Assessing the effect of body mass index on perioperative outcomes and short-term recurrence after paraesophageal hernia repair.

Previous assessments suggest that surgical results of paraesophageal hernia (PEH) repair were negatively impacted by increasing levels of obesity. A better understanding of the association of obesity on outcomes of PEH repair will support surgeons making evidence-based decisions on the surgical candidacy of individual patients. This single institution retrospective cohort study included 884 consecutive patients with giant PEH undergoing surgical repair between 1 January 2000 and 30 June 2020. Preoperative body mass index (BMI) was documented at the time of surgery. Main outcomes included perioperative blood loss, length of hospital stay, major complications, early hernia recurrence, and mortality. The mean (standard deviation [SD]) age at surgery was 68.4 (11.1), and 645 (73.0%) were women. Among the 884 patients, 875 had a documented immediate preoperative BMI and were included in the analysis. Mean (SD) BMI was 29.24 (4.91) kg/m2. Increasing BMI was not associated with increased perioperative blood loss (coefficient, 0.01; 95% confidence interval [CI], -0.01 to 0.02), prolonged length of stay (coefficient, -0.01; 95% CI, -0.02 to 0.01), increased incidence of recurrent hernia (odds ratio [OR], 1.03; 95% CI, 0.95-1.10), or increased major complications (OR, 0.93; 95% CI, 0.82-1.05). The 90-day mortality rate was 0.3%. Furthermore, when compared with the normal weight group, overweight and all levels of obesity were not related to unfavorable outcomes. No association was found between BMI and perioperative outcomes or short-term recurrence in patients undergoing PEH repair. Although preoperative weight loss is advisable, a higher BMI should not preclude or delay surgical management of giant PEH.

Delayed Surgical Intervention After Chemoradiotherapy in Esophageal Cancer: (DICE) Study.

OBJECTIVE: To determine the impact of delayed surgical intervention following chemoradiotherapy (CRT) on survival from esophageal cancer. BACKGROUND: CRT is a core component of multimodality treatment for locally advanced esophageal cancer. The timing of surgery following CRT may influence the probability of performing an oncological resection and the associated operative morbidity. METHODS: This was an international, multicenter, cohort study, including patients from 17 centers who received CRT followed by surgery between 2010 and 2020. In the main analysis, patients were divided into 4 groups based upon the interval between CRT and surgery (0-50, 51-100, 101-200, and >200 days) to assess the impact upon 90-day mortality and 5-year overall survival. Multivariable logistic and Cox regression provided hazard ratios (HRs) with 95% CIs adjusted for relevant patient, oncological, and pathologic confounding factors. RESULTS: A total of 2867 patients who underwent esophagectomy after CRT were included. After adjustment for relevant confounders, prolonged interval following CRT was associated with an increased 90-day mortality compared with 0 to 50 days (reference): 51 to 100 days (HR=1.54, 95% CI: 1.04-2.29), 101 to 200 days (HR=2.14, 95% CI: 1.37-3.35), and >200 days (HR=3.06, 95% CI: 1.64-5.69). Similarly, a poorer 5-year overall survival was also observed with prolonged interval following CRT compared with 0 to 50 days (reference): 101 to 200 days (HR=1.41, 95% CI: 1.17-1.70), and >200 days (HR=1.64, 95% CI: 1.24-2.17). CONCLUSIONS: Prolonged interval following CRT before esophagectomy is associated with increased 90-day mortality and poorer long-term survival. Further investigation is needed to understand the mechanism that underpins these adverse outcomes observed with a prolonged interval to surgery.

Impact of Early Jejunostomy Tube Feeding on Clinical Outcome and Parameters of Body Composition in Esophageal Cancer Patients Receiving Multimodal Therapy.

BACKGROUND: Malnutrition commonly affects patients with esophageal cancer and has the potential to negatively influence treatment outcomes. The aim of this study was to investigate the impact of early (preoperative) jejunostomy tube feeding (JTF) in nutritionally 'high risk' patients receiving multimodal therapy for esophageal cancer. METHODS: Patients were selected to undergo early JTF during neoadjuvant chemoradiotherapy (nCRT) in accordance with European Society for Clinical Nutrition and Metabolism (ESPEN) and Enhanced Recovery after Surgery (ERAS®) Society guidelines. Clinical outcomes were compared with patients who received routine JTF from the time of esophagectomy. Body composition was determined from computed tomography (CT) images acquired at diagnosis, after nCRT, and ≥ 3 months after surgery. RESULTS: In total, 81 patients received early JTF and 91 patients received routine JTF. Patients who received early JTF had lower body mass index (BMI; 26.1 ± 4.6 vs. 28.4 ± 4.9; p = 0.002), greater weight loss, and worse performance status at diagnosis. Groups were otherwise well-matched for baseline characteristics. Rate of re-intubation (8.8% vs. 1.1%; p = 0.027), pulmonary embolism (5.0% vs. 0.0%; p = 0.046), and 90-day mortality (10.0% vs. 1.1%; p = 0.010) were worse in the early JTF group; however, overall survival was equivalent for both the early and routine JTF groups (p = 0.053). Wide variation in the degree of preoperative muscle loss and total adipose tissue loss was observed across the entire study cohort. Relative preoperative muscle and adipose tissue loss in patients with early and routine JTF was equivalent. CONCLUSIONS: In patients determined to be at 'high risk' of malnutrition, early JTF may prevent excess morbidity after esophagectomy with an associated relative preservation of parameters of body composition.

Analysis of Compliance with Enhanced Recovery After Surgery (ERAS) Protocol for Esophagectomy.

BACKGROUND: ERAS guidelines have provided an effective recovery approach for esophagectomy. This study aimed to identify the relationship between the length of hospital stay (LOS) and compliance with clinical benchmarks of an established institutional ERAS program. METHODS: A single-center prospective database of esophageal cancer patients was retrospectively analyzed between January 2016 and January 2020. All patients underwent surgery within a standardized ERAS pathway for esophagectomy. Compliance with individual ERAS benchmarks and postoperative outcomes were evaluated according to patient's LOS; accelerated (≤ 6 days, AR), targeted (7-8 days, TR), and delayed recovery (≥ 9 days, DR). RESULTS: The study included 100 consecutive patients undergoing esophagectomy with a median LOS of 7 (3.8-40.8) days, and a 30-day readmission rate of 12.6%. LOS was not affected by comorbidities, tumor type or stage, neoadjuvant therapy, operative approach or anastomotic leak. Postoperative complications were 49.5%, and 90-day mortality was 3.8%. AR, TR, and DL were achieved by 45%, 31%, and 24% of patients, respectively. Postoperative morbidity differed significantly among groups, impacting LOS (p < 0.001). Overall compliance with ERAS protocol was 82.7% and adherence to specific benchmarks was initially (< 48 h) high, but significantly affected by postoperative complications afterwards. CONCLUSIONS: Adherence to recovery benchmarks in patients undergoing esophagectomy is most commonly impacted by postoperative complications. In esophageal cancer surgery, the adherence to ERAS benchmarks after esophagectomy should be regularly audited. Modification to ERAS protocols to increase application in patients with complications should be considered.

Dual-frequency pulse laser based on acousto-optic modulation.

Non-collinear stimulated Brillouin scattering (SBS) amplification can obtain high peak power Stokes output while ensuring the stability, but the frequency mismatch reduces the energy conversion efficiency of the system. In this paper, a dual-frequency pulse laser based on acousto-optic crystal modulation is designed. The output pulse pair can be used as pump and Stokes light, respectively, which realizes the active frequency matching of the gain medium Brillouin frequency shift during the SBS amplification process and helps to maintain ideal energy conversion efficiency. The dual-frequency laser finally produced a laser pulse pair with a pulse width adjustment range of 100 ps-50 ns, a frequency shift range of 0 GHz-2 GHz, and the polarization extinction ratio (PER) reaches 20.82dB.

Contrast-enhanced paravertebrogram to confirm paravertebral catheter position in elective thoracic surgery: a proof of concept study.

BACKGROUND: Paravertebral pain catheters have been shown to be equally effective as epidural pain catheters for postoperative analgesia after thoracic surgery with the possible additional benefit of less hemodynamic effect. However, a methodology for verifying correct paravertebral catheter placement has not been tested or objectively confirmed in previous studies. The aim of the current study was to describe a technique to confirm the correct position of a paravertebral pain catheter using a contrast-enhanced paravertebrogram. METHODS: A retrospective cohort proof of concept study was performed including 10 consecutive patients undergoing elective thoracic surgery with radiographic contrast-enhanced confirmation of intraoperative paravertebral catheter placement (paravertebrogram). RESULTS: The results of the paravertebrograms, which were done in the operating room at the end of the procedure, verified correct paravertebral catheter placement in 10 of 10 patients. The radiographs documented dissemination of local anesthetic within the paravertebral space. CONCLUSION: This proof of concept study demonstrated that a contrast-enhanced paravertebrogram could be used in conjunction with standard postoperative chest radiography to add valuable information for the assessment of paravertebral catheter placement. This technique has the potential to increase the accuracy and efficiency of postoperative analgesia, and to set a quality standard for future studies of paravertebral pain catheters.

Stromal response to Hedgehog signaling restrains pancreatic cancer progression.

Pancreatic ductal adenocarcinoma (PDA) is the most lethal of common human malignancies, with no truly effective therapies for advanced disease. Preclinical studies have suggested a therapeutic benefit of targeting the Hedgehog (Hh) signaling pathway, which is activated throughout the course of PDA progression by expression of Hh ligands in the neoplastic epithelium and paracrine response in the stromal fibroblasts. Clinical trials to test this possibility, however, have yielded disappointing results. To further investigate the role of Hh signaling in the formation of PDA and its precursor lesion, pancreatic intraepithelial neoplasia (PanIN), we examined the effects of genetic or pharmacologic inhibition of Hh pathway activity in three distinct genetically engineered mouse models and found that Hh pathway inhibition accelerates rather than delays progression of oncogenic Kras-driven disease. Notably, pharmacologic inhibition of Hh pathway activity affected the balance between epithelial and stromal elements, suppressing stromal desmoplasia but also causing accelerated growth of the PanIN epithelium. In striking contrast, pathway activation using a small molecule agonist caused stromal hyperplasia and reduced epithelial proliferation. These results indicate that stromal response to Hh signaling is protective against PDA and that pharmacologic activation of pathway response can slow tumorigenesis. Our results provide evidence for a restraining role of stroma in PDA progression, suggesting an explanation for the failure of Hh inhibitors in clinical trials and pointing to the possibility of a novel type of therapeutic intervention.

Sustainable and Recyclable Acrylate Resins for Liquid-Crystal Display 3D Printing Based on Lipoic Acid.

The development of renewable vinyl-based photopolymer resins offers a promising solution to reducing the environmental impact associated with 3D printed materials. This study introduces a bifunctional lipoate cross-linker containing a dynamic disulfide bond, which is combined with acrylic monomers (n-butyl acrylate) and conventional photoinitiators to develop photopolymer resins that are compatible with commercial stereolithography 3D printing. The incorporation of disulfide bonds within the polymer network's backbone imparts the 3D printed objects with self-healing capabilities and complete degradability. Remarkably, the degraded resin can be fully recycled and reused for high-resolution reprinting of complex structures while preserving mechanical properties that are comparable to the original material. This proof-of-concept study not only presents a sustainable strategy for advancing acrylate-based 3D printing materials, but also introduces a novel approach for fabricating fully recyclable 3D-printed structures. This method paves the way for reducing the environmental impact while enhancing material reusability, offering significant potential for the development of eco-friendly additive manufacturing.

GA-Net: A geographical attention neural network for the segmentation of body torso tissue composition.

PURPOSE: Body composition analysis (BCA) of the body torso plays a vital role in the study of physical health and pathology and provides biomarkers that facilitate the diagnosis and treatment of many diseases, such as type 2 diabetes mellitus, cardiovascular disease, obstructive sleep apnea, and osteoarthritis. In this work, we propose a body composition tissue segmentation method that can automatically delineate those key tissues, including subcutaneous adipose tissue, skeleton, skeletal muscle tissue, and visceral adipose tissue, on positron emission tomography/computed tomography scans of the body torso. METHODS: To provide appropriate and precise semantic and spatial information that is strongly related to body composition tissues for the deep neural network, first we introduce a new concept of the body area and integrate it into our proposed segmentation network called Geographical Attention Network (GA-Net). The body areas are defined following anatomical principles such that the whole body torso region is partitioned into three non-overlapping body areas. Each body composition tissue of interest is fully contained in exactly one specific minimal body area. Secondly, the proposed GA-Net has a novel dual-decoder schema that is composed of a tissue decoder and an area decoder. The tissue decoder segments the body composition tissues, while the area decoder segments the body areas as an auxiliary task. The features of body areas and body composition tissues are fused through a soft attention mechanism to gain geographical attention relevant to the body tissues. Thirdly, we propose a body composition tissue annotation approach that takes the body area labels as the region of interest, which significantly improves the reproducibility, precision, and efficiency of delineating body composition tissues. RESULTS: Our evaluations on 50 low-dose unenhanced CT images indicate that GA-Net outperforms other architectures statistically significantly based on the Dice metric. GA-Net also shows improvements for the 95% Hausdorff Distance metric in most comparisons. Notably, GA-Net exhibits more sensitivity to subtle boundary information and produces more reliable and robust predictions for such structures, which are the most challenging parts to manually mend in practice, with potentially significant time-savings in the post hoc correction of these subtle boundary placement errors. Due to the prior knowledge provided from body areas, GA-Net achieves competitive performance with less training data. Our extension of the dual-decoder schema to TransUNet and 3D U-Net demonstrates that the new schema significantly improves the performance of these classical neural networks as well. Heatmaps obtained from attention gate layers further illustrate the geographical guidance function of body areas for identifying body tissues. CONCLUSIONS: (i) Prior anatomic knowledge supplied in the form of appropriately designed anatomic container objects significantly improves the segmentation of bodily tissues. (ii) Of particular note are the improvements achieved in the delineation of subtle boundary features which otherwise would take much effort for manual correction. (iii) The method can be easily extended to existing networks to improve their accuracy for this application.

A patient with spontaneous bilateral renal vein thrombosis but no risk factors.

INTRODUCTION AND IMPORTANCE: Spontaneous bilateral renal vein thrombosis is a rare condition, especially when the patient has no risk factors. CASE PRESENTATION: In this report, we describe a patient with bilateral renal vein thrombosis who presented with severe flank pain, renal functions remained normal, and the thrombus resolved completely with anticoagulation. There is no history of hypercoagulable condition in our patient. A one-year followup with CT angiogram revealed that the kidney was functioning normally and that the thrombus in the renal veins had completely resolved. CLINICAL DISCUSSION: Management of an acute renal vein thrombosis depends upon whether the patient presents with acute kidney injury. In general, patients without acute kidney injury can be treated with therapeutic anticoagulation, whereas those with acute kidney injury should undergo dissolution or removal of the thrombus with thrombolytic therapy with or without thrombectomy. CONCLUSION: Diagnosis of spontaneous renal vein thrombosis requires a high index of suspicion. Patient can be managed with therapeutic anticoagulation if renal function is intact. If thrombolysis and/or thrombectomy are performed on time, kidney function can be fully restored.

Rare renal embolic manifestation of left atrial myxoma: A case report.

INTRODUCTION AND IMPORTANCE: A complete occlusion of the renal artery due to atrial myxoma is a rare occurrence. CASE PRESENTATION: Here we present a case of a completely occluded left renal artery caused by atrial myxoma emboli that presented with a 14-hour history of sudden onset sharp left flank pain radiating to the left lower quadrant of the abdomen, nausea, with preserved kidney function. Revascularization is unlikely to benefit the patient because it has been more than 6 h since the onset of ischemia. Anticoagulation therapy was initiated, followed by myxoma resection. The patient was discharged with no evidence of nephropathy. CLINICAL DISCUSSION: Anticoagulation with or without thrombolysis is the standard treatment strategy for renal artery embolism. Given the delayed presentation of renal artery occlusion and the nature of the embolism, revisualization is not beneficial for this case. CONCLUSION: Emboli of atrial myxoma caused renal artery occlusion is rare. Thrombolysis or surgical revascularization can be used to restore perfusion for renal artery embolism. However, the likelihood of benefit from revascularization must be assessed.

The impact of an enhanced recovery after surgery pathway for video-assisted and robotic-assisted lobectomy on surgical outcomes and costs: a retrospective single-center cohort study.

To determine the impact of enhanced recovery after surgery (ERAS) pathway implementation on outcomes and cost of robotic- and video-assisted thoracoscopic (RATS and VATS) lobectomy. Retrospective review of 116 consecutive VATS and RATS lobectomies in the pre-ERAS (Oct 2018-Sep 2019) and ERAS (Oct 2019-Sep 2020) period. Multivariate analysis was used to determine the impact of ERAS and operative approach alone, and in combination, on length of hospital stay (LOS) and overall cost. Operative approach was 49.1% VATS, 50.9% RATS, with 44.8% pre-ERAS, and 55.2% ERAS (median age 68, 65.5% female). ERAS patients had shorter LOS (2.22 vs 3.45 days) and decreased total cost ($15,022 vs $20,155) compared with non-ERAS patients, while RATS was associated with decreased LOS (2.16 vs 4.19 days) and decreased total cost ($14,729 vs $20,484) compared with VATS. The combination of ERAS + RATS showed the shortest LOS and the lowest total cost (1.35 days and $13,588, P < 0.001 vs other combinations). On multivariate analysis, ERAS significantly decreased LOS (P = 0.001) and total cost (P = 0.003) compared with pre-ERAS patients; RATS significantly decreased LOS (P < 0.001) and total cost (P = 0.004) compared with VATS approach. ERAS implementation and robotic approach were independently associated with LOS reduction and cost savings in patients undergoing minimally invasive lobectomy. A combination of ERAS and RATS approach synergistically decreases LOS and overall cost.

A Deep Learning Based Geographic Attention Model for Body Composition Tissue Segmentation.

Measurement of body composition, including multiple types of adipose tissue, skeletal tissue, and skeletal muscle, on computed tomography (CT) images is practical given the powerful anatomical structure visualization ability of CT, and is useful for clinical and research applications related to health care and underlying pathology. In recent years, deep learning-based methods have contributed significantly to the development of automatic body composition analysis (BCA). However, the unsatisfactory segmentation performance for indistinguishable boundaries of multiple body composition tissues and the need for large-scale datasets for training deep neural networks still need to be addressed. This paper proposes a deep learning-based approach, called Geographic Attention Network (GA-Net), for body composition tissue segmentation on body torso positron emission tomography/computed tomography (PET/CT) images which leverages the body area information. The representation ability of GA-Net is significantly enhanced with the body area information as it strongly correlates with the target body composition tissue. This method achieves precise segmentation performance for multiple body composition tissues, especially for boundaries that are hard to distinguish, and effectively reduces the data requirements for training the network. We evaluate the proposed model on a dataset that includes 50 body torso PET/CT scans for segmenting 4 key bodily tissues - subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), skeletal muscle tissue (SMT), and skeleton (Sk). Experiments show that our proposed method increases segmentation accuracy, especially with a limited training dataset, by providing geographic information of target body composition tissues.

Identification of suitable reference genes for qPCR analysis of serum microRNA in gastric cancer patients.

BACKGROUND: Circulating microRNA expression profiles may be promising biomarkers for diagnosis and assessment of the prognosis of cancer patients. Quantitative polymerase chain reaction (qPCR) is a sensitive technique for estimating expression levels of circulating microRNAs. However, there is no current consensus on the reference genes for qPCR analysis of circulating microRNAs. AIMS: In this study we tried to identify suitable reference genes for qPCR analysis of serum microRNA in gastric cancer patients and healthy individuals. METHODS: Six microRNAs (let-7a, miR-16, miR-93, miR-103, miR-192, and miR-451) and RNU6B were chosen as candidate reference genes on the basis of the literature. Expression levels of these candidates were analyzed by qPCR in serum samples from 40 gastric cancer patients and 20 healthy volunteers. The geNorm, Normfinder, bestkeeper, and comparative delta-Ct method algorithms were used to select the most suitable reference gene from the seven candidates. This was then validated by normalizing the expression levels of serum miR-21 across all gastric cancer patients and healthy volunteers. RESULTS: The algorithms revealed miR-16 and miR-93 were the most stably expressed reference genes, with stability values of 1.778 and 2.213, respectively, for serum microRNA analysis across all the patients and healthy controls. The effect of different normalization strategies was compared; when normalized to the serum volume there were no significant differences between patients and controls. However, when the data were normalized to miR-93, miR-16, or miR-93 and miR-16 combined, significant differences were detected. CONCLUSIONS: Our results demonstrated that reference gene choice for qPCR data analysis has a great effect on the study outcome, and that it is necessary to choose a suitable reference for reliable expression data. We recommend miR-16 and miR-93 as suitable reference genes for serum miRNA analysis for gastric cancer patients and healthy controls.

Feasibility and efficacy of cryoneurolysis analgesia in robotic-assisted thoracoscopic surgery (CARTS): a pilot study.

Opioid therapy has been the mainstay therapy of post-operative pain management in thoracic surgery patients. With the high incidence of chronic pain in thoracic surgery patients and adverse effects of opioids, we examined the safety and efficacy of cryoneurolysis as an adjunct for narcotic-free pain management in robotic-assisted thoracoscopic lobectomies. Ten consecutive patients undergoing robotic-assisted (DaVinci) pulmonary resection and cryoneurolysis were compared to ten patients managed without intraoperative cryoneurolysis. All patients received multimodal pain regimen including paravertebral blocks as per our institutional enhanced recovery pathway. Patients with chronic pain and chronic opioid use were excluded. We compared inpatient and outpatient opioid consumption measured in morphine equivalents (mme), incidence of opioid-free outpatient recovery, and adverse events. The two groups did not differ significantly in terms of baseline demographics. Both inpatient (88.13 vs 26.92 mme) and outpatient (118.5 vs 34.5 mme) use of narcotics were significantly lower in the cryoneurolysis group (p < 0.05) with seven of ten patients receiving cryoneurolysis able to recover without the use of opioids in the outpatient setting, compared to two in the control group. One patient reported post-operative neuralgia in each cryoneurolysis and control group. There were no readmissions in either group and mean length of stay was identical at 1.7 days in control group and 1.1 days in experimental group (p = 0.33). The use of intraoperative intercostal cryoneurolysis may safely reduce the utilization of outpatient opioids in patients undergoing robotic-assisted thoracoscopic surgery. A randomized controlled trial is warranted to validate these findings in a larger cohort of patients.

Induction of autophagy-dependent apoptosis in cancer cells through activation of ER stress: an uncovered anti-cancer mechanism by anti-alcoholism drug disulfiram.

Due to its potent anticancer activity, there is interest in repurposing of the FDA-approved anti-alcoholism drug, disulfiram (DSF). DSF forms potent complexes with copper (DSF/Cu) that induce apoptosis of many types of cancer cells. Here, we investigated the role of DSF/Cu in autophagy, a mechanism of cell death or survival, and its interplay with DSF/Cu induced apoptosis of human pancreatic and breast cancer cells. METHODS: Levels of autophagy and apoptosis were assessed by Western blot, flow cytometry and immunofluorescence analysis. Cell viability was measured by MTT assays. Activation of inositol-requiring enzyme 1α (IRE1α)-mRNA X-box binding protein 1 (XBP1) pathway and spliced XBP1 (XBP1s) expression were analyzed by Western blot, Phos-tag gel assay, RT-PCR, qRT-PCR and flow cytometry. RESULTS: The apoptosis induced by DSF/Cu in pancreatic and breast cancer cells is autophagy dependent. This is accomplished by activating IRE1α, the sensor of unfolded protein response (UPR) via promotion of phosphorylation of IRE1α and its downstream XBP1 splicing into active XBP1s. CONCLUSIONS: DSF/Cu induces ER-stress through activation of IRE1α-XBP1 pathway which is responsible, at least in part, for induction of autophagy-dependent apoptosis of cancer cells. Insight into the ER-stress inducing ability by DSF/Cu may open a new research area for rational design of innovative therapeutic strategies for pancreatic and breast cancers.

The crosstalk between breast carcinoma-associated fibroblasts and cancer cells promotes RhoA-dependent invasion via IGF-1 and PAI-1.

Carcinoma-associated fibroblasts (CAFs) can remodel the extracellular matrix to promote cancer cell invasion, but the paracrine signaling between CAFs and cancer cells that regulates tumor cell migration remains to be identified. To determine how the interaction between CAFs and cancer cells modulates the invasiveness of cancer cells, we developed a 3-dimensional co-culture model composed of breast cancer (BC) MDA-MB-231 cell spheroids embedded in a collagen gel with and without CAFs. We found that the crosstalk between CAFs and cancer cells promotes invasion by stimulating the scattering of MDA-MB-231 cells, which was dependent on RhoA/ROCK/phospho MLC signaling in cancer cells but independent of RhoA in CAFs. The activation of RhoA/ROCK in cancer cells activates MLC and increases migration, while the genetic-down-regulation of RhoA and pharmacological inhibition of ROCK reduced cell scattering and invasion. Two distinct mechanisms induced the activation of the RhoA/ROCK pathway in MDA-MB-231 cells, the secretion of IGF-1 by CAFs and the upregulation of PAI-1 in cancer cells. In an orthotopic model of BC, IGF-1R inhibition decreased the incidence of lung metastasis, while Y27632-inhibition of ROCK enhanced the lung metastasis burden, which was associated with an increased recruitment of CAFs and expression of PAI-1. Thus the crosstalk between CAFs and BC cells increases the secretion of IGF-1 in CAFs and PAI-1 activity in cancer cells. Both IGF1 and PAI-1 activate RhoA/ROCK signaling in cancer cells, which increases cell scattering and invasion.

NK Cells Mediate Synergistic Antitumor Effects of Combined Inhibition of HDAC6 and BET in a SCLC Preclinical Model.

Small-cell lung cancer (SCLC) has the highest malignancy among all lung cancers, exhibiting aggressive growth and early metastasis to distant sites. For 30 years, treatment options for SCLC have been limited to chemotherapy, warranting the need for more effective treatments. Frequent inactivation of TP53 and RB1 as well as histone dysmodifications in SCLC suggest that transcriptional and epigenetic regulations play a major role in SCLC disease evolution. Here we performed a synthetic lethal screen using the BET inhibitor JQ1 and an shRNA library targeting 550 epigenetic genes in treatment-refractory SCLC xenograft models and identified HDAC6 as a synthetic lethal target in combination with JQ1. Combined treatment of human and mouse SCLC cell line-derived xenograft tumors with the HDAC6 inhibitor ricolinostat (ACY-1215) and JQ1 demonstrated significant inhibition of tumor growth; this effect was abolished upon depletion of NK cells, suggesting that these innate immune lymphoid cells play a role in SCLC tumor treatment response. Collectively, these findings suggest a potential new treatment for recurrent SCLC.Significance: These findings identify a novel therapeutic strategy for SCLC using a combination of HDAC6 and BET inhibitors. Cancer Res; 78(13); 3709-17. ©2018 AACR.

Synergistic Immunostimulatory Effects and Therapeutic Benefit of Combined Histone Deacetylase and Bromodomain Inhibition in Non-Small Cell Lung Cancer.

Effective therapies for non-small cell lung cancer (NSCLC) remain challenging despite an increasingly comprehensive understanding of somatically altered oncogenic pathways. It is now clear that therapeutic agents with potential to impact the tumor immune microenvironment potentiate immune-orchestrated therapeutic benefit. Herein, we evaluated the immunoregulatory properties of histone deacetylase (HDAC) and bromodomain inhibitors, two classes of drugs that modulate the epigenome, with a focus on key cell subsets that are engaged in an immune response. By evaluating human peripheral blood and NSCLC tumors, we show that the selective HDAC6 inhibitor ricolinostat promotes phenotypic changes that support enhanced T-cell activation and improved function of antigen-presenting cells. The bromodomain inhibitor JQ1 attenuated CD4+FOXP3+ T regulatory cell suppressive function and synergized with ricolinostat to facilitate immune-mediated tumor growth arrest, leading to prolonged survival of mice with lung adenocarcinomas. Collectively, our findings highlight the immunomodulatory effects of two epigenetic modifiers that, together, promote T cell-mediated antitumor immunity and demonstrate their therapeutic potential for treatment of NSCLC.Significance: Selective inhibition of HDACs and bromodomain proteins modulates tumor-associated immune cells in a manner that favors improved T-cell function and reduced inhibitory cellular mechanisms. These effects facilitated robust antitumor responses in tumor-bearing mice, demonstrating the therapeutic potential of combining these epigenetic modulators for the treatment of NSCLC. Cancer Discov; 7(8); 852-67. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 783.