Tumorigenic circulating tumor cells from xenograft mouse models of non-metastatic NSCLC patients reveal distinct single cell heterogeneity and drug responses.

BACKGROUND: Circulating tumor cells (CTCs) are liquid biopsies that represent micrometastatic disease and may offer unique insights into future recurrences in non-small cell lung cancer (NSCLC). Due to CTC rarity and limited stability, no stable CTC-derived xenograft (CDX) models have ever been generated from non-metastatic NSCLC patients directly. Alternative strategies are needed to molecularly characterize CTCs and means of potential future metastases in this potentially curable patient group. METHODS: Surgically resected NSCLC primary tumor tissues from non-metastatic patients were implanted subcutaneously in immunodeficient mice to establish primary tumor patient-derived xenograft (ptPDX) models. CTCs were isolated as liquid biopsies from the blood of ptPDX mice and re-implanted subcutaneously into naïve immunodeficient mice to generate liquid biopsy CTC-derived xenograft (CDX) tumor models. Single cell RNA sequencing was performed and validated in an external dataset of non-xenografted human NSCLC primary tumor and metastases tissues. Drug response testing in CDX models was performed with standard of care chemotherapy (carboplatin/paclitaxel). Blockade of MYC, which has a known role in drug resistance, was performed with a MYC/MAX dimerization inhibitor (10058-F4). RESULTS: Out of ten ptPDX, two (20%) stable liquid biopsy CDX mouse models were generated. Single cell RNA sequencing analysis revealed an additional regenerative alveolar epithelial type II (AT2)-like cell population in CDX tumors that was also identified in non-xenografted NSCLC patients' metastases tissues. Drug testing using these CDX models revealed different treatment responses to carboplatin/paclitaxel. MYC target genes and c-MYC protein were upregulated in the chemoresistant CDX model, while MYC/MAX dimerization blocking could overcome chemoresistance to carboplatin/paclitaxel. CONCLUSIONS: To overcome the lack of liquid biopsy CDX models from non-metastatic NSCLC patients, CDX models can be generated with CTCs from ptPDX models that were originally established from patients' primary tumors. Single cell analyses can identify distinct drug responses and cell heterogeneities in CDX tumors that can be validated in NSCLC metastases tissues. CDX models deserve further development and study to discover personalized strategies against micrometastases in non-metastatic NSCLC patients.

Lung transplantation in patients with lung disease secondary to coronavirus disease 2019 infection.

PURPOSE OF REVIEW: In this article, we describe preoperative patient selection and outcomes of patients with lung disease secondary to infection from COVID-19 who receive lung transplantation. RECENT FINDINGS: Lung transplants for patients with lung disease secondary to infection from COVID-19 have been performed successfully in over 200 patients in the United States. The preoperative course of these patients is somewhat atypical in comparison with patients who have had lung transplants related to chronic lung diseases, where there are more traditional indications for lung transplants. COVID-19 patients have more severe pulmonary disease often requiring mechanical ventilation and extracorporeal mechanical ventilation (ECMO), frequent nosocomial infections, and renal and cardiac dysfunction. The intraoperative course of these COVID-19 patients is often longer and requires increased transfusions of blood products in comparison with non-COVID-19 patients. Additionally, in the postoperative period, COVID-19 patients more frequently require mechanical ventilation and ECMO support. However, the survival rate of such patients at 6 months is greater than 90%. SUMMARY: Patients with respiratory failure secondary to COVID-19 infection that require a lung transplant generally have a complicated preoperative course and the operations are more complex, but the long-term outcomes are excellent.

Tumor-Cell-Macrophage Fusion Cells as Liquid Biomarkers and Tumor Enhancers in Cancer.

Although molecular mechanisms driving tumor progression have been extensively studied, the biological nature of the various populations of circulating tumor cells (CTCs) within the blood is still not well understood. Tumor cell fusion with immune cells is a longstanding hypothesis that has caught more attention in recent times. Specifically, fusion of tumor cells with macrophages might lead to the development of metastasis by acquiring features such as genetic and epigenetic heterogeneity, chemotherapeutic resistance, and immune tolerance. In addition to the traditional FDA-approved definition of a CTC (CD45-, EpCAM+, cytokeratins 8+, 18+ or 19+, with a DAPI+ nucleus), an additional circulating cell population has been identified as being potential fusions cells, characterized by distinct, large, polymorphonuclear cancer-associated cells with a dual epithelial and macrophage/myeloid phenotype. Artificial fusion of tumor cells with macrophages leads to migratory, invasive, and metastatic phenotypes. Further studies might investigate whether these have a potential impact on the immune response towards the cancer. In this review, the background, evidence, and potential relevance of tumor cell fusions with macrophages is discussed, along with the potential role of intercellular connections in their formation. Such fusion cells could be a key component in cancer metastasis, and therefore, evolve as a diagnostic and therapeutic target in cancer precision medicine.

Nanoliposome C6-Ceramide Increases the Anti-tumor Immune Response and Slows Growth of Liver Tumors in Mice.

BACKGROUND & AIMS: Ceramide, a sphingolipid metabolite, affects T-cell signaling, induces apoptosis of cancer cells, and slows tumor growth in mice. However, it has not been used as a chemotherapeutic agent because of its cell impermeability and precipitation in aqueous solution. We developed a nanoliposome-loaded C6-ceremide (LipC6) to overcome this limitation and investigated its effects in mice with liver tumors. METHODS: Immune competent C57BL/6 mice received intraperitoneal injections of carbon tetrachloride and intra-splenic injections of oncogenic hepatocytes. As a result, tumors resembling human hepatocellular carcinomas developed in a fibrotic liver setting. After tumors formed, mice were given an injection of LipC6 or vehicle via tail vein every other day for 2 weeks. This was followed by administration, also via tail vein, of tumor antigen-specific (TAS) CD8+ T cells isolated from the spleens of line 416 mice, and subsequent immunization by intraperitoneal injection of tumor antigen-expressing B6/WT-19 cells. Tumor growth was monitored with magnetic resonance imaging. Tumor apoptosis, proliferation, and AKT expression were analyzed using immunohistochemistry and immunoblots. Cytokine production, phenotype, and function of TAS CD8+ T cells and tumor-associated macrophages (TAMs) were studied with flow cytometry, real-time polymerase chain reaction (PCR), and ELISA. Reactive oxygen species (ROS) in TAMs and bone marrow-derived macrophages, induced by colony stimulating factor 2 (GMCSF or CSF2) or colony stimulating factor 1 (MCSF or CSF1), were detected using a luminescent assay. RESULTS: Injection of LipC6 slowed tumor growth by reducing tumor cell proliferation and phosphorylation of AKT, and increasing tumor cell apoptosis, compared with vehicle. Tumors grew more slowly in mice given the combination of LipC6 injection and TAS CD8+ T cells followed by immunization compared with mice given vehicle, LipC6, the T cells, or immunization alone. LipC6 injection also reduced numbers of TAMs and their production of ROS. LipC6 induced TAMs to differentiate into an M1 phenotype, which reduced immune suppression and increased activity of CD8+ T cells. These results were validated by experiments with bone marrow-derived macrophages induced by GMCSF or MCSF. CONCLUSIONS: In mice with liver tumors, injection of LipC6 reduces the number of TAMs and the ability of TAMs to suppress the anti-tumor immune response. LipC6 also increases the anti-tumor effects of TAS CD8+ T cells. LipC6 might therefore increase the efficacy of immune therapy in patients with hepatocellular carcinoma.

Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model.

BACKGROUND & AIMS: We have established a clinically relevant animal model of hepatocellular cancer (HCC) in immune competent mice to elucidate the complex dialog between host immunity and tumors during HCC initiation and progression. Mechanistic findings have been leveraged to develop a clinically feasible anti-tumor chemoimmunotherapeutic strategy. METHODS: Intraperitoneal injection of carbon tetrachloride and intrasplenic inoculation of oncogenic hepatocytes were combined to induce progressive HCCs in fibrotic livers of immunocompetent mice. Immunization and adoptive cell transfer (ACT) were used to dissect the tumor antigen-specific immune response. The ability of the tyrosine kinase inhibitor sunitinib to enhance immunotherapy in the setting of HCC was evaluated. RESULTS: This new mouse model mimics human HCC and reflects its typical features. Tumor-antigen-specific CD8+ T cells maintained a naïve phenotype and remained responsive during early-stage tumor progression. Late tumor progression produced circulating tumor cells, tumor migration into draining lymph nodes, and profound exhaustion of tumor-antigen-specific CD8+ T cells associated with accumulation of programmed cell death protein 1 (PD-1)hi CD8+ T cells and regulatory T cells (Tregs). Sunitinib-mediated tumoricidal effect and Treg suppression synergized with antibody-mediated blockade of PD-1 to powerfully suppress tumor growth and activate anti-tumor immunity. CONCLUSION: Treg accumulation and upregulation of PD-1 provide two independent mechanisms to induce profound immune tolerance in HCC. Chemoimmunotherapy using Food and Drug Administration-approved sunitinib with anti-PD-1 antibodies achieved significant tumor control, supporting translation of this approach for the treatment of HCC patients. LAY SUMMARY: In the current study, we have established a clinically relevant mouse model which mimics human liver cancer. Using this unique model, we studied the response of the immune system to this aggressive cancer. Findings from this trial have led to the development of an innovative and clinically feasible chemoimmunotherapeutic strategy.

Emphysematous gastritis and gastric emphysema: similar radiographic findings, distinct clinical entities.

INTRODUCTION: Despite similar appearances on imaging studies, emphysematous gastritis (EG) and gastric emphysema (GE) are rare clinical entities encountered in surgical practices. The purpose of this review is to clarify the presentation, natural history, and optimal treatment strategies for these two disorders. METHODS: We conducted a comprehensive literature review for reported adult cases of EG and GE in MEDLINE. Two cases from our institution were also included. Patient with demographics, diagnostic and therapeutic data, and outcomes were compared between patients with EG and GE. RESULTS: A total of 75 cases were included for our review. The finding of intramural air in the stomach was often associated with portal vein gas, pneumatosis intestinalis, or pneumoperitoneum in both groups. Surgical removal of the stomach was performed in 23.1% of EG patients, but only one patient in the GE group. In the EG group, overall mortality (55%) appeared to be driven by sepsis and its complications, whereas in the GE group, mortality (29%) was attributable to comorbid conditions and the underlying illness. CONCLUSIONS: Prompt surgical intervention is more commonly indicated for severe EG and is directed at removal of the septic organ, while the primary indication for surgical intervention in GE is the uncertainty of the diagnosis.

Pleural space infections after image-guided percutaneous drainage of infected intraabdominal fluid collections: a retrospective single institution analysis.

BACKGROUND: Percutaneous drainage of infected intraabdominal fluid collections is preferred over surgical drainage due to lower morbidity and costs. However, it can be a challenging procedure and catheter insertion carries the potential to contaminate the pleural space from the abdomen. This retrospective analysis demonstrates the clinical and radiographic correlation between percutaneous drainage of infected intraabdominal collections and the development of iatrogenic pleural space infections. METHODS: A retrospective single institution analysis of 550 consecutive percutaneous drainage procedures for intraabdominal fluid collections was performed over 24 months. Patient charts and imaging were reviewed with regard to pleural space infections that were attributed to percutaneous drain placements. Institutional review board approval was obtained for conduct of the study. RESULTS: 6/550 (1.1%) patients developed iatrogenic pleural space infections after percutaneous drainage of intraabdominal fluid collections. All 6 patients presented with respiratory symptoms and required pleural space drainage (either by needle aspiration or chest tube placement), 2 received intrapleural fibrinolytic therapy and 1 patient had to undergo surgical drainage. Pleural effusion cultures revealed same bacteria in both intraabdominal and pleural fluid in 3 (50%) cases. A video with a dynamic radiographic sequence demonstrating the contamination of the pleural space from percutaneous drainage of an infected intraabdominal collection is included. CONCLUSIONS: Iatrogenic pleural space infections after percutaneous drainage of intraabdominal fluid collections occur at a low incidence, but the pleural empyema can be progressive requiring prompt chest tube drainage, intrapleural fibrinolytic therapy or even surgery. Expertise in intraabdominal drain placements, awareness and early recognition of this complication is critical to minimize incidence, morbidity and mortality in these patients.

Regression of established hepatocellular carcinoma is induced by chemoimmunotherapy in an orthotopic murine model.

UNLABELLED: The high rate of mortality and frequent incidence of recurrence associated with hepatocellular carcinoma (HCC) reveal the need for new therapeutic approaches. In this study we evaluated the efficacy of a novel chemoimmunotherapeutic strategy to control HCC and investigated the underlying mechanism that increased the antitumor immune response. We developed a novel orthotopic mouse model of HCC through seeding of tumorigenic hepatocytes from SV40 T antigen (Tag) transgenic MTD2 mice into the livers of syngeneic C57BL/6 mice. These MTD2-derived hepatocytes form Tag-expressing HCC tumors specifically within the liver. This approach provides a platform to test therapeutic strategies and antigen-specific immune-directed therapy in an immunocompetent murine model. Using this model we tested the efficacy of a combination of oral sunitinib, a small molecule multitargeted receptor tyrosine kinase (RTK) inhibitor, and adoptive transfer of tumor antigen-specific CD8(+) T cells to eliminate HCC. Sunitinib treatment alone promoted a transient reduction in tumor size. Sunitinib treatment combined with adoptive transfer of tumor antigen-specific CD8(+) T cells led to elimination of established tumors without recurrence. In vitro studies revealed that HCC growth was inhibited through suppression of STAT3 signaling. In addition, sunitinib treatment of tumor-bearing mice was associated with suppression of STAT3 and a block in T-cell tolerance. CONCLUSION: These findings indicate that sunitinib inhibits HCC tumor growth directly through the STAT3 pathway and prevents tumor antigen-specific CD8(+) T-cell tolerance, thus defining a synergistic chemoimmunotherapeutic approach for HCC.

Lung Transplantation for Coronavirus Disease-2019 Patients and Coronavirus Disease-2019 in Lung Transplant Recipients.

Lung transplant is a life-saving treatment for carefully selected patients with respiratory failure related to the infection with coronavirus disease-2019. Despite a complex pretransplant medical course, the posttransplant outcomes are excellent when performed by experienced centers.

Association of travel distance, surgical volume, and receipt of adjuvant chemotherapy with survival among patients with resectable lung cancer.

Objective: Regionalization of surgery for non-small cell lung cancer (NSCLC) to high-volume centers (HVCs) improves perioperative outcomes but frequently increases patient travel distance. Travel might decrease rates of adjuvant chemotherapy (AC) use, however, the relationship of distance, volume, and receipt of AC with outcomes is unknown. Our objective was to evaluate the association of distance, volume, and receipt of AC with overall survival among patients with NSCLC. Methods: Patients with stage I to IIIA (N0-N1) NSCLC were identified between 2004 and 2018 using the National Cancer Database. Distance to surgical facility was categorized into quartiles (<5.1, 5.1 to <11.5, 11.5 to <28.1, and ≥28.1 miles), and HVCs were defined as those that perform ≥40 annual resections. Patient characteristics and likelihood of receiving AC anywhere were determined. Propensity score-matched survival analysis was performed using Cox models and Kaplan-Meier curves. Results: Of the 131,982 patients included, 35,658 (27.0%) were stage II to IIIA. Of the stage II to IIIA cohort, 49.6% received AC, 13.1% traveled <5.1 miles to low-volume centers (LVCs), and 18.1% traveled ≥28.1 miles to HVCs (P < .001). Among stage II to IIIA patients who traveled ≥28.1 miles to HVCs, 45% received AC versus 51.5% who traveled <5.1 miles to LVCs (incidence rate ratio, 0.88; 95% CI, 0.83-0.94; <5.1 miles to LVC reference). Patients with stage II to IIIA NSCLC who traveled ≥28.1 miles to HVCs and did not receive AC had higher mortality rates than those who traveled <5.1 miles to LVCs and received AC (median overall survival, 52.3 vs 36.7 months; adjusted hazard ratio, 1.41; 95% CI, 1.26-1.57). Conclusions: Increasing travel distance to surgical treatment is associated with decreased likelihood of receiving AC for patients with stage II to IIIA (N0-N1) NSCLC.

Nanoliposomal ceramide prevents in vivo growth of hepatocellular carcinoma.

BACKGROUND AND OBJECTIVES: Hepatocellular carcinoma (HCC) affects an increasing number of people worldwide. The poor survival rate of patients with HCC is manifested by an aggressive and metastatic phenotype, as well as a poor response to common therapeutic strategies. The purpose of this study was to evaluate the efficacy of nanoliposomal C6-ceramide as an antineoplastic agent in an in vivo model of human HCC. METHODS: The growth-arresting and pro-apoptotic properties of nanoliposomal C6-ceramide were first evaluated in vitro in human SK-HEP-1 cells by assessing cellular viability, caspase 3/7 activity, annexin-V expression, DNA fragmentation, cell cycle distribution and AKT phosphorylation. SK-HEP-1 cells were then engrafted subcutaneously into athymic nude mice and nanoliposomal C6-ceramide was administered by tail vein injection. Tumour size was monitored over time, followed by excision of tumours to evaluate tumour vascularisation, proliferation, apoptosis and cellular signalling. RESULTS: Nanoliposomal C6-ceramide, but not ghost (no ceramide) nanoliposomes, induced apoptotic cell death of SK-HEP-1 cells in vitro, concomitant with an accumulation of cells in the G2 phase of the cell cycle and decreased phosphorylation of AKT. Systemic administration of nanoliposomal C6-ceramide to mice engrafted with SK-HEP-1 tumours reduced tumour vascularisation and proliferation, induced tumour cell apoptosis, decreased phosphorylation of AKT and ultimately blocked tumour growth. CONCLUSIONS: These studies show that nanoliposomal ceramide is an efficacious antineoplastic agent for the treatment of in vitro and in vivo models of human HCC.

Somatic mutation variant analysis in rural, resectable non-small cell lung carcinoma patients.

Rural non-small cell lung cancer (NSCLC) patients do worse, largely related to lack of access to care. In this study, the mutational characteristics and potential for targeted therapy in rural, resectable NSCLC patients using whole exome sequencing (WES) were analyzed. WES was performed on tumor-adjacent normal pairs from rural patients undergoing resection for NSCLC. Sequencing alignment, variant-calling, annotation, and tumor mutational burden (TMB) calculations were performed using standard methods. cBioportal and OncoKB were used for comparisons of mutational frequencies and actionable targets. Thirty-four NSCLC patients underwent WES after surgical resection. The gene most frequently containing somatic variants was TP53. The median number of somatic variants was 188 (Range 11-1056), and median TMB was 3.30 (0.33-18.56) nonsynonymous mutations per Mb. Tumor stage and survival were not associated with number of variants, TMB or TP53 mutational status. Significant concordance among the most common mutations when cross-referenced to cBioportal (R = 0.78, p < 0.0001) was observed. 24% of patients had variants in actionable genes based on OncoKB annotation. In summary, we demonstrate baseline mutational frequency and establish foundations for targeted adjuvant trials in rural NSCLC patients with specific differences. Future studies must ensure to include rural patients to improve NSCLC patient outcomes.

Benign Tracheoenteric Fistula to a Zenker's Diverticulum With Complete Esophageal Obstruction.

A fistula between a Zenker's diverticulum and the trachea has only been reported once, in 1983. Here, we report a case of a fistula between a large Zenker's diverticulum and the trachea with complete occlusion of the esophagus. The fistula was repaired, first by an esophageal myotomy, followed by proximal resection of the diverticulum, completion of the esophageal myotomy, transection of the fistula, and repair of the trachea. The surgical repair provided complete resolution of symptoms without complications.

Computerized tomography-Guided Microwave Ablation of Patients with Stage I Non-small Cell Lung Cancers: A Single-Institution Retrospective Study.

OBJECTIVES: The objective of the study was to retrospectively investigate the safety and efficacy of computerized tomography-guided microwave ablation (MWA) in the treatment of Stage I non-small cell lung cancers (NSCLCs). MATERIAL AND METHODS: This retrospective, single-center study evaluated 21 patients (10 males and 11 females; mean age 73.8 ± 8.2 years) with Stage I peripheral NSCLCs treated with MWA between 2010 and 2020. All patients were surveyed for metastatic disease. Clinical success was defined as absence of FDG avidity on follow-up imaging. Tumor growth within 5 mm of the original ablated territory was defined as local recurrence. Welch t-test and Fisher's exact test were used for univariate analysis. Hazard ratio (HR) and odds ratio (OR) were determined using Cox regression and Firth logistic regression. Significance was P < 0.05. Data are expressed as mean ± standard deviation. RESULTS: Ablated tumors had longest dimension 17.4 ± 5.4 mm and depth 19.7 ± 15.1 mm from the pleural surface. Median follow-up was 20 months (range, 0.6-56 months). Mean overall survival (OS) following lung cancer diagnosis or MWA was 26.2 ± 15.4 months (range, 5-56 months) and 23.7 ± 15.1 months (range, 3-55 months). OS at 1, 2, and 5 years was 67.6%, 61.8%, and 45.7%, respectively. Progression-free survival (PFS) was 19.1 ± 16.2 months (range, 1-55 months). PFS at 1, 2, and 5 years was 44.5%, 32.9%, and 32.9%, respectively. Technical success was 100%, while clinical success was observed in 95.2% (20/21) of patients. One patient had local residual disease following MWA and was treated with chemotherapy. Local control was 90% with recurrence in two patients following ablation. Six patients (28.6%) experienced post-ablation complications, with pneumothorax being the most common event (23.8% of patients). Female gender was associated with 90% reduction in risk of death (HR 0.1, P = 0.014). Tumor longest dimension was associated with a 10% increase in risk of death (P = 0.197). Several comorbidities were associated with increased hazard. Univariate analysis revealed pre-ablation forced vital capacity trended higher among survivors (84.7 ± 15.2% vs. 73 ± 21.6%, P = 0.093). Adjusted for age and sex, adenocarcinoma, and neuroendocrine histology trended toward improved OS (OR: 0.13, 0.13) and PFS (OR: 0.88, 0.37) compared to squamous cell carcinoma. CONCLUSION: MWA provides a safe and effective alternative to stereotactic brachytherapy resulting in promising OS and PFS in patients with Stage I peripheral NSCLC. Larger sample sizes are needed to further define the effects of underlying comorbidities and tumor biology.

LMO7 as an Unrecognized Factor Promoting Pancreatic Cancer Progression and Metastasis.

Pancreatic cancer (PC) is one of the most lethal human malignancies without effective treatment. In an effort to discover key genes and molecular pathways underlying PC growth, we have identified LIM domain only 7 (LMO7) as an under-investigated molecule, which highly expresses in primary and metastatic human and mouse PC with the potential of impacting PC tumorigenesis and metastasis. Using genetic methods with siRNA, shRNA, and CRISPR-Cas9, we have successfully generated stable mouse PC cells with LMO7 knockdown or knockout. Using these cells with loss of LMO7 function, we have demonstrated that intrinsic LMO7 defect significantly suppresses PC cell proliferation, anchorage-free colony formation, and mobility in vitro and slows orthotopic PC tumor growth and metastasis in vivo. Mechanistic studies demonstrated that loss of LMO7 function causes PC cell-cycle arrest and apoptosis. These data indicate that LMO7 functions as an independent and unrecognized druggable factor significantly impacting PC growth and metastasis, which could be harnessed for developing a new targeted therapy for PC.

The opioid growth factor-opioid growth factor receptor axis regulates cell proliferation of human hepatocellular cancer.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide, with a mortality rate approximating its incidence. Understanding the biology of these tumors, as well as treatment modalities, has been challenging. The opioid growth factor (OGF; [Met(5)]-enkephalin) and the OGF receptor (OGFr) form an endogenous growth-regulating pathway in homeostasis and neoplasia. In this investigation, we examined the relationship of the OGF-OGFr axis in HCC and define its presence, function, and mechanism. Using SK-HEP-1, Hep G2, and Hep 3B human HCC cell lines, we found that OGF and OGFr were present and functional. Exogenous OGF was observed to have a dose-dependent, reversible, and receptor-mediated inhibitory action on cell proliferation. Endogenous OGF was found to be constitutively produced and tonically active on cell replicative activities, with neutralization of this peptide accelerating cell proliferation. Silencing of OGFr using siRNA stimulated cell replication, even when exogenous OGF was added to the cultures, documenting its importance in mediating OGF activity. The mechanism of OGF-OGFr action on cell number was related to inhibition of DNA synthesis and not to apoptotic or necrotic pathways. Both OGF and OGFr were detected in surgical specimens of HCC, and no quantitative differences were recorded in peptide or receptor between pathological and normal specimens. These data are the first to report that the OGF-OGFr system is a native biological regulator of cell proliferation in HCC. The findings may provide important insight in designing treatment strategies for this deadly disease.

CT-guided cryoablation for post-thoracotomy pain syndrome: a retrospective analysis.

PURPOSE Post-thoracotomy pain syndrome is a common condition affecting up to 50% of post-thoracotomy patients. However, percutaneous computed tomography (CT)-guided intercostal nerve cryoablation may provide symptomatic benefit in chronic and/or refractory cases. METHODS A retrospective review of our institution's comprehensive case log from October 2017 to September 2018 for patients who underwent cryoablation was analyzed. Thirteen patients with post-thoracotomy pain syndrome, refractory to medical management, were treated with CT-guided intercostal nerve cryoablation. Most patients had treatment of the intercostal nerve at the level of their thoracotomy scar, two levels above and below. The safety and technical success of this technique and the clinical outcomes of the study population were then retrospectively reviewed. RESULTS Of the patients, 69% experienced significant improvement in their pain symptoms with a median pain improvement score of 3 points (range, -1 to 8 points) over a median follow-up of 11 months (range, 2-18.6 months). Complications included pneumothorax in 8% and pseudohernia in 23% of patients. CONCLUSION CT-guided intercostal nerve cryoablation may be an effective technique in the treatment of post-thoracotomy pain syndrome and requires further study.

18F-FDG PET/CT total lesion glycolysis is associated with circulating tumor cell counts in patients with stage I to IIIA non-small cell lung cancer.

BACKGROUND: In non-small cell lung cancer (NSCLC), 18F-fluoro-2-deoxy-D-glucose (18F-FDG) uptake determined by PET and presence of circulating tumor cells (CTCs) in the peripheral blood independently predict outcomes. For 18F-FDG PET/CT staging interpretation, standardized uptake values (SUVmax/avg) are routinely used in clinical reporting. The goal was to investigate whether 18F-FDG uptake measured by SUVmax/avg, but also measures of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) (MTV × SUVavg), are associated with CTCs. METHODS: Prospectively, 7.5 mL blood was drawn from NSCLC patients at the time of staging 18F-FDG PET/CT and from healthy control subjects. CTCs were identified by immunofluorescent staining (CK8/18/19pos/EpCAMpos/CD45neg/DAPIpos nucleus). 18F-FDG PET/CTs were analyzed for SUVmax, SUVavg, MTV, and TLG. RESULTS: In 16 NSCLC patients with stage I-IIIA, MTV and TLG, in contrast to SUVmax and SUVavg, were positively associated with CTCs (linear regression analysis). No CTCs were detectable in 20 healthy control subjects. CONCLUSIONS: This pilot study demonstrates that 18F-FDG PET/CT TLG correlates with CTCs in NSCLC patients without distant metastases. TLG might be a more appropriate marker for hematogenous micrometastatic potential than SUVs.

Synergizing sunitinib and radiofrequency ablation to treat hepatocellular cancer by triggering the antitumor immune response.

BACKGROUND: Minimally invasive radiofrequency ablation (RFA) is used as a first-line treatment option for hepatocellular cancer (HCC) with the weaknesses of incomplete ablation, tumor recurrence, and inferior outcomes. To overcome this limitation, we proposed to develop sunitinib-RFA integrated therapy with a potential of activating anti-HCC immune response. METHODS: Using our unique murine model, we developed a novel RFA platform with a modified human cardiac RF generator. Therapeutic efficacy of sunitinib-RFA combined treatment in HCC was tested in this platform. Tumor progression was monitored by MRI; tumor necrosis and apoptosis were detected by H&E and terminal deoxynucleotidyl transferase dUTP nick end labeling; immune reaction was defined by flow cytometry; and signaling molecules were examined with real-time PCR (qPCR), western blot, and immunohistochemical staining. RESULTS: A significantly reduced tumor growth and extended lift span were observed in the mice receiving combined treatment with RFA and sunitinib. This combined treatment significantly increased the frequency of CD8+ T cell, memory CD8+ T cell, and dendritic cells (DCs); decreased the frequency of regulatory T cells; and activated tumor-specific antigen (TSA) immune response in tumor microenvironment. We found that RFA caused PD-1 upregulation in tumor-infiltrated T cells by boosting hepatocyte growth factor (HGF) expression, which was suppressed by sunitinib treatment. We have also demonstrated that sunitinib suppressed VEGF's effect in enhancing PD-L1 expression in DCs and attenuated heat-sink effect. The results indicate that RFA induced tumor destruction and release of in situ TSAs which can activate a tumoricidal immune response in sunitinib-treated mice, significantly improving anti-HCC therapeutic efficacy. CONCLUSIONS: Sunitinib enables RFA-released in situ TSA to ignite an effective anti-tumor immune response by suppressing HGF and VEGF signaling pathways. Sunitinib-RFA as a synergistic therapeutic approach significantly suppresses HCC growth.

Circulating Giant Tumor-Macrophage Fusion Cells Are Independent Prognosticators in Patients With NSCLC.

INTRODUCTION: Various subtypes of circulating cancer-associated cells in the blood are described. A unique circulating, large, and polymorphonuclear cell with a dual epithelial and myeloid phenotype has been suggested as a tumor-macrophage fusion cell (TMF). The goal of the study was to identify the impact of distinct TMFs on survival among patients with NSCLC. METHODS: In this prospective trial, 7.5 mL of whole blood sample was collected. After microfilter enrichment, immunofluorescent staining was performed, identifying TMFs as greater than or equal to 30 µm in size and dual epithelial (cytokeratin 8, 18, or 19-, or epithelial cell adhesion molecule-positive) and myeloid- or macrophage-positive (CD14- or CD45-positive) cells with at least one 4',6-diamidino-2-phenylindole+ nucleus. RESULTS: Circulating TMFs were identified in 88 of 115 patients (76.5%) with NSCLC (mean 3.052 [SEM ± 0.306]; median 2 [range 0-17]) but were rare in long-term smokers without cancer (6 of 87 [6.9%]; 0.081 [±0.034]; 0 [0-2]), and absent in 20 healthy controls. Comparing the presence of TMFs in patients with NSCLC versus smokers without cancer, specificity was 93.1% (95% confidence interval: 85.6-97.4%) and sensitivity 76.5% (95% confidence interval: 67.7%-83.9%). TMF counts correlated with American Joint Committee on Cancer tumor stages. More importantly, more than one TMF and giant TMFs sizes greater than or equal to 50 µm were associated with statistically significantly shorter overall and cancer-specific disease-free (p < 0.05) survival after curative resection for stage I to IIIA. Giant TMFs greater than or equal to 50 µm size were an independent survival predictor by multivariate analysis. CONCLUSIONS: Circulating, in particular, giant TMFs are associated with aggressive clinical behavior in surgically treated patients with NSCLC. The biological role of unique TMFs will need to be further investigated, as these may have a potential impact on immune responses toward cancer.