Real-world association between systemic corticosteroid exposure and complications in US patients with severe asthma.

BACKGROUND: Systemic corticosteroid (SCS) use remains widespread among patients with severe asthma, despite associated complications. OBJECTIVE: Evaluate the association between cumulative SCS exposure and SCS-related complications in severe asthma. METHODS: This retrospective, longitudinal study used claims data from the Optum Clinformatics Data Mart database (GSK ID: 214469). Eligible patients (≥ 12 years old) had an asthma diagnosis and were divided into two cohorts: SCS use and non/burst-SCS use. Patients in the SCS use cohort had a claim for a daily prednisone-equivalent dose ≥ 5 mg SCS following ≥ 6 months of continuous SCS use; those in the non/burst-SCS cohort had no evidence of continuous SCS use and had a non-SCS controller/rescue medication initiation claim. For each cohort, the date of the qualifying claim was the index date. SCS users were further stratified by SCS use during each quarter of follow-up: low (≤ 6 mg/day), medium (> 6-12 mg/day), high (> 12 mg/day), and continuous high (≥ 20 mg/day for 90 days). SCS-related complications were evaluated in the quarter following SCS exposure. The adjusted odds ratios (OR) of experiencing SCS-related complications during follow-up in each of the SCS use groups versus the non/burst SCS cohort were calculated using generalized estimating equations models. RESULTS: SCS and non/burst-SCS use cohorts included 7473 and 89,281 patients (mean follow-up: 24.6 and 24.2 months), respectively. Compared with the non/burst-SCS use cohort, medium, high, and continuous high SCS use was associated with greater odds of any SCS-related complication (adjusted OR [95% confidence interval]: 1.30 [1.21, 1.39], 1.49 [1.35, 1.64] and 1.63 [1.40, 1.89], respectively) including increased acute gastrointestinal, cardiovascular, and immune system-related complications, and chronic cardiovascular, metabolic/endocrine, central nervous system, bone-/muscle-related, ophthalmologic, and hematologic/oncologic complications. Low-dose SCS use was also associated with significantly increased odds of acute gastrointestinal and immune system-related complications, and chronic bone-/muscle-related and hematologic/oncologic complications versus the non/burst-SCS use cohort. CONCLUSION: SCS use, even at low doses, is associated with increased risk of SCS-related complications among patients with severe asthma.

Diabetes mellitus in Kabuki syndrome 1 on a background of post-transplant diabetes mellitus.

Summary: Kabuki syndrome is a genetic disorder characterised by distinctive facial features, developmental delays, and multisystem congenital anomalies. Endocrine complications such as premature thelarche and short stature are common, whereas disorders of glycaemic control are less frequent. We describe a 23-year-old white female referred to the diabetes clinic for hyperglycaemia during haemodialysis. She was subsequently diagnosed with Kabuki syndrome based on characteristic clinical features, confirmed by detecting a heterozygous pathogenic variant in KMT2D. She was known to have had multiple congenital anomalies at birth, including complex congenital heart disease and a single dysplastic ectopic kidney, and received a cadaveric transplanted kidney at the age of 13. She had hyperglycaemia consistent with post-transplant diabetes mellitus (DM) and was started on insulin. Examination at the time revealed truncal obesity. She developed acute graft rejection and graft failure 14 months post-transplant and she was started on haemodialysis. Her blood glucose levels normalised post-graft explant, but she was hyperglycaemic again during haemodialysis at the age of 23. Given her clinical phenotype, negative diabetes antibodies and normal pancreas on ultrasound, she was assumed to have type 2 DM and achieved good glycaemic control with gliclazide. Learning points: Involve clinical genetics early in the investigative pathway of sick neonates born with multiple congenital anomalies to establish a diagnosis to direct medical care. Consider the possibility of Kabuki syndrome (KS) in the differential diagnoses in any neonate with normal karyotyping or microarray analysis and with multiple congenital anomalies (especially cardiac, renal, or skeletal), dysmorphic facial features, transient neonatal hypoglycaemia and failure to thrive. Consider the possibility of diabetes as an endocrine complication in KS patients who are obese or who have autoimmune disorders.

[Analysis of clinical and genetic variation in neonatal intrahepatic cholestasis caused by citrin deficiency].

Objective: To investigate the clinical phenotype and gene variation conditions in neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), so as to provide a basis for genetic counseling and clinical diagnosis and treatment of the family. Methods: 11 cases of neonatal intrahepatic cholestasis who visited the Children's Hospital Affiliated to Zhengzhou University between February 2019 and March 2021 were selected as the study subjects. High-throughput sequencing technology was used to detect the gene variation condition in 11 neonatal patients and 100 normal control neonates. The suspicious loci and family members were verified by Sanger sequencing and QPCR technology. Results: All 11 children with NICCD had different degrees of jaundice and liver damage symptoms, combined with coagulation dysfunction and anemia (n = 7), cardiac malformation (n = 2), elevated myocardial enzymes (n = 4), hyperlipidemia (n = 1), hyperkalemia (n = 1), persistent diarrhea (n = 3), developmental delay (n = 1). A total of 10 different types of SLC25A13 gene mutations were detected in 11 cases, including three frameshift mutations, two splicing changes, two missense mutations, one intron insertion, one nonsense mutation, and one heterozygous deletion. After reviewing literature and databases, c.1878delG(p.I627Sfs*73) and exon11 deletion were novel mutations that had not been reported at home or abroad. Conclusion: The clinical features of NICCD are non-specific, and genetic testing aids in the early and accurate diagnosis of the disease, providing an important basis for clinical treatment and genetic counseling for family members. In addition, the detection of novel mutation sites has enriched the SLC25A13 gene variation spectrum.

Cerebral arterial gas embolism and neurogenic stunned myocardium in a previously healthy freediver.

Cardiomyopathy is a known but rare sequelae of diving-related cerebral arterial gas embolism (CAGE). In previously reported cases, patient findings have been consistent with takotsubo cardiomyopathy (TCM) per the revised Mayo Clinic's diagnostic criteria. A lesser-known variant of stress-related cardiomyopathy is neurogenic stunned myocardium (NSM), which occurs after a neurological event such as subarachnoid hemorrhage and typically presents in younger patients. Presentation tends to differ slightly to TCM with non-specific left ventricular dysfunction and T wave inversions. This case adds to the rare numbers of reported cardiomyopathy from diving and is the first reported case of suspected NSM associated with CAGE.

Laparoscopic posterior pelvic exenteration is safe and feasible for locally advanced primary rectal cancer in female patients: a comparative study from China PelvEx collaborative.

PURPOSE: Posterior pelvic exenteration (PPE) for locally advanced rectal cancer is a technical and challenging procedure. The safety and feasibility of laparoscopic PPE remain to be determined. This study aims to compare short-term and survival outcomes of laparoscopic PPE (LPPE) with open PPE (OPPE) in female patients. METHOD: From January 2015 to December 2020, data from 105 female patients who underwent PPE at three institutions were retrospectively analyzed. The short-term and oncological outcomes between LPPE and OPPE were compared. RESULTS: A total of 54 cases with LPPE and 51 cases with OPPE were enrolled. The operative time (240 vs. 295 min, p = 0.009), blood loss (100 vs. 300 ml, p < 0.001), surgical site infection (SSI) rate (20.4% vs. 58.8%, p = 0.003), urinary retention rate (3.7% vs. 17.6%, p = 0.020), and postoperative hospital stay (10 vs. 13 days, p = 0.009) were significantly lower in the LPPE group. The two groups showed no significant differences in the local recurrence rate (p = 0.296), 3-year overall survival (p = 0.129), or 3-year disease-free survival (p = 0.082). A higher CEA level (HR 1.02, p = 0.002), poor tumor differentiation (HR 3.05, p = 0.004), and (y)pT4b stage (HR 2.35, p = 0.035) were independent risk factors for disease-free survival. CONCLUSION: LPPE is safe and feasible for locally advanced rectal cancers and shows lower operative time and blood loss, fewer SSI complications, and better preservation of bladder function without compromising oncological outcomes.

Impact of Therapy Management on Axitinib-Related Adverse Events in Patients With Advanced Renal Cell Carcinoma Receiving First-Line Axitinib + Checkpoint Inhibitor.

INTRODUCTION: There are limited real-world data on the effectiveness of strategies used to manage adverse events (AEs) in patients with advanced renal cell carcinoma (RCC) treated with axitinib. This retrospective chart review examined the AE profile and effect of axitinib modifications on AE resolution/improvement and treatment discontinuation. METHODS: A retrospective physician-administered chart review was conducted. Adult patients with advanced RCC treated with first-line axitinib plus checkpoint inhibitor (CPI) therapy (ie, avelumab or pembrolizumab) and who had documented frequently reported axitinib-related AEs of fatigue, diarrhea, nausea, hypertension, or palmar-plantar erythrodysesthesia were included. Physician characteristics, patient characteristics, AE characteristics, AE management strategies used, AE resolution/improvement, and treatment duration were described. The effect of strategies used to manage AEs (axitinib dose reduction or treatment interruption) on AE resolution/improvement was evaluated by logistic regression. RESULTS: Among 219 patients (median age: 62 years, 65% male), 70 (32%) were treated with axitinib + avelumab and 149 (68%) received axitinib + pembrolizumab. Axitinib modifications increased the likelihood of AE resolution/improvement compared with no modifications (adjusted odds ratio: 6.34, P < .001). In the subset of patients who discontinued treatment among those with or without axitinib modifications, mean treatment duration was 7.0 and 1.7 months, respectively. CONCLUSION: Toxicities experienced by patients with advanced RCC treated with first-line axitinib-CPI in the real world can be effectively managed by axitinib modifications, thereby prolonging treatment duration. (Clinicaltrials.gov identifier: NCT04682587).

[Laparoscopic versus open pelvic exenteration for locally advanced rectal cancer: analysis of short- and long-term effects].

Objective: To explore the feasibility, safety, and short- and long-term efficacy of laparoscopic pelvic exenteration (LPE) in treating locally advanced rectal cancer. Methods: The clinical data of 173 patients who had undergone pelvic exenteration (PE) for locally advanced rectal cancer that had been shown by preoperative imaging or intraoperative exploration to have invaded beyond the mesorectal excision plane and adjacent organs in the Cancer Hospital, Chinese Academy of Medical Sciences (n=64) and Peking University First Hospital (n=109) from 2010 January to 2021 December were collected retrospectively. Laparoscopic PE (LPE) had been performed on 82 of these patients and open PE (OPE) on 91. Short- and long-term outcomes (1-, 3-, and 5-year overall and disease-free survival and 1- and 3-year cumulative local recurrence rates) were compared between these groups. Results: The only statistically significant difference in baseline data between the two groups (P>0.05) was administration of neoadjuvant therapy. Compared with OPE, LPE had a significantly shorter operative time (319.3±129.3 minutes versus 417.3±155.0 minutes, t=4.531, P<0.001) and less intraoperative blood loss (175 [20-2000] ml vs. 500 [20-4500] ml, U=2206.500, P<0.001). The R0 resection rates were 98.8% and 94.5%, respectively (χ2=2.355, P=0.214). At 18.3% (15/82), and the incidence of perioperative complications was lower in the LPE group than in the OPE group (37.4% [34/91], χ2=7.727, P=0.005). The rates of surgical site infection were 7.3% (6/82) and 23.1% (21/91) in the LPE and OPE group, respectively (χ2=8.134, P=0.004). The rates of abdominal wound infection were 0 and 12.1% (11/91) (χ2=10.585, P=0.001), respectively, and of urinary tract infection 0 and 6.6% (6/91) (χ2=5.601, P=0.030), respectively. Postoperative hospital stay was shorter in the LPE than OPE group (12 [4-60] days vs. 15 [7-87] days, U=2498.000, P<0.001). The median follow-up time was 40 (2-88) months in the LPE group and 59 (1-130) months in the OPE group. The 1-, 3-, and 5-year overall survival rates were 91.3%, 76.0%, and 62.5%, respectively, in the LPE group, and 91.2%, 68.9%, and 57.6%, respectively, in the OPE group. The 1, 3, and 5-year disease-free survival rates were 82.8%, 64.9%, and 59.7%, respectively, in the LPE group and 76.9%, 57.8%, and 52.7%, respectively, in the OPE group. The 1- and 3-year cumulative local recurrence rates were 5.1% and 14.1%, respectively, in the LPE group and 8.0% and 15.1%, respectively, in the OPE group (both P>0.05). Conclusions: In locally advanced rectal cancer patients, LPE is associated with shorter operative time, less intraoperative blood loss, fewer perioperative complications, and shorter hospital stay compared with OPE. It is safe and feasible without compromising oncological effect.

Retrospective Study to Examine Prognostic Value of C-Reactive Protein in Patients With Surgically Resectable Non-Small-Cell Lung Cancer.

BACKGROUND: This study evaluated the association between elevated C-reactive protein (CRP) and clinical outcomes among adults treated with surgery for non-small cell lung cancer (NSCLC) in the US. MATERIALS AND METHODS: Adults with NSCLC who underwent lung cancer surgery and had ≥1 CRP measurement prior to, or >1 month following, index surgery were identified in the Optum Clinformatics claims database. The association between elevated CRP (>10 mg/L) and risk of NSCLC recurrence/death was assessed separately during the 6 months before surgery (pre surgery cohort) and 2 years following surgery (post-surgery cohort) using multivariate regressions and Kaplan-Meier analysis. RESULTS: After adjusting for baseline demographic and clinical characteristics among patients in the pre surgery cohort with index surgery between 2016 to 2020 (n = 104), the incidence rate ratio (IRR) for NSCLC recurrence between elevated vs. non-elevated CRP was 2.17 (95% confidence interval [CI]=1.03-4.60; P = .04). In the post surgery cohort (n = 264), the adjusted IRR for disease recurrence (elevated vs. non-elevated CRP) was 2.22 (95% CI=1.05-4.70; P = .04). In the pre surgery cohort, the odds of death were nearly two-fold (odds ratio [OR]=1.91; 95% CI=1.06-3.42; P = .03) among patients with elevated CRP. In the post surgery cohort, the OR was 1.62 (95% CI=0.88-2.97; P = .12). Among those with persistently elevated CRP prior to surgery, there was a significant overall trend of increased CRP over the 5-year period. CONCLUSION: These results support the association between elevated CRP and a higher risk of NSCLC recurrence/death in pre- and postsurgery cohorts. This study may shed lights on inflammation-suppressing treatments in patients with NSCLC.

[Survival analysis of early-onset locally advanced rectal cancer: a retrospective study based on the Surveillance, Epidemiology, and End Results (SEER) database].

Objective: To investigate the factors influencing tumor-specific survival of early-onset locally advanced rectal cancer. Methods: All-age patients with primary locally advanced rectal cancer from the Surveillance, Epidemiology, and End Results (SEER) database (2010 to 2019) were included in this study. Early- and late-onset locally advanced rectal cancer was defined according to age of 50 years at diagnosis. Early-onset locally advanced rectal cancer was divided into five age groups for subgroup analyses. Age, sex, tumor-specific survival time and survival status of patients at diagnosis, pathological grade, TNM stage, perineural invasion, tumor deposits, tumor size, pretreatment CEA , radiotherapy, chemotherapy, and number of lymph node dissections were included. Progression-free survival (PFS) was analyzed and compared between patients with early- and late-onset rectal cancer. Results: A total of 5,048 patients with locally advanced rectal cancer were included in the study (aged 27-70 years): 1,290 (25.55%) patients with early-onset rectal cancer and 3,758 (74.45%) patients with late-onset rectal cancer. Patients with early-onset rectal cancer had a higher rate of perineural invasion (P<0.001), more positive lymph nodes dissected (P<0.001), higher positive lymph node ratios (P<0.001), and a higher proportion receiving preoperative radiotherapy (P=0.002). Patients with early-onset rectal cancer had slightly better short-term survival than those with late-onset rectal cancer (median (IQR ): 54 (33-83) vs 50 (31-79) months, χ2=5.192, P=0.023). Multivariate Cox regression for all patients with locally advanced rectal cancer showed that age (P=0.008), grade of tumor differentiation (P=0.002), pretreatment CEA (P=0.008), perineural invasion (P=0.021), positive number (P=0.004) and positive ratio (P=0.001) of dissected lymph nodes, and sequence of surgery and radiotherapy (P=0.005) influenced PFS. This suggests that the Cox regression results for all patients may not be applicable to patients with early-onset cancer. Cox analysis showed tumor differentiation grade (patients with low differentiation had a higher risk of death, P=0.027), TNM stage (stage III patients had a higher risk of death, P=0.025), T stage (higher risk of death in stage T4, P<0.001), pretreatment CEA (P=0.002), perineural invasion (P<0.001), tumor deposits (P=0.005), number of dissected lymph nodes (patients with removal of 12-20 lymph nodes had a lower risk of death, P<0.001), and positive number of dissected lymph nodes (P<0.001) were independent factors influencing PFS of patients with early-onset locally advanced rectal cancer. Conclusion: Patients with early-onset locally advanced rectal cancer were more likely to have adverse prognostic factors, but an adequate number of lymph node dissections (12-20) resulted in better survival outcomes.

Nuclear stabilization of p53 requires a functional nucleolar surveillance pathway.

The nucleolar surveillance pathway monitors nucleolar integrity and responds to nucleolar stress by mediating binding of ribosomal proteins to MDM2, resulting in p53 accumulation. Inappropriate pathway activation is implicated in the pathogenesis of ribosomopathies, while drugs selectively activating the pathway are in trials for cancer. Despite this, the molecular mechanism(s) regulating this process are poorly understood. Using genome-wide loss-of-function screens, we demonstrate the ribosome biogenesis axis as the most potent class of genes whose disruption stabilizes p53. Mechanistically, we identify genes critical for regulation of this pathway, including HEATR3. By selectively disabling the nucleolar surveillance pathway, we demonstrate that it is essential for the ability of all nuclear-acting stresses, including DNA damage, to induce p53 accumulation. Our data support a paradigm whereby the nucleolar surveillance pathway is the central integrator of stresses that regulate nuclear p53 abundance, ensuring that ribosome biogenesis is hardwired to cellular proliferative capacity.

[Risk factor and nomogram for predicting the probability of a permanent stoma after laparoscopic intersphincteric resection for ultralow rectal cancer].

Objective: A permanent stoma can seriously affect patients' quality of life. Clinicians need to consider the risk of a permanent stoma when making clinical decisions. This study analyzed preoperative predictors of a permanent stoma after laparoscopic intersphincteric resection for low rectal cancer (LISR), and a prediction model was constructed validated. Methods: This was a retrospective study that analyzed clinical data of 331 ultralow rectal cancer patients who were diagnosed with primary rectal adenocarcinoma by endoscopy and pathology, including 218 males and 113 female, (58.8±11.2) years and (23.7±3.1) kg/m2. The patients underwent LISR with a preventive stoma from January 2012 to December 2020. Patients with multiple primary colorectal cancers, who underwent emergency surgery for intestinal obstruction or bleeding or perforation, and did not complete 18 months follow up were exclucled. R software was used to randomly select 234 patients as the modeling group with a ratio of approximately 7:3, and the remaining 97 patients comprised the validation group. The stoma site was determined by the surgeon before the operation, and the ileum 30 cm from the ileocecal valve was selected. The rates of a permanent stoma for the entire group and the preoperative clinical factors that may affect the permanency of a stoma in the modeling group were determined. A permanent stoma was defined as failure to close the stoma at 18 months after surgery. Multivariate logistic regression analysis was used to analyze the preoperative independent risk factors for a permanent stoma after LISR. R software was used to create the nomogram model, and the predictive ability of the nomogram model was evaluated by receiver operating characteristic (ROC) curve analysis. Results: Among the 331 patients who underwent LISR, 37 (26 cases in the modeling group and 11 cases in the validation group, 11.2%) developed a permanent stoma for the following reasons: anastomotic stenosis due to leakage (16 cases, 43.2%), distant metastasis (16 cases, 43.2%), intolerant to stoma closure surgery (3 cases, 8.1%), stenosis due to postoperative radiation (1 case, 2.7%), and poor recovery of anorectal function (1 case, 2.7%). Univariate analysis showed that preoperative neoadjuvant chemoradiotherapy, poorly differentiated tumor, cT3 stage, and distant metastasis were associated with a permanent stoma. Multivariate logistic regression analysis showed that neoadjuvant chemoradiotherapy [OR=3.078, 95% confidence interval (CI): 1.326-7.147; P=0.009], cT3 stage (OR=2.257, 95%CI: 1.001-5.091; P=0.049), and stage IV cancer (OR=16.180, 95%CI: 2.753-95.102; P=0.002) were independent risk factors for permanent stoma after LISR. Based on the selected risk factors, a nomogram model for predicting permanent stoma was constructed. The area under the ROC curve of the modeling group was 0.793, the optimal cut-off value was 0.890, the sensitivity was 0.577, and the specificity was 0.885. The area under the ROC curve of the validation group was 0.953. The corrected curves of the modeling group and the validation group showed a good degree of fit. Conclusion: Neoadjuvant chemoradiotherapy, cT3 stage, and distant metastasis are independent predictors of a permanent stoma after LISR, and the nomogram model is helpful to predict the probability of a permanent stoma. Patients with high-risk factors should be adequately informed of the risk of a permanent stoma before colorectal surgery.

Burden Among Caregivers of Pediatric Patients with Neurofibromatosis Type 1 (NF1) and Plexiform Neurofibroma (PN) in the United States: A Cross-Sectional Study.

INTRODUCTION: Patients with neurofibromatosis type 1 (NF1) may develop plexiform neurofibromas (PNs) that can cause disfigurement, pain, and dysfunction, and may even be life-threatening. Studies have indicated NF1-PN can substantially impact the quality of life (QoL) of pediatric patients. However, research on caregiver burden is scarce. METHODS: Caregivers of pediatric patients ages 2-18 years with NF1-PN in the USA were recruited through the Children's Tumor Foundation to participate in an online cross-sectional survey (December 2020-January 2021). Caregiver burden was measured using the Zarit Burden Interview (ZBI), and productivity loss from patientcare was measured using the Work Productivity and Activity Impairment questionnaire, adapted for caregiving (WPAI:CG). RESULTS: Ninety-five caregivers were recruited with a median age of 44.0 years. Most were female (88.4%), white/Caucasian (85.3%), and did not have NF1 or PN (86.3% and 89.5%, respectively). Commonly reported health conditions among caregivers include anxiety (48.4%) and depression (34.7%). On the ZBI (range 0-88; higher = greater burden), mean (SD) scores were 23.0 (13.8) and 12.7% of caregivers reported moderate-severe (scores 41-60) or severe burden (scores 61-88). Fifty-six caregivers were employed and working in the 7 days prior to completing the WPAI:CG. They reported missing an average of 6.9% of their working hours and an average reduction of 17.3% of on-the-job effectiveness, contributing to 22.3% loss in work productivity. Among all 95 caregivers, an average of 17.2% of regular daily activities were impaired. CONCLUSIONS: The burden among caregivers of pediatric patients with NF1-PN is considerable and underscores an unmet need for better disease management.

Excretory/secretory proteins of adult Toxocara canis induce changes in the expression of proteins involved in the NOD1-RIP2-NF-κB pathway and modulate cytokine production in mouse macrophages.

Dog roundworm (Toxocara canis) is the major causative agent of toxocarosis, a parasitic disease of both veterinary and medical importance. Knowledge gaps in fundamental and applied aspects hinder the control of this important zoonotic disease. To have a better understanding of Toxocara infection and host immune responses, mouse macrophages were exposed to excretory/secretory (ES) proteins released by adult worms of T. canis in vitro. The messenger RNA transcription and protein expression of nucleotide-binding oligomerization domain-containing protein 1 (NOD1), receptor interacting protein 2 (RIP2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in macrophages were analysed using quantitative real-time PCR (qRT-PCR) and Western blot. The levels of tumour necrosis factor alpha (TNF-ɑ), interleukin-1 beta (IL-1ß) and IL-6 released by the stimulated macrophages were analysed using enzyme-linked immunosorbent assay. It was found that 20 µg/mL ES proteins of adult T. canis induced the expression of NOD1, RIP2 and NF-κB in mouse macrophages at both transcriptional and translational levels after 9 h of incubation in vitro. Incubation with 20 µg/mL ES proteins also modulated the production of pro-inflammatory cytokines TNF-ɑ, IL-1ß and IL-6 by the macrophages. Taken together, ES proteins of adult T. canis appeared to be able to affect the macrophage NOD1-RIP2-NF-κB signalling pathway, which might play a role in regulating the production of proinflammatory cytokines. Further investigation of these aspects should lead to a better understanding of immune recognition of and modulation by Toxocara canis in host animals.

[Comparison on efficacy between fascia-oriented versus vascular-oriented lateral lymph node dissection in patients with rectal cancer].

Objective: To compare the postoperative function, the short-term and long-term outcomes between fascia-oriented and vascular-oriented lateral lymph node dissection (LLND) in patients with rectal cancer. Methods: A retrospective cohort study was performed. Clinical data of patients who received total mesorectal excision (TME) with LLND at National Cancer Center, Cancer Hospital of Chinese Academy of Medical Science from January 2014 to December 2019 were retrospectively collected. Inclusion criteria were as follows: (1) rectal cancer was pathologically diagnosed, and the lower margin was below the peritoneal reflection. (2) resectable advanced rectal cancer with suspected lateral lymph node metastasis was evaluated based on rectal MRI assessment. (3) preoperative MRI showed lateral lymph node short diameter ≥5 mm and/or lymph node morphology (spike, blur, irregular) as well as heterogenous signal intensity. Lymph node shrinkage was less than 60% after receiving neoadjuvant therapy based on the reassessment of rectal MRI. (4) TME+LLND surgery was performed synchronously. Exclusion criteria were as follows: (1) previous history of pelvic surgery; (2) preoperative cystitis, urethritis, moderate and severe prostatic hyperplasia and other diseases resulting in abnormal urination function; (3) preoperative sexual dysfunction or loss of function; (4) patients receiving LLND due to lateral recurrence after TME; (5) distant metastasis of the tumor at initial diagnosis; (6) Incomplete collection of clinical data. A total of 73 consecutive patients were enrolled in this study. Based on the surgical approaches in performing LLND, patients were divided into fascia-oriented group (n=30) and vascular-oriented group (n=43). There were no significant differences in baseline data between the two groups (all P>0.05). The main outcome indicators of this study were the incidence of postoperative urinary and male sexual dysfunction, the efficacy, the number of lateral lymph nodes harvested and the detection rate of positive lymph nodes. Overall survival (OS) rates and progression free survival (PFS) rates were calculated by the Kaplan-Meier method and compared by log-rank test. Results: All patients in both groups completed surgery successfully. There were no significant differences in operation time, intraoperative blood loss, postoperative complications, and the length of hospital stay between the two groups (all P>0.05). In the whole group, the incidence of postoperative urinary dysfunction and male sexual dysfunction was 43.8% (32/73) and 62.5% (25/40), respectively. The median number of lateral lymph nodes harvested was 8.0(4.0,11.0) with a positive rate of 20.5%(15/73). Compared to the vascular-oriented group, the fascia-oriented group demonstrated a decreased rate of urinary dysfunction [26.7% (8/30) vs. 55.8% (24/43), χ(2)=6.098, P=0.014], lower rate of sexual dysfunction in males [6/15 vs. 76% (19/25), χ(2)=5.184, P=0.023], more harvested lateral lymph nodes [M (P25, P75): 9.5 (6.8, 15.3) vs. 6.0 (3.0, 9.0), Z=-2.849, P=0.004]. There was no significant difference in the positvie rate of lateral lymph nodes between the two groups [20% (6/30) versus 20.9% (9/43), χ(2)=0.009, P=0.923]. Three(4.1%) patients were lost during a median follow-up of 34 (1-66) months. The 3-year PFS and OS of the whole cohort were 69.5% and 88.3%, respectively. No significant difference in 3-year PFS rates (79.6% vs. 62.0%, P=0.172) and 3-year OS rates (91.2% vs. 85.9%, P=0.333) were observed between the fascia-oriented group and the vascular-oriented group (both P>0.05). Conclusion: Fascia-oriented LLND is associated with lower risk of postoperative urinary and male sexual dysfunction in patients with rectal carcinoma, and harvest of more lymph nodes, but no significant advantage in long-term survival.

Cigarette Smoke Exposure Inhibits Osteoclast Apoptosis via the mtROS Pathway.

It is widely known that smoking is a risk factor for bone loss and plays a key role in osteopenia. Despite this well-known association, the mechanisms by which smoking affects bone have not been definitively established. Since smoking increases bone loss and potentially affects bone resorption in response to mechanical force, we investigated the impact of cigarette smoke on osteoclast numbers and underlying mechanisms in a mouse model of orthodontic tooth movement (OTM). The experimental group was exposed to once-daily cigarette smoke while the control group was not, and tooth movement distance and osteoclast numbers were assessed. In addition, the effect of cigarette smoke extract (CSE) on osteoclast precursor proliferation and osteoclast apoptosis was assessed in vitro. We found that cigarette smoke exposure enhanced bone remodeling stimulated by mechanical force and increased osteoclast numbers in vivo. Also, CSE increased the number of osteoclasts by inhibiting osteoclast apoptosis via the mitochondrial reactive oxygen species/cytochrome C/caspase 3 pathway in vitro. Moreover, exposure of mice to cigarette smoke affected bone marrow cells, leading to increased formation of osteoclasts in vitro. This study identifies a previously unknown mechanism of how smoking has a detrimental impact on bone.

Clinical Effectiveness of Second-line Sunitinib Following Immuno-oncology Therapy in Patients with Metastatic Renal Cell Carcinoma: A Real-world Study.

BACKGROUND: Limited data exist on the clinical effectiveness of second-line (2L) vascular endothelial growth factor (receptor) targeted inhibitor (VEGF(R)i) sunitinib after first-line (1L) immuno-oncology (IO) therapy for patients with metastatic renal cell carcinoma (mRCC) in real-world settings. METHODS: A retrospective cohort study among adult patients with mRCC treated with 2L sunitinib following 1L IO was conducted from select International mRCC Database Consortium (IMDC) centers. All analyses were performed overall and by 1L ipilimumab + nivolumab (IPI+NIVO) or 1L IO+VEGF(R)i. Median overall survival (mOS) and time-to-treatment discontinuation (mTTD) in 2L were estimated using Kaplan-Meier analysis. The 2L objective response rate (ORR) (complete/partial response) was reported. RESULTS: Among 102 patients on 2L sunitinib, mean age was 61.3 years. IMDC risk scores at 2L initiation was available for 83 patients: 8 (9.6%) were favorable, 45 (54.2%) were intermediate, and 30 (36.1%) were poor risk. The 1L consisted of IPI+NIVO in 62 (60.8%), IO+VEGF(R)i therapy in 27 (26.5%), and IO monotherapy in 13 (12.7%) patients. Among all patients, mOS was 15.6 months (95% confidence interval [CI], 9.8-21.7), with a 1-year OS rate of 57.5% (95% CI, 45.2-68.0). mTTD was 5.4 months (95% CI, 4.2-7.2) and ORR was 22.5%. CONCLUSION: Despite availability of effective 1L therapies in recent years, 2L sunitinib continues to have clinical activity after failure of 1L IO. Further studies on optimal treatment sequencing after 1L IO progression are needed.

Veterans Affairs Prostate Cancer Treatment Sequencing (VAPCaTS): A Real-World Evidence Study of Men with Metastatic Prostate Cancer.

INTRODUCTION: Limited real-world data are available on treatment sequences for patients with metastatic hormone-sensitive prostate cancer treated with androgen deprivation therapy plus docetaxel or abiraterone who progress to castrate resistance. METHODS: Veterans Health Affairs electronic medical records were used to analyze 240 men treated for metastatic hormone-sensitive prostate cancer with androgen deprivation therapy plus either docetaxel ("docetaxel cohort," 208 patients, selected to be overrepresented, July 2014 to August 2018) or abiraterone ("abiraterone cohort," 32 patients, December 2016 to September 2018) who received at least 1 treatment after progressing to castrate resistance. RESULTS: For docetaxel and abiraterone cohorts, respectively, mean age at androgen deprivation therapy initiation was 65 and 72 years, and median followup was 2.2 and 1.4 years. Overall, the maximum number of metastatic castrate resistant prostate cancer treatment lines was 6; 106 patients (44%) had 1, 71 (30%) had 2, and 63 (26%) had 3 or more lines. Most patients received an androgen receptor targeted agent for initial metastatic castrate resistant prostate cancer treatment (94% vs 78% in docetaxel vs abiraterone cohort). Androgen receptor targeted agents were given consecutively to 62% of the docetaxel cohort receiving second line therapy, and to 78% of the abiraterone cohort. Across all metastatic castrate resistant prostate cancer treatment lines 72 (30%) received a taxane (47 docetaxel and 41 cabazitaxel). CONCLUSIONS: Most patients received androgen receptor targeted agents as first metastatic castrate resistant prostate cancer treatment regardless of initial metastatic hormone-sensitive treatment. Moreover, a large proportion were treated with consecutive androgen receptor targeted agents. Given recent evidence suggesting poorer outcomes with this treatment in some patients, longer followup is needed to assess the association between treatment sequence and optimal outcomes.

Outcomes of Patients with Metastatic Renal Cell Carcinoma Treated with Targeted Therapy After Immuno-oncology Checkpoint Inhibitors.

BACKGROUND: Immuno-oncology (IO) therapies have changed the treatment standards of metastatic renal cell carcinoma (mRCC). However, the effectiveness of targeted therapy following discontinuation of IO therapy in real-world settings has not been well studied. OBJECTIVE: To describe treatment sequence and assess clinical effectiveness of targeted therapy for mRCC patients who received prior IO therapy. DESIGN, SETTING, AND PARTICIPANTS: A retrospective, longitudinal cohort study using data from eight international cancer centers was conducted. Patients with mRCC were ≥18yr old, received IO therapy in any line, and initiated targeted therapy following IO therapy discontinuation. INTERVENTION: Patients were treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) or mammalian target of rapamycin inhibitors (mTORIs). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes were time to treatment discontinuation (TTD), overall survival (OS), and objective response rate (ORR). Crude and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazard models. Models were adjusted for age, sex, therapy line, and International Metastatic RCC Database Consortium risk group. RESULTS AND LIMITATIONS: Among 314 patients, 276 (87.9%) and 38 (12.1%) were treated with VEGFR-TKI and mTORI therapy, respectively. The most common tyrosine kinase inhibitor treatments were axitinib, cabozantinib, and sunitinib following IO therapy. In adjusted models, patients treated with VEGFR-TKI versus mTORI therapy had lower hazard of TTD after IO treatment (aHR=0.46; 95% CI: 0.30-0.71; p < 0.01). One-year OS probability (65% vs 47%, p < 0.01) and proportion of ORR (29.8% vs 3.6%, p < 0.01) were significantly greater for patients treated with VEGFR-TKIs versus those treated with mTORIs. CONCLUSIONS: Targeted therapy has clinical activity following IO treatment. Patients who received VEGFR-TKIs versus mTORIs following IO therapy had improved clinical outcomes. These findings may help inform treatment guidelines and clinical practice for patients post-IO therapy. PATIENT SUMMARY: Patients may continue to experience clinical benefits from targeted therapies after progression on immuno-oncology treatment.