or bundled-payment environments. Locoregional failure of the primary site is the second most common pattern of failure, suggesting a role for optimization of primary control during metastasis-directed therapy.

PET/CT Variants and Pitfalls in Breast Cancers.

There are a number of normal variants and pitfalls which are important to consider when evaluating F-18 Fluorodeoxyglucose (FDG) with Positron Emission Tomography (PET) in breast cancer patients. Although FDG-PET is not indicated for the initial diagnosis of breast cancer, focally increased glucose metabolism within breast tissue represents a high likelihood for a neoplastic process and requires further evaluation. Focally increased glucose metabolism is not unique to breast cancer. Other malignancies such as lymphoma, metastases from solid tumors as well as inflammatory changes also may demonstrate increased glucose metabolism either within the breast or at other sites throughout the body. Importantly, benign breast disease may also exhibit increased glucose metabolism, limiting the specificity of FDG-PET. Breast cancer has a wide range of metabolic activity attributed to tumor heterogeneity and breast cancer subtype. Intracellular signaling pathways regulating tumor glucose utilization contribute to these pitfalls of PET/CT in breast cancer. The evaluation of axillary lymph nodes by FDG-PET is less accurate than sentinel lymph node procedure, however is very accurate in identifying level II and III axillary lymph node metastases or retropectoral metastases. It is important to note that non-malignant inflammation in lymph nodes are often detected by modern PET/CT technology. Therefore, particular consideration should be given to recent vaccinations, particularly to COVID-19, which can commonly result in increased metabolic activity of axillary nodes. Whole body FDG-PET for staging of breast cancer requires specific attention to physiologic variants of FDG distribution and a careful comparison with co-registered anatomical imaging. The most important pitfalls are related to inflammatory changes including sarcoidosis, sarcoid like reactions, and other granulomatous diseases as well as secondary neoplastic processes.