Risk-adapted stereotactic body radiotherapy for patients with cervical spinal metastases.

Owing to the complex anatomical structure and biomechanics, the current standard palliative treatments for cervical spinal metastases are associated with a high risk of recurrence and complications. Stereotactic body radiotherapy (SBRT) can provide radical dose to tumors while protecting normal organs to the maximum extent. However, the efficacy and safety of SBRT for cervical spinal metastases is not well characterized. Data from 71 patients with cervical spine metastases who were treated with SBRT using CyberKnife between 2006 and 2021 were obtained from our prospectively maintained database. Primary endpoint was pain response at 12 weeks following SBRT completion; secondary endpoints included local control (LC), overall survival (OS), and adverse events. Standard-risk patients were planned to receive 30 Gy (range 21-36) with median fractions of 3 (range 1-3) and high-risk patients 35 Gy (range 24-50) with median fractions of 5 (range 4-5) according to the spinal cord and esophagus dose constraints. The median follow-up time was 17.07 months (range 3.1-118.9). After 12 weeks of SBRT completion, 54 (98.2%) of 55 patients with baseline pain achieved pain response and 46 (83.6%) achieved complete pain response. LC rates were 93.1% and 90% at 1 year and 2 year, respectively. The 1-year and 2-year OS rates were 66.2% and 37.4%, respectively. Eight patients experienced grades 1-4 adverse events (six vertebral compression fracture [VCF], five of them had VCF before SBRT; and two hemiparesis). No grade 5 adverse events were observed. Therefore, risk-adapted SBRT for cervical spine metastases achieved high pain control and LC rates with acceptable adverse events.

Risk-adapted stereotactic body radiation therapy for central and ultra-central early-stage inoperable non-small cell lung cancer.

To determine the therapeutic efficacy and safety of risk-adapted stereotactic body radiation therapy (SBRT) schedules for patients with early-stage central and ultra-central inoperable non-small cell lung cancer. From 2006 to 2015, 80 inoperable T1-2N0M0 NSCLC patients were treated with two median dose levels: 60 Gy in six fractions (range, 48-60 Gy in 4-8 fractions) prescribed to the 74% isodose line (range, 58%-79%) for central lesions (ie within 2 cm of, but not abutting, the proximal bronchial tree; n = 43), and 56 Gy in seven fractions (range, 48-60 Gy in 5-10 fractions) prescribed to the 74% isodose line (range, 60%-80%) for ultra-central lesions (ie abutting the proximal bronchial tree; n = 37) on consecutive days. Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), tumor local control rate (LC), and toxicity. Median OS and PFS were 64.47 and 32.10 months (respectively) for ultra-central patients, and not reached for central patients. Median time to local failure, regional failure, and any distant failures for central versus ultra-central lesions were: 27.37 versus 26.07 months, 20.90 versus 12.53 months, and 20.85 versus 15.53 months, respectively, all P < .05. Multivariate analyses showed that tumor categorization (ultra-central) and planning target volume ≥52.76 mL were poor prognostic factors of OS, PFS, and LC, respectively (all P < .05). There was one grade 5 toxicity; all other toxicities were grade 1-2. Our results showed that ultra-central tumors have a poor OS, PFS, and LC compared with central patients because of the use of risk-adapted SBRT schedules that allow for equal and favorable toxicity profiles.

DNA repair gene polymorphisms and clinical outcome of patients with primary small cell carcinoma of the esophagus.

Polymorphisms in DNA repair genes impact on the synthesis of DNA repair proteins that are crucial to the repair of DNA damages induced by chemotherapy and radiotherapy. We retrospectively examined whether there was an association between the selected six single nucleotide polymorphisms (SNPs) of five DNA repair genes (PARP1-Val762Ala, XRCC1-Arg194Trp, XRCC1-Arg399Gln, XPC-Lys939Gln, BRCA1-Lys1183Arg, and BRCA2-Asn372His) and the clinical outcome of patients with primary small cell carcinoma of esophagus (SCCE), and it showed that the median progression-free survival (PFS) and the overall survival (OS) were 11.8 versus 9.7 months (P = 0.041) and 17.4 versus 14.8 months (P = 0.032) for patients carrying the variant allele (T/C + C/C) and the wild-type allele (T/T) of PARP1-Val762Ala polymorphism, respectively. However, no statistical significance was observed in the other five polymorphic loci (P > 0.05). When these six SNPs were combined, however, patients with at least three variant genotypes had significantly longer PFS and OS compared with those carrying less than three variant genotypes (P = 0.009 and P = 0.007, respectively). The presence of at least three polymorphic variants in certain DNA repair genes may impact on patient survival and could be a potential genomic predictor of clinical response to DNA-damaging treatment in SCCE patients.

Pericytes: a double-edged sword in cancer therapy.

Pericytes, which envelope the vascular endothelium throughout the body, are often targeted to promote vascular normalization and restore normal function of blood vessels in cancer treatment. The goals of pericyte-targeted therapy tend to promote proper vascular normalization of the tumor. Tumor vascular normalization prevents metastasis, increases tumor oxygenation (making radiation more effective in killing tumor cells), optimizes Starling forces to increase delivery of cancer cell-directed therapies (e.g., chemotherapy or targeted agents), increases the efficacy of focal therapies (e.g., surgery or radiation), and increases recognition by the host immune system. We review how approaches in pericyte-targeted therapy aim to reach a balance between pro-angiogenic and anti-angiogenic function (i.e., by targeting platelet-derived growth factor beta receptors, vascular endothelial growth factor receptors and Tie-2) for tumor vascular normalization.

Dosimetric analysis of brachial plexopathy after stereotactic body radiotherapy: Significance of organ delineation.

OBJECTIVES: Examine the significance of contouring the brachial plexus (BP) for toxicity estimation and select metrics for predicting radiation-induced brachial plexopathy (RIBP) after stereotactic body radiotherapy. MATERIALS AND METHODS: Patients with planning target volume (PTV) ≤ 2 cm from the BP were eligible. The BP was contoured primarily according to the RTOG 1106 atlas, while subclavian-axillary veins (SAV) were contoured according to RTOG 0236. Apical PTVs were classified as anterior (PTV-A) or posterior (PTV-B) PTVs. Variables predicting grade 2 or higher RIBP (RIBP2) were selected through least absolute shrinkage and selection operator regression and logistic regression. RESULTS: Among 137 patients with 140 BPs (median follow-up, 32.1 months), 11 experienced RIBP2. For patients with RIBP2, the maximum physical dose to the BP (BP-Dmax) was 46.5 Gy (median; range, 35.7 to 60.7 Gy). Of these patients, 54.5 % (6/11) satisfied the RTOG limits when using SAV delineation; among them, 83.3 % (5/6) had PTV-B. For patients with PTV-B, the maximum physical dose to SAV (SAV-Dmax) was 11.2 Gy (median) lower than BP-Dmax. Maximum and 0.3 cc biologically effective doses to the BP based on the linear-quadratic-linear model (BP-BEDmax LQL and BP-BED0.3cc LQL, α/ß = 3) were selected as predictive variables with thresholds of 118 and 73 Gy, respectively. CONCLUSION: Contouring SAV may significantly underestimate the RIBP2 risk in dosimetry, especially for patients with PTV-B. BP contouring indicated BP-BED0.3cc LQL and BP-BEDmax LQL as potential predictors of RIBP2.

Reirradiation with stereotactic body radiotherapy for primary or secondary lung malignancies: Tumor control probability and safety analyses.

BACKGROUND: Reirradiation with stereotactic body radiotherapy (SBRT) for patients with primary or secondary lung malignancies represents an appealing definitive approach, but its feasibility and safety are not well defined. The purpose of this study was to investigate the tumor control probability (TCP) and toxicity for patients receiving reirradiation with SBRT. PATIENTS AND METHODS: Eligible patients with recurrence of primary or secondary lung malignancies from our hospital were subjected to reirradiation with SBRT, and PubMed- and Embase-indexed articles were reviewed. The patient characteristics, pertinent SBRT dosimetric details, local tumor control, and toxicities were extracted. The logistic dose-response models were compared for TCP and overall survival (OS) in terms of the physical dose and three-, four-, and five-fraction equivalent doses. RESULTS: The data of 17 patients from our hospital and 195 patients extracted from 12 articles were summarized. Reirradiation with SBRT yielded 2-year estimates of 80% TCP for doses of 50.10 Gy, 55.85 Gy, and 60.54 Gy in three, four, and five fractions, respectively. The estimated TCP with common fractionation schemes were 50%, 60%, and 70% for 42.04 Gy, 47.44 Gy, and 53.32 Gy in five fractions, respectively. Similarly, the 2-year estimated OS was 50%, 60%, and 70% for 41.62 Gy, 46.88 Gy, and 52.55 Gy in five fractions, respectively. Central tumor localization may be associated with severe toxicity. CONCLUSIONS: Reirradiation with SBRT doses of 50-60 Gy in 3-5 fractions is feasible for appropriately selected patients with recurrence of peripheral primary or secondary lung malignancies, but should be carefully considered for centrally-located tumors due to potentially severe toxicity. Further studies are warranted for optimal dose/fractionation schedules and more accurate selection of patients suitable for reirradiation with SBRT.

Treatment of common cold patients with the shi-cha capsule: a multicenter, double-blind, randomized, placebo-controlled, dose-escalation trial.

This study was designed to determine the therapeutic efficacy and safety of the Shi-cha capsule, a Chinese herbal formula, in the treatment of patients with wind-cold type common cold. In our multi-center, prospective, double-blind, randomized, placebo-controlled, dose-escalation trial, patients with wind-cold type common cold received 0.6 g of Shi-cha capsule plus 0.6 g placebo (group A), 1.2 g of Shi-cha capsule (group B), or 1.2 g placebo (group C), three times daily for 3 days and followed up to 10 days. The primary end point was all symptom duration. The secondary end points were main symptom duration, minor symptom duration, the changes in cumulative symptom score, main symptom score, and minor symptom score 4 days after the treatment, as well as adverse events. A total of 377 patients were recruited and 360 met the inclusive criteria; 120 patients constituted each treatment group. Compared with patients in group C, patients in groups A and B had significant improvement in the all symptom duration, main symptom duration, minor symptom duration, as well as change from baseline of cumulative symptom score, main symptom score, and minor symptom score at day 4. The symptom durations and scores showed slight superiority of group B over group A, although these differences were not statistically significant. There were no differences in adverse events. The Shi-cha capsule is efficacious and safe for the treatment of patients with wind-cold type common cold. Larger trials are required to fully assess the benefits and safety of this treatment for common cold.

The Epidemiology of Lung Metastases.

Introduction: Lung metastasis is usually associated with poor outcomes in cancer patients. This study was performed to characterize and analyze the population of patients with de novo (synchronous) lung metastases using the Surveillance, Epidemiology and End Results (SEER) database. Materials and Methods: Baseline characteristics of lung metastasis patients were obtained from SEER case listings. Incidence rates and counts of synchronous lung metastasis were also obtained using the SEER*Stat software. Survival outcomes were analyzed using univariate and multivariable Cox regressions, controlling for confounders. An alpha threshold of 0.05 was used for statistical significance and p-values were subject to correction for multiple comparisons. Results: The age-adjusted incidence rate of synchronous lung metastasis was 17.92 per 100,000 between 2010 and 2015. Synchronous lung metastases most commonly arose from primary lung cancers, colorectal cancers, kidney cancers, pancreatic cancers and breast cancers. During this time period, 4% of all cancer cases presented with synchronous lung metastasis. The percentage of patients presenting with synchronous lung metastasis ranged from 0.5% of all prostate cancers to 13% of all primary lung cancers. The percentage of all cancer cases presenting with synchronous lung metastasis increased over time. De novo metastatic patients with lung metastases had worse overall survival [hazard ratio = 1.22 (1.21-1.23), p < 0.001] compared to those with only extrapulmonary metastases, controlling for potential confounders. Conclusions: Synchronous lung metastasis occurs frequently and is an independent predictors of poor patient outcomes. As treatment for lung metastases becomes more complicated, patients with synchronous lung metastasis represent a high-risk population.

Safety and Survival Rates Associated With Ablative Stereotactic Radiotherapy for Patients With Oligometastatic Cancer: A Systematic Review and Meta-analysis.

IMPORTANCE: The oligometastatic paradigm postulates that patients with a limited number of metastases can be treated with ablative local therapy to each site of disease with curative intent. Stereotactic ablative radiotherapy (SABR) is a radiation technique that has become widely used in this setting. However, prospective data are limited and are mainly from single institutional studies. OBJECTIVE: To conduct a meta-analysis to characterize the safety and clinical benefit of SABR in oligometastatic cancer. DATA SOURCES: A comprehensive search was conducted in PubMed/MEDLINE, Embase, Cochrane Database of Systematic Reviews, and Cumulative Index to Nursing and Allied Health Literature on December 23, 2019, that included prospective clinical trials and review articles that were published within the past 15 years. STUDY SELECTION: Inclusion criteria were single-arm or multiarm prospective trials including patients with oligometastatic cancer (ie, ≤5 sites of extracranial disease), and SABR was administered in less than or equal to 8 fractions with greater than or equal to 5 Gy/fraction. DATA EXTRACTION AND SYNTHESIS: The Population, Intervention, Control, Outcomes and Study Design; Preferred Reporting Items for Systematic Reviews and Meta-analyses; and Meta-analysis of Observational Studies in Epidemiology methods were used to identify eligible studies. Study eligibility and data extraction were reviewed by 3 authors independently. Random-effects meta-analyses using the Knapp-Hartung correction, arcsine transformation, and restricted maximum likelihood method were conducted. MAIN OUTCOMES AND MEASURES: Safety (acute and late grade 3-5 toxic effects) and clinical benefit (1-year local control, 1-year overall survival, and 1-year progression-free survival). RESULTS: Twenty-one studies comprising 943 patients and 1290 oligometastases were included. Median age was 63.8 years (interquartile range, 59.6-66.1 years) and median follow-up was 16.9 months (interquartile range, 13.7-24.5 months). The most common primary sites were prostate (22.9%), colorectal (16.6%), breast (13.1%), and lung (12.8%). The estimate for acute grade 3 to 5 toxic effect rates under the random-effects models was 1.2% (95% CI, 0%-3.8%; I2 = 50%; 95% CI, 3%-74%; and τ = 0.20%; 95% CI, 0.00%-1.43%), and the estimate for late grade 3 to 5 toxic effects was 1.7% (95% CI, 0.2%-4.6%; I2 = 54%; 95% CI, 11%-76%; and τ = 0.25%; 0.01%-1.00%). The random-effects estimate for 1-year local control was 94.7% (95% CI, 88.6%-98.6%; I2 = 90%; 95% CI, 86%-94%; and τ = 0.81%; 95% CI, 0.36%-2.38%]). The estimate for 1-year overall survival was 85.4% (95% CI, 77.1%-92.0%; I2 = 82%; 95% CI, 71%-88%; and τ = 0.72%; 95% CI, 0.30%-2.09%) and 51.4% (95% CI, 42.7%-60.1%; I2 = 58%; 95% CI, 17%-78%; and τ = 0.20%; 95% CI, 0.02%-1.21%) for 1-year progression-free survival. CONCLUSIONS AND RELEVANCE: In this meta-analysis, SABR appears to be relatively safe in patients with oligometastatic cancer with clinically acceptable rates of acute and late grade 3 to 5 toxic effects less than 13% and with clinically acceptable rates of 1-year local control overall survival, and progression-free survival. These findings are hypothesis generating and require validation by ongoing and planned prospective clinical trials.

Treatment of functional constipation with the Yun-chang capsule: a double-blind, randomized, placebo-controlled, dose-escalation trial.

BACKGROUND AND AIM: Functional constipation is a common functional bowel disorder for which there is no reliable medical treatment. This study was designed to determine the therapeutic efficacy and safety of the Yun-chang capsule, a Chinese herbal formula, in the treatment of patients with functional constipation. METHODS: In our multi-center, prospective, double-blind, randomized, placebo-controlled, dose-escalation trial, patients with functional constipation received 70 mg of Yun-chang capsule plus 35 mg placebo (group A), 105 mg of Yun-chang capsule (group B), or 105 mg placebo (group C), three times daily for 2 weeks. The primary end-points were the changes in main symptom score and cumulative symptom score 2 weeks after the treatment. The secondary end-points were adverse events. RESULTS: A total of 140 patients were recruited and 132 met the inclusion criteria; 44 patients constituted each of the three treatment groups. Compared with patients in group C, patients in groups A and B had significant improvement in the main symptom score, cumulative symptom score, the change from baseline of the main symptom score, and the change from baseline of the cumulative symptom score at week 1 and week 2. The scores showed slight superiority of group B over group A at week 1 and week 2, although these differences were not statistically significant. There were no differences in adverse events. CONCLUSIONS: The Yun-chang capsule is efficacious and safe for the treatment of patients with functional constipation. Larger and longer-term trials are required to fully assess the benefits and safety of this treatment for functional constipation.

Malignant fibrous histiocytoma like pleomorphic leiomyosarcoma with laryngeal cancer as a second primary neoplasm: a case report.

BACKGROUND: Leiomyosarcoma is one of the most common sarcomas arising in the soft tissue and somatic organs. Pleomorphic leiomyosarcoma (P-LMS) may be easily confused with a malignant fibrous histiocytoma (MFH) as both may share nonspecific morphologic features. It is reported that the larynx is the most common site for a second primary neoplasm (SPN) in a patient with a head and neck malignancy, although an SPN of the larynx following a P-LMS is extremely rare. CASE: A 57-year-old male initially underwent fine needle aspiration (FNA) of a soft tissue tumor (STS) located in the left upper arm. FNA showed the presence of clustered, large tumor cells with clear, eosinophilic and ill-defined cytoplasm and pleomorphic nuclei. A diagnosis of an undifferentiated malignant tumor was made. Histology showed the presence of MFH. This diagnosis was changed to P-LMS following a lung metastasis. A laryngeal biopsy 37 months after the initial biopsy was performed and showed squamous carcinoma. This squamous carcinoma was presumed to be an SPN. CONCLUSION: This is the first case report of a patient with a P-LMS who then developed laryngeal squamous carcinoma as an SPN.

Effects of heterochromatin in colorectal cancer stem cells on radiosensitivity.

BACKGROUND AND OBJECTIVE: Radiotherapy (RT) is a major non-surgical modality in the comprehensive treatment for colorectal adenocarcinoma. The radioresistance of cancer stem cells (CSCs) is a key factor that influences therapeutic effectiveness. This study was to investigate the effects of specific chromosome structure and histone modification in CSCs in colorectal adenocarcinoma radioresistance. METHODS: Samples were collected from resected human colorectal adenocarcinomas. Subcutaneous colorectal cancer model was established in nude mice. Immunohistochemistry showed that xenografts generated from bulk colorectal cancer cells resembled the original tumor specimen. Flow cytometry was performed to sort CSCs (CD133+) and non-CSCs (CD133-) from both resected samples of colorectal adenocarcinoma and xenograft before and after high single-dose radiation. The markers labeling heterochromatin (H3K9me3, HP1-alpha and H3K4me1) and euchromatin (H3K4me3) in CD133+ and CD133- nucleus were detected by immunofluorescence. RESULTS: There was distinct difference in chromatin structure between colorectal CSCs (CD133+) and non-CSCs (CD133-). The chromatin displayed compact patches in CD133+ nucleus, but loosely latticed structure in CD133- nucleus; immunofluorescence verified that the compact patches existing in CSCs was generated from heterochromatin construction. In addition, the vacuole-like defect in heterochromatin regions of CSCs was observed within 24 h after exposure to 10 gray (Gy) single-dose RT. Interestingly, this phenomenon was repaired from 96 h, and recovered to dense plaque structure in heterochromatin regions of CSCs after 144 h. However, no significant difference in non-CSCs was observed after RT exception for a loose chromatin structure. CONCLUSIONS: CSCs play a role in radiosensitivity in colorectal cancer. The mechanism may be related to heterochromatin formation and histone methylation.

Endostar, a recombined humanized endostatin, enhances the radioresponse for human nasopharyngeal carcinoma and human lung adenocarcinoma xenografts in mice.

The purpose of this paper is to determine the efficacy of combining radiation therapy with endostar, a recombined humanized endostatin, in human nasopharyngeal carcinoma and human lung adenocarcinoma xenografts. Tumor xenografts were established in the hind limb of male athymic nude mice (BALB/c-nu) by subcutaneous transplantation. The tumor-bearing mice were assigned into four treatment groups: sham therapy (control), endostar (20 mg/kg, once daily for 10 days), radiation therapy (6 Gray per day to 30 Gray, once a day for 1 week), and endostar plus radiation therapy (combination). The experiment was repeated and mice were killed at days 3, 6, and 10 after initiation therapy, and the tumor tissues and blood samples were collected to analyze the kinetics of antitumor, antiangiogenesis, and antivascularization responses of different therapies. In human nasopharyngeal carcinoma and human lung adenocarcinoma xenografts, endostar significantly enhanced the effects of tumor growth inhibition, endothelial cell and tumor cell apoptosis induction, and improved tumor cell hypoxia of radiation therapy. Histological analyses demonstrated that endostar plus radiation also induced a significant reduction in microvascular density, microvascular area, and vascular endothelial growth factor and matrix metalloproteinase-2 expression compared with radiation and endostar alone respectively. We concluded that endostar significantly sensitized the function of radiation in antitumor and antiangiogenesis in human nasopharyngeal carcinoma and human lung adenocarcinoma xenografts by increasing the apoptosis of the endothelial cell and tumor cell, improving the hypoxia of the tumor cell, and changing the proangiogenic factors. These data provided a rational basis for clinical practice of this multimodality therapy.

Effectiveness and tolerability of NSAIDs in the prophylaxis of pancreatitis after endoscopic retrograde cholangiopancreatography: A systematic review and meta-analysis.

BACKGROUND: Acute pancreatitis is a common complication of endoscopic retrograde cholangiopancreatography (ERCP). The beneficial effects of pharmaco-logic treatment of acute pancreatitis are unclear. Although the prophylactic use of NSAIDs for the reduction of the risk for pancreatic injury after ERCP has been assessed, the beneficial effects of NSAIDs on pancreatic injury are still being debated. OBJECTIVE: The aim of this study was to determine the effectiveness and tolerability of NSAIDs in the prophylaxis of post-ERCP pancreatitis (PEP). METHODS: MEDLINE (January 1966-January 2009), EMBASE (January 1966-January 2009), and the Cochrane Central Register of Controlled Trials (Issue 1, 2009) were searched using the key terms: pancreatitis, post-ERCP pancreatitis, nonsteroidal anti-inflammatory drugs, indomethacin, and diclofenac. The methods recommended by the Cochrane Collaboration and the Quality of Reporting Meta-Analyses guideline were used to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) of NSAIDs in the prevention of PEP. RESULTS: Four multinational RCTs were included in the meta-analysis (969 patients). The pooled odds ratio for NSAIDs for mild PEP was 0.69 (95% CI, 0.40-1.17; P = NS); moderate to severe PEP, 0.22 (95% CI, 0.05-1.01; P = 0.05); PEP (pooled), 0.44 (95% CI, 0.21-0.93; P = 0.03); in high-risk patients, 0.49 (95% CI, 0.17-1.39; P = NS); and in low-risk patients, 0.29 (95% CI, 0.12-0.71; P = 0.006). No evidence of publication bias was found. CONCLUSION: Based on the findings from the present systematic review of 4 RCTs, NSAIDs were effective and well tolerated in the prevention of PEP, especially in low-risk patients.

Gabexate mesylate in the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis: A systematic review and meta-analysis update.

BACKGROUND: Acute pancreatitis is a common complication of endoscopic retrograde cholangiopancreatography (ERCP), and the benefit of pharmacologic treatment of the condition is unclear. Although prophylactic use of gabexate mesylate (GM) for the reduction of pancreatic injury after ERCP has been evaluated, uncertainty remains regarding the effectiveness of GM treatment in post-ERCP pancreatitis (PEP). OBJECTIVE: The aim of this study was to determine through systematic review and meta-analysis the effectiveness and tolerability of GM in the prophylaxis of PEP. METHODS: MEDLINE (January 1966-July 2007), EMBASE (January 1966- July 2007), the Cochrane Controlled Trials Register on The Cochrane Library (Issue 2, 2007), and the China Biological Medicine Database (January 1978-July 2007) were searched. We used the method recommended by The Cochrane Collaboration to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) of GM in the prevention of PEP. RESULTS: Of the 38 studies identified, 31 were excluded for the following reasons: they were reviews or editorials (9 articles); were meta-analyses (4); had differences in cointerventions (4); were nonrandomized controlled trials or had incorrect randomization (4); were repeat publications (2); lacked a placebo group (1); or other (7). Seven RCTs, totaling 2883 patients, conducted in a variety of languages were included in the meta-analysis. When the RCTs were analyzed, odds ratios for GM were 0.65 (95% CI, 0.36-1.18; P 0.16) for PER 1.90 (95% CI, 0.54-6.65; P 0.32) for severe PEP, 0.55 (95% CI, 0.17-1.77; P 0.32) for the case-fatality ratio of PEP, 0.88 (95% CI, 0.74-1.05; P 0.16) for post-ERCP hyperamylasemia, and 0.78 (95% CI, 0.49 1.25; P 0.30) for post-ERCP abdominal pain. No evidence of publication bias was found. CONCLUSIONS: No beneficial effects of GM on acute pancreatitis, the PEP mortality rate, or post-ERCP abdominal pain or hyperamylasemia were found; therefore, GM cannot be recommended for the prophylaxis of PEP.

Targeting Myeloid-derived Suppressor Cells and Programmed Death Ligand 1 Confers Therapeutic Advantage of Ablative Hypofractionated Radiation Therapy Compared With Conventional Fractionated Radiation Therapy.

PURPOSE: Ablative hypofractionated radiation therapy (AHFRT) presents a therapeutic advantage compared with conventional fractionated radiation therapy (CFRT) for primary and oligometastatic cancers. However, the underlying mechanisms remain largely unknown. In the present study, we compared the immune alterations in response to AHFRT versus CFRT and examined the significance of immune regulations contributing to the efficacy of AHFRT. METHODS AND MATERIALS: We established subcutaneous tumors using syngeneic lung cancer and melanoma cells in both immunocompetent and immunocompromised mice and treated them with AHFRT and CFRT under the same biologically equivalent dose. RESULTS: Compared with CFRT, AHFRT significantly inhibited tumor growth in immunocompetent, but not immunocompromised, mice. On the cellular level, AHFRT reduced the recruitment of myeloid-derived suppressor cells (MDSCs) into tumors and decreased the expression of programmed death-ligand 1 (PD-L1) on those cells, which unlashed the cytotoxicity of CD8+ T cells. Through the downregulation of vascular endothelial growth factor (VEGF), AHFRT inhibited VEGF/VEGF receptor signaling, which was essential for MDSC recruitment. When combined with anti-PD-L1 antibody, AHFRT presented with greater efficacy in controlling tumor growth and improving mouse survival. By altering immune regulation, AHFRT, but not CFRT, significantly delayed the growth of secondary tumors implanted outside the irradiation field. CONCLUSIONS: Targeting MDSC recruitment and enhancing antitumor immunity are crucial for the therapeutic efficacy of AHFRT. When combined with anti-PD-L1 immunotherapy, AHFRT was more potent for cancer treatment.

Ablative Hypofractionated Radiation Therapy Enhances Non-Small Cell Lung Cancer Cell Killing via Preferential Stimulation of Necroptosis In Vitro and In Vivo.

PURPOSE: To investigate how necroptosis (ie, programmed necrosis) is involved in killing of non-small cell lung cancer (NSCLC) after ablative hypofractionated radiation therapy (HFRT). METHODS AND MATERIALS: Deoxyribonucleic acid damage, DNA repair, and the death form of NSCLC cells were assessed after radiation therapy. The overexpression and silencing of receptor-interacting protein kinases 3 (RIP3, a key protein involved activation of necroptosis)-stable NSCLC cell lines were successfully constructed. The form of cell death, the number and area of colonies, and the regulatory proteins of necroptosis were characterized after radiation therapy in vitro. Finally, NSCLC xenografts and patient specimens were used to examine involvement of necroptosis after ablative HFRT in vivo. RESULTS: Radiation therapy induced expected DNA damage and repair of NSCLC cell lines, but ablative HFRT at ≥10 Gy per fraction preferentially stimulated necroptosis in NSCLC cells and xenografts with high RIP3 expression, as characterized by induction and activation of RIP3 and mixed-lineage kinase domain-like protein and release of immune-activating chemokine high-mobility group box 1. In contrast, RNA interference of RIP3 attenuated ablative HFRT-induced necroptosis and activation of its regulatory proteins. Among central early-stage NSCLC patients receiving stereotactic body radiation therapy, high expression of RIP3 was associated with improved local control and progression-free survival (all P < .05). CONCLUSIONS: Ablative HFRT at ≥10 Gy per fraction enhances killing of NSCLC with high RIP3 expression via preferential stimulation of necroptosis. RIP3 may serve as a useful biomarker to predict favorable response to stereotactic body radiation therapy.

Sublobar resection is associated with improved outcomes over radiotherapy in the management of high-risk elderly patients with Stage I non-small cell lung cancer: a systematic review and meta-analysis.

BACKGROUND AND AIM: A matched-pair comparison was performed to compare the efficacy and safety of sublobar resection versus radiotherapy for high-risk elderly patients with Stage I non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: We searched the Cochrane Library, MEDLINE, CENTRAL, EMBASE and manual searches. The meta-analysis was performed to compare overall survival, pattern of failure, and toxicity among the homogeneous studies. Subdivided analyses were also performed. RESULTS: Sixteen studies containing 11540 patients were included in the meta-analysis. Among these studies, 9 were propensity-score matched (PSM) cohort studies, and 7 were cohort studies. Sublobar resection, compared with radiotherapy (either conventional fraction radiation therapy or stereotactic body radiation therapy), significantly improved the overall survival regardless in both PSM and non-PSM analyses (all p < 0.05). However, the difference in the pattern of failure and toxicity were not significant (all p > 0.05). CONCLUSIONS: Sublobar resection was associated with improved outcomes in high-risk elderly patients with Stage I NSCLC, which supports the need to compare both treatments in large prospective, randomized, controlled clinical trials.

Early postoperative radiotherapy is associated with improved outcomes over late postoperative radiotherapy in the management of completely resected (R0) Stage IIIA-N2 non-small cell lung cancer.

AIMS: The aim of this study was to evaluate the ideal timing of PORT in the management of completely resected (R0) Stage IIIA-N2 NSCLC. PATIENTS AND METHODS: Between January 2008 and December 2015, patients with known histologies of pathologic Stage IIIA-N2 NSCLC who underwent R0 resection and received PORT concurrent with or prior to two sequential cycles of chemotherapy ("early PORT") or with PORT administered after two cycles of chemotherapy ("late PORT") at multiple hospitals. The primary endpoint was OS; secondary end points included pattern of the first failure, LRRFS, and DMFS. Kaplan-Meier OS, LRRFS, and DMFS curves were compared with the log-rank test. Cox regression analysis was used to determine prognosticators for OS, LRRFS, and DMFS. RESULTS: Of 112 included patients, 41 (36.6%) and 71 (63.4%) patients received early PORT and late PORT, respectively. The median OS, LRRFS, and DMFS were longer for those who received early PORT than for those who received late PORT at the median follow-up of 29.6 months (all p < 0.05). Uni- and multi-variate analyses showed that number of POCT cycles and the combination schedule of PORT and POCT were independent prognostic factors for OS, LRRFS, and DMFS. CONCLUSIONS: Early PORT is associated with improved outcomes in pathologic Stage IIIA-N2 R0 NSCLC patients.

Necroptosis in tumorigenesis, activation of anti-tumor immunity, and cancer therapy.

While the mechanisms underlying apoptosis and autophagy have been well characterized over recent decades, another regulated cell death event, necroptosis, remains poorly understood. Elucidating the signaling networks involved in the regulation of necroptosis may allow this form of regulated cell death to be exploited for diagnosis and treatment of cancer, and will contribute to the understanding of the complex tumor microenvironment. In this review, we have summarized the mechanisms and regulation of necroptosis, the converging and diverging features of necroptosis in tumorigenesis, activation of anti-tumor immunity, and cancer therapy, as well as attempts to exploit this newly gained knowledge to provide therapeutics for cancer.