Evaluation of the Lifetime Benefits of Metformin and SGLT2 Inhibitors in Type 2 Diabetes Mellitus Patients with Cardiovascular Disease: A Systematic Review and Two-Stage Meta-Analysis.

BACKGROUND: Metformin and sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated cardiovascular benefits but their comparative effects on mortality in type 2 diabetes mellitus (T2DM) patients with cardiovascular disease (CVD) are unknown. Hence, we evaluated and compared lifetime benefits arising from metformin or SGLT2 inhibitors in T2DM patients with CVD. MATERIALS AND METHODS: Studies published in the PubMed, EMBASE and CENTRAL databases before 28 October 2023 were retrieved. Treatment effects of metformin against US FDA-approved SGLT2 inhibitors in T2DM patients with CVD were evaluated and lifetime gains in event-free survival were estimated from our primary endpoints of all-cause and cardiovascular mortality. Risk ratios were derived to assess their impact on secondary outcomes such as major adverse cardiovascular events and hospitalizations for heart failure. RESULTS: Overall, 14 studies were included. Five studies published Kaplan-Meier curves for the primary outcome of all-cause mortality. Individual participant data were reconstructed from these Kaplan-Meier curves, from which we conducted our two-stage meta-analysis. Participants receiving metformin and SGLT2 inhibitors experienced a reduction in the risk for all-cause mortality as compared with those not taking metformin and placebo. However, participants receiving SGLT2 inhibitors had a higher all-cause mortality (hazard ratio 1.308, 95% confidence interval 1.103-1.550) versus metformin. Treatment with metformin was estimated to offer an additional 23.26 months of survival free from all-cause mortality versus 23.04 months with SGLT2 inhibitors. CONCLUSIONS: In patients with T2DM and CVD, metformin and SGLT2 inhibitors were associated with substantially lower all-cause mortality rates and slightly longer life expectancies than in patients without. Metformin presented an advantage over SGLT2 inhibitors in reducing all-cause mortality.

Bridging bytes and biopsies: A comparative analysis of ChatGPT and histopathologists in pathology diagnosis and collaborative potential.

BACKGROUND AND AIMS: ChatGPT is a powerful artificial intelligence (AI) chatbot developed by the OpenAI research laboratory which is capable of analysing human input and generating human-like responses. Early research into the potential application of ChatGPT in healthcare has focused mainly on clinical and administrative functions. The diagnostic ability and utility of ChatGPT in histopathology is not well defined. We benchmarked the performance of ChatGPT against pathologists in diagnostic histopathology, and evaluated the collaborative potential between pathologists and ChatGPT to deliver more accurate diagnoses. METHODS AND RESULTS: In Part 1 of the study, pathologists and ChatGPT were subjected to a series of questions encompassing common diagnostic conundrums in histopathology. For Part 2, pathologists reviewed a series of challenging virtual slides and provided their diagnoses before and after consultation with ChatGPT. We found that ChatGPT performed worse than pathologists in reaching the correct diagnosis. Consultation with ChatGPT provided limited help and information generated from ChatGPT is dependent on the prompts provided by the pathologists and is not always correct. Finally, we surveyed pathologists who rated the diagnostic accuracy of ChatGPT poorly, but found it useful as an advanced search engine. CONCLUSIONS: The use of ChatGPT4 as a diagnostic tool in histopathology is limited by its inherent shortcomings. Judicious evaluation of the information and histopathology diagnosis generated from ChatGPT4 is essential and cannot replace the acuity and judgement of a pathologist. However, future advances in generative AI may expand its role in the field of histopathology.

Surgery for liver metastases from primary breast cancer: A reconstructed individual patient data meta-analysis.

BACKGROUND: Currently, the outcomes of standard-of-care palliative treatment for BCLM remain poor. Recent literature has shown promising results of hepatic resection, however, not all studies concur. Given the lack of standardized international guidelines in this field, the aim of this study is to provide gold-standard evidence for breast cancer liver metastases (BCLM) through a reconstructed individual patient data meta-analysis approach. METHODS: Four databases were searched for articles comparing surgical and non-surgical treatment for BCLM. One-stage meta-analysis was performed using patient-level survival data reconstructed from Kaplan-Meier curves with plot digitizer software. Shared-frailty and stratified Cox models were fitted to compare survival endpoints. RESULTS: Four propensity-score matched (PSM) studies involving 205 surgical and 291 non-surgical patients for BCLM were included. There was a significant difference between both groups for overall survival (OS) (Hazard Ratio [HR] = 0.40, 95%CI 0.32-0.51). Sensitivity analyses for hormone receptor status of breast cancer (HR = 0.41, 95%CI 0.31-0.55) and type of resection performed (HR = 0.45, 95%CI 0.33-0.61) yielded HRs in favor of surgery. CONCLUSIONS: This meta-analysis concludes that surgery offers superior OS outcomes, compared to non-surgery, in a select group of patients. Future randomized controlled trials and PSM studies are warranted, using this study as a point of reference for similar parameters.

Association Between Calcium Supplementation and the Risk of Cardiovascular Disease and Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND: Some observational studies and randomised controlled trials (RCTs) have reported an association between calcium supplementation and increased risk of cardiovascular disease. Previous meta-analyses on the topic, based on data from RCTs and observational studies, have contradictory findings. This meta-analysis was conducted to determine the difference in associated risks of calcium supplementation with cardiovascular disease and stroke in RCTs. METHODS: Relevant studies published from database inception to 6 August 2021 were sourced from PubMed, Embase, Scopus, and the Cochrane Central Register of Controlled Trials. Any RCTs focusing on the relationship between calcium supplementation and incidence of cardiovascular disease or stroke were included. Articles were screened independently by two authors, according to the PICO criteria, with disagreements resolved by a third author. RESULTS: Twelve RCTs were included in the meta-analysis. Calcium supplementation was not associated with myocardial infarction, total stroke, heart failure admission, and all-cause/cardiovascular mortality. Subgroup analysis focusing on calcium monotherapy/calcium co-therapy with vitamin D, female sex, follow-up duration, and geographical region did not affect the findings. CONCLUSION: Calcium supplementation was not associated with myocardial infarction, total stroke, heart failure admission, and cardiovascular/all-cause mortality. Further studies are required to examine and understand these associations.

Oncologic outcomes after breast-conserving surgery with radiotherapy versus mastectomy in patients with Paget's disease of the breast: systematic review and meta-analysis.

BACKGROUND: The conventional approach to treatment for Paget's disease of the breast has been mastectomy, but there is an increasing trend to consider breast-conserving surgery (BCS) followed by radiotherapy (RT) in these patients. This study aimed to provide an updated systematic review and meta-analysis comparing outcomes after BCS with RT versus mastectomy in the treatment of Paget's disease of the breast. METHODS: Studies before May 2021 were included. Primary outcomes were overall survival and local recurrence. Separate analyses of Paget's disease associated with ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) were undertaken. Meta-regression was used to adjust for imbalance in the proportion of IDC among patients selected to undergo BCS versus mastectomy. RESULTS: Overall survival in patients with Paget's disease who underwent BCS with RT was higher than for those who underwent mastectomy with pooled mortality hazard ratio (HR) of 0.68, (95% per cent c.i. 0.45 to 1.01). Patients with Paget's disease with DCIS had higher overall survival after BCS with or without RT versus mastectomy, with adjusted HR of 0.14 (0.10 to 0.20) and 0.28 (0.22 to 0.36), respectively. For patients with Paget's disease and IDC, overall survival was lower for BCS with or without RT versus mastectomy, with adjusted HR of 0.84 (0.57 to 1.25) and 1.64 (1.04 to 2.58), respectively. In Paget's disease and IDC, local recurrence risk was much higher for BCS with RT, RR 26.8 (1.60 to 456) versus without RT, RR 51.8 (6.80 to 391). In patients with Paget's disease and DCIS, risk of local recurrence versus mastectomy was lower for BCS with RT 0.72 (0.11 to 4.50) but slightly higher for BCS alone 1.38 (0.09 to 21.20). CONCLUSION: BCS with RT may be a comparable treatment alternative to mastectomy for patients with Paget's disease with DCIS, and for selected patients with Paget's disease and IDC.

Impact of Tumor Size on the Difficulty of Laparoscopic Major Hepatectomies: An International Multicenter Study.

INTRODUCTION: Although tumor size (TS) is known to affect surgical outcomes in laparoscopic liver resection (LLR), its impact on laparoscopic major hepatectomy (L-MH) is not well studied. The objectives of this study were to investigate the impact of TS on the perioperative outcomes of L-MH and to elucidate the optimal TS cutoff for stratifying the difficulty of L-MH. METHODS: This was a post-hoc analysis of 3008 patients who underwent L-MH at 48 international centers. A total 1396 patients met study criteria and were included. The impact of TS cutoffs was investigated by stratifying TS at each 10-mm interval. The optimal cutoffs were determined taking into consideration the number of endpoints which showed a statistically significant split around the cut-points of interest and the magnitude of relative risk after correction for multiple risk factors. RESULTS: We identified 2 optimal TS cutoffs, 50 mm and 100 mm, which segregated L-MH into 3 groups. An increasing TS across these 3 groups (≤ 50 mm, 51-100 mm, > 100 mm), was significantly associated with a higher open conversion rate (11.2%, 14.7%, 23.0%, P < 0.001), longer operating time (median, 340 min, 346 min, 365 min, P = 0.025), increased blood loss (median, 300 ml,  ml, 400 ml, P = 0.002) and higher rate of intraoperative blood transfusion (13.1%, 15.9%, 27.6%, P < 0.001). Postoperative outcomes such as overall morbidity, major morbidity, and length of stay were comparable across the three groups. CONCLUSION: Increasing TS was associated with poorer intraoperative but not postoperative outcomes after L-MH. We determined 2 TS cutoffs (50 mm and 10 mm) which could optimally stratify the surgical difficulty of L-MH.

Trial watch: immunotherapeutic strategies on the horizon for hepatocellular carcinoma.

The use of immune checkpoint inhibitors (ICIs) targeting PD-L1/PD-1 and CTLA-4 has transformed the oncology practice of hepatocellular carcinoma. However, only 25-30% of the patients with advanced HCC treated with atezolizumab-bevacizumab or tremelimumab-durvalumab (STRIDE) respond initially, and mechanistic biomarkers and novel treatment strategies are urgently needed for patients who present with or acquire resistance to first-line ICI-based therapies. The recent approval of the STRIDE regimen has also engendered new questions, such as patient selection factors (e.g. portal hypertension and history of variceal bleed) and biomarkers, and the optimal combination and sequencing of ICI-based regimens. Triumphs in the setting of advanced HCC have also galvanized considerable interest in the broader application of ICIs to early- and intermediate-stage diseases, including clinical combination of ICIs with locoregional therapies. Among these clinical contexts, the role of ICIs in liver transplantation - which is a potentially curative strategy unique to HCC management - as a bridge to liver transplant in potential candidates or in the setting of post-transplant recurrence, warrants investigation in view of the notable theoretical risk of allograft rejection. In this review, we summarize and chart the landscape of seminal immuno-oncology trials in HCC and envision future clinical developments.

Impact of body mass index on perioperative outcomes of laparoscopic major hepatectomies.

BACKGROUND: Data on the effect of body mass index on laparoscopic liver resections are conflicting. We performed this study to investigate the association between body mass index and postoperative outcomes after laparoscopic major hepatectomies. METHODS: This is a retrospective review of 4,348 laparoscopic major hepatectomies at 58 centers between 2005 and 2021, of which 3,383 met the study inclusion criteria. Concomitant major operations, vascular resections, and previous liver resections were excluded. Associations between body mass index and perioperative outcomes were analyzed using restricted cubic splines. Modeled effect sizes were visually rendered and summarized. RESULTS: A total of 1,810 patients (53.5%) had normal weight, whereas 1,057 (31.2%) were overweight and 392 (11.6%) were obese. One hundred and twenty-four patients (3.6%) were underweight. Most perioperative outcomes showed a linear worsening trend with increasing body mass index. There was a statistically significant increase in open conversion rate (16.3%, 10.8%, 9.2%, and 5.6%, P < .001), longer operation time (320 vs 305 vs 300 and 266 minutes, P < .001), increasing blood loss (300 vs 300 vs 295 vs 250 mL, P = .022), and higher postoperative morbidity (33.4% vs 26.3% vs 25.0% vs 25.0%, P = .009) in obese, overweight, normal weight, and underweight patients, respectively (P < .001). However, postoperative major morbidity demonstrated a "U"-shaped association with body mass index, whereby the highest major morbidity rates were observed in underweight and obese patients. CONCLUSION: Laparoscopic major hepatectomy was associated with poorer outcomes with increasing body mass index for most perioperative outcome measures.

Impact of body mass index on the difficulty and outcomes of laparoscopic left lateral sectionectomy.

INTRODUCTION: Currently, the impact of body mass index (BMI) on the outcomes of laparoscopic liver resections (LLR) is poorly defined. This study attempts to evaluate the impact of BMI on the peri-operative outcomes following laparoscopic left lateral sectionectomy (L-LLS). METHODS: A retrospective analysis of 2183 patients who underwent pure L-LLS at 59 international centers between 2004 and 2021 was performed. Associations between BMI and selected peri-operative outcomes were analyzed using restricted cubic splines. RESULTS: A BMI of >27kg/m2 was associated with increased in blood loss (Mean difference (MD) 21 mls, 95% CI 5-36), open conversions (Relative risk (RR) 1.13, 95% CI 1.03-1.25), operative time (MD 11 min, 95% CI 6-16), use of Pringles maneuver (RR 1.15, 95% CI 1.06-1.26) and reductions in length of stay (MD -0.2 days, 95% CI -0.3 to -0.1). The magnitude of these differences increased with each unit increase in BMI. However, there was a "U" shaped association between BMI and morbidity with the highest complication rates observed in underweight and obese patients. CONCLUSION: Increasing BMI resulted in increasing difficulty of L-LLS. Consideration should be given to its incorporation in future difficulty scoring systems in laparoscopic liver resections.

Comparing bronchial thermoplasty with biologicals for severe asthma: Systematic review and network meta-analysis.

BACKGROUND: Bronchial thermoplasty (BT) has shown favorable safety and efficacy in several randomized controlled trials (RCTs), but has not been directly compared to biological therapies. METHODS: Electronic literature searches were performed on PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials, to retrieve RCTs of BT or FDA-approved biologicals against controls in patients with severe asthma. Six outcomes were analyzed: Asthma Control Questionnaire (ACQ), Asthma Quality of Life Questionnaire (AQLQ), the number of patients experiencing ≥1 asthma exacerbation, annualized exacerbation rate ratio (AERR), oral corticosteroid dose reduction (OCDR), and morning peak expiratory flow rate (amPEF). Random-effects, Frequentist network meta-analysis (NMA) were performed, and therapies were ranked using P-scores. RESULTS: Twenty-nine RCTs (15,547 patients) were included. Fewer patients treated with BT experienced ≥1 asthma exacerbation (risk ratio [RR] = 0.66, 95%CI = 0.45-0.98) compared to control. AERR of BT versus control was non-significant, but significant improvements in ACQ score (mean difference [MD] -0.41, 95%CI -0.63 to -0.20), AQLQ score (MD = 0.54, 95%CI = 0.30-0.77), amPEF and OCDR were found. No significant differences between BT and biologics were seen across indirect comparisons of all studies. CONCLUSIONS: Despite the lack of head-to-head comparative trials, this NMA suggests that BT is non-inferior to biologicals in terms of quality-of-life scores, and represents a promising alternative for patients with severe asthma.

Robotic versus laparoscopic liver resection for huge (≥10 cm) liver tumors: an international multicenter propensity-score matched cohort study of 799 cases.

Background: The use of laparoscopic (LLR) and robotic liver resections (RLR) has been safely performed in many institutions for liver tumours. A large scale international multicenter study would provide stronger evidence and insight into application of these techniques for huge liver tumours ≥10 cm. Methods: This was a retrospective review of 971 patients who underwent LLR and RLR for huge (≥10 cm) tumors at 42 international centers between 2002-2020. Results: One hundred RLR and 699 LLR which met study criteria were included. The comparison between the 2 approaches for patients with huge tumors were performed using 1:3 propensity-score matching (PSM) (73 vs. 219). Before PSM, LLR was associated with significantly increased frequency of previous abdominal surgery, malignant pathology, liver cirrhosis and increased median blood. After PSM, RLR and LLR was associated with no significant difference in key perioperative outcomes including media operation time (242 vs. 290 min, P=0.286), transfusion rate rate (19.2% vs. 16.9%, P=0.652), median blood loss (200 vs. 300 mL, P=0.694), open conversion rate (8.2% vs. 11.0%, P=0.519), morbidity (28.8% vs. 21.9%, P=0.221), major morbidity (4.1% vs. 9.6%, P=0.152), mortality and postoperative length of stay (6 vs. 6 days, P=0.435). Conclusions: RLR and LLR can be performed safely for selected patients with huge liver tumours with excellent outcomes. There was no significant difference in perioperative outcomes after RLR or LLR.

Robotic versus laparoscopic liver resections for hepatolithiasis: an international multicenter propensity score matched analysis.

INTRODUCTION: Minimally invasive liver resection (MILR) is widely recognized as a safe and beneficial procedure in the treatment of both malignant and benign liver diseases. Hepatolithiasis has traditionally been reported to be endemic only in East Asia, but has seen a worldwide uptrend in recent decades with increasingly frequent and invasive endoscopic instrumentation of the biliary tract for a myriad of conditions. To date, there has been a woeful lack of high-quality evidence comparing the laparoscopic (LLR) and robotic (RLR) approaches to treatment hepatolithiasis. METHODS: This is an international multicenter retrospective analysis of 273 patients who underwent RLR or LRR for hepatolithiasis at 33 centers in 2003-2020. The baseline clinicopathological characteristics and perioperative outcomes of these patients were assessed. To minimize selection bias, 1:1 (48 and 48 cases of RLR and LLR, respectively) and 1:2 (37 and 74 cases of RLR and LLR, respectively) propensity score matching (PSM) was performed. RESULTS: In the unmatched cohort, 63 (23.1%) patients underwent RLR, and 210 (76.9%) patients underwent LLR. Patient clinicopathological characteristics were comparable between the groups after PSM. After 1:1 and 1:2 PSM, RLR was associated with less blood loss (p = 0.003 in 1:2 PSM; p = 0.005 in 1:1 PSM), less patients with blood loss greater than 300 ml (p = 0.024 in 1:2 PSM; p = 0.027 in 1:1 PSM), and lower conversion rate to open surgery (p = 0.003 in 1:2 PSM; p < 0.001 in 1:1 PSM). There was no significant difference between RLR and LLR in use of the Pringle maneuver, median Pringle maneuver duration, 30-day readmission rate, postoperative morbidity, major morbidity, reoperation, and mortality. CONCLUSION: Both RLR and LLR were safe and feasible for hepatolithiasis. RLR was associated with significantly less blood loss and lower open conversion rate.

Propensity score-matched analysis of laparoscopic-assisted and hand-assisted laparoscopic liver resection versus pure laparoscopic liver resection: an international multicenter study.

BACKGROUND: Laparoscopic-assisted (LALR) and hand-assisted (HALR) liver resections have been utilized during the early adoption phase by surgeons when transitioning from open surgery to pure LLR. To date, there are limited data reporting on the outcomes of LALR or HALR compared to LLR. The objective was to compare the perioperative outcomes after LALR and HALR versus pure LLR. METHODS: This is an international multicentric analysis of 6609 patients undergoing minimal-invasive liver resection at 21 centers between 2004 and 2019. Perioperative outcomes were analyzed after propensity score matching (PSM) comparison between LALR and HALR versus LLR. RESULTS: 5279 cases met study criteria of whom 5033 underwent LLR (95.3%), 146 underwent LALR (2.8%) and 100 underwent HALR (1.9%). After 1:4 PSM, LALR was associated with inferior outcomes as evidenced by the longer postoperative stay, higher readmission rate, higher major morbidity rate and higher in-hospital mortality rate. Similarly, 1:6 PSM comparison between HALR and LLR also demonstrated poorer outcomes associated with HALR as demonstrated by the higher open conversion rate and higher blood transfusion rate. All 3 approaches technical variants demonstrated the same oncological radicality (R1 rate). CONCLUSION: LALR and HALR performed during the learning curve was associated with inferior perioperative outcomes compared to pure LLR.

Propensity-score Matched and Coarsened-exact Matched Analysis Comparing Robotic and Laparoscopic Major Hepatectomies: An International Multicenter Study of 4822 Cases.

OBJECTIVE: To compare the outcomes between robotic major hepatectomy (R-MH) and laparoscopic major hepatectomy (L-MH). BACKGROUND: Robotic techniques may overcome the limitations of laparoscopic liver resection. However, it is unknown whether R-MH is superior to L-MH. METHODS: This is a post hoc analysis of a multicenter database of patients undergoing R-MH or L-MH at 59 international centers from 2008 to 2021. Data on patient demographics, center experience volume, perioperative outcomes, and tumor characteristics were collected and analyzed. Both 1:1 propensity-score matched (PSM) and coarsened-exact matched (CEM) analyses were performed to minimize selection bias between both groups. RESULTS: A total of 4822 cases met the study criteria, of which 892 underwent R-MH and 3930 underwent L-MH. Both 1:1 PSM (841 R-MH vs. 841 L-MH) and CEM (237 R-MH vs. 356 L-MH) were performed. R-MH was associated with significantly less blood loss {PSM:200.0 [interquartile range (IQR):100.0, 450.0] vs 300.0 (IQR:150.0, 500.0) mL; P = 0.012; CEM:170.0 (IQR: 90.0, 400.0) vs 200.0 (IQR:100.0, 400.0) mL; P = 0.006}, lower rates of Pringle maneuver application (PSM: 47.1% vs 63.0%; P < 0.001; CEM: 54.0% vs 65.0%; P = 0.007) and open conversion (PSM: 5.1% vs 11.9%; P < 0.001; CEM: 5.5% vs 10.4%, P = 0.04) compared with L-MH. On subset analysis of 1273 patients with cirrhosis, R-MH was associated with a lower postoperative morbidity rate (PSM: 19.5% vs 29.9%; P = 0.02; CEM 10.4% vs 25.5%; P = 0.02) and shorter postoperative stay [PSM: 6.9 (IQR: 5.0, 9.0) days vs 8.0 (IQR: 6.0 11.3) days; P < 0.001; CEM 7.0 (IQR: 5.0, 9.0) days vs 7.0 (IQR: 6.0, 10.0) days; P = 0.047]. CONCLUSIONS: This international multicenter study demonstrated that R-MH was comparable to L-MH in safety and was associated with reduced blood loss, lower rates of Pringle maneuver application, and conversion to open surgery.

Sub-classification of laparoscopic left hepatectomy based on hierarchic interaction of tumor location and size with perioperative outcomes.

BACKGROUND: The aim of this multicentric study was to investigate the impact of tumor location and size on the difficulty of Laparoscopic-Left Hepatectomy (L-LH). METHODS: Patients who underwent L-LH performed across 46 centers from 2004 to 2020 were analyzed. Of 1236 L-LH, 770 patients met the study criteria. Baseline clinical and surgical characteristics with a potential impact on LLR were included in a multi-label conditional interference tree. Tumor size cut-off was algorithmically determined. RESULTS: Patients were stratified into 3 groups based on tumor location and dimension: 457 in antero-lateral location (Group 1), 144 in postero-superior segment (4a) with tumor size ≤40 mm (Group 2), and 169 in postero-superior segment (4a) with tumor size >40 mm (Group 3). Patients in the Group 3 had higher conversion rate (7.0% vs. 7.6% vs. 13.0%, p-value .048), longer operating time (median, 240 min vs. 285 min vs. 286 min, p-value <.001), greater blood loss (median, 150 mL vs. 200 mL vs. 250 mL, p-value <.001) and higher intraoperative blood transfusion rate (5.7% vs. 5.6% vs. 11.3%, p-value .039). Pringle's maneuver was also utilized more frequently in Group 3 (66.7%), compared to Group 1 (53.2%) and Group 2 (51.8%) (p = .006). There were no significant differences in postoperative stay, major morbidity, and mortality between the three groups. CONCLUSION: L-LH for tumors that are >40 mm in diameter and located in PS Segment 4a are associated with the highest degree of technical difficulty. However, post-operative outcomes were not different from L-LH of smaller tumors located in PS segments, or tumors located in the antero-lateral segments.

Low-Dose Computed Tomography (LDCT) Lung Cancer Screening in Asian Female Never-Smokers Is as Efficacious in Detecting Lung Cancer as in Asian Male Ever-Smokers: A Systematic Review and Meta-Analysis.

INTRODUCTION: Lung cancer in never-smokers is the major cancer cause of death globally. We compared the efficacy of low-dose computed tomography (LDCT) lung cancer screening among never-smokers versus ever-smokers using systematic review and meta-analysis. METHODS: LDCT lung cancer screening studies that simultaneously included both ever-smoker and never-smoker participants published by April 30, 2021, were searched through PubMed and Scopus. Primary outcome measure was relative risk (RR) of lung cancer diagnosed among never-smokers versus ever-smokers. RESULTS: A total of 14 studies (13 from Asia) were included (141,396 ever-smokers, 109,251 never-smokers, 1961 lung cancer cases diagnosed). RR of lung cancer diagnosed between ever-smokers versus never-smokers overall was 1.21 (95% confidence interval [CI]: 0.89-1.65), 1.37 (95% CI: 1.08-1.75) among males, and 0.88 (95% CI: 0.59-1.31) among females. RR was 1.78 (95% CI: 1.41-2.24) and 1.22 (95% CI: 0.89-1.68) for Asian female never-smokers versus male never-smokers and versus male ever-smokers, respectively, and 0.99 (95% CI: 0.65-1.50) versus high-risk ever-smokers (≥30 pack-years). Proportional meta-analysis revealed significantly more lung cancers diagnosed at first scan (95.4% [95% CI: 84.9-100.0] versus 70.9% [95% CI: 54.6-84.9], p = 0.010) and at stage 1 (88.5% [95% CI: 79.3-95.4] versus 79.7% [95% CI: 71.1-87.4], p = 0.071) among never-smokers versus ever-smokers, respectively. RR of lung cancer death and 5-year all-cause mortality in never-smokers versus ever-smokers was 0.27 (95% CI: 0.1-0.55, p < 0.001) and 0.13 (95% CI: 0.05-0.33, p < 0.001), respectively. CONCLUSIONS: The RR of lung cancer detected by LDCT screening among female never-smokers and male ever-smokers in Asia was statistically similar. Overall and lung cancer specific mortality from the lung cancer diagnosed from LDCT screening was significantly reduced among never-smokers compared to ever-smokers.

Impact of neoadjuvant chemotherapy on the difficulty and outcomes of laparoscopic and robotic major liver resections for colorectal liver metastases: A propensity-score and coarsened exact-matched controlled study.

BACKGROUND: Minimal invasive liver resections are a safe alternative to open surgery. Different scoring systems considering different risks factors have been developed to predict the risks associated with these procedures, especially challenging major liver resections (MLR). However, the impact of neoadjuvant chemotherapy (NAT) on the difficulty of minimally invasive MLRs remains poorly investigated. METHODS: Patients who underwent laparoscopic and robotic MLRs for colorectal liver metastases (CRLM) performed across 57 centers between January 2005 to December 2021 were included in this analysis. Patients who did or did not receive NAT were matched based on 1:1 coarsened exact and 1:2 propensity-score matching. Pre- and post-matching comparisons were performed. RESULTS: In total, the data of 5189 patients were reviewed. Of these, 1411 procedures were performed for CRLM, and 1061 cases met the inclusion criteria. After excluding 27 cases with missing data on NAT, 1034 patients (NAT: n = 641; non-NAT: n = 393) were included. Before matching, baseline characteristics were vastly different. Before matching, the morbidity rate was significantly higher in the NAT-group (33.2% vs. 27.2%, p-value = 0.043). No significant differences were seen in perioperative outcomes after the coarsened exact matching. After the propensity-score matching, statistically significant higher blood loss (mean, 300 (SD 128-596) vs. 250 (SD 100-400) ml, p-value = 0.047) but shorter hospital stay (mean, 6 [4-8] vs. 6 [5-9] days, p-value = 0.043) were found in the NAT-group. CONCLUSION: The current study demonstrated that NAT had minimal impact on the difficulty and outcomes of minimally-invasive MLR for CRLM.

FAM3C in circulating tumor-derived extracellular vesicles promotes non-small cell lung cancer growth in secondary sites.

Rationale: Metastasis is a complex process with a molecular underpinning that remains unclear. We hypothesize that cargo proteins conducted by extracellular vesicles (EVs) released from tumors may confer growth and metastasis potential on recipient cells. Here, we report that a cytokine-like secreted protein, FAM3C, contributes to late-stage lung tumor progression. Methods: EV protein profiling was conducted with an unbiased proteomic mass spectrometry analysis on non-small cell lung cancer (NSCLC) and normal lung fibroblast cell lines. Expression of FAM3C was confirmed in a panel of NSCLC cell lines, and correlated to the invasive and metastatic potentials. Functional phenotype of endogenous FAM3C and tumor-derived EVs (TDEs) were further investigated using various biological approaches in RNA and protein levels. Metastasis potential of TDEs secreted by FAM3C-overexpressing carcinoma cells was validated in mouse models. Results: Transcriptomic meta-analysis of pan-cancer datasets confirmed the overexpression of FAM3C - a gene encoding for interleukin-like EMT inducer (ILEI) - in NSCLC tumors, with strong association with poor patient prognosis and cancer metastasis. Aberrant expression of FAM3C in lung carcinoma cells enhances cellular transformation and promotes distant lung tumor colonization. In addition, higher FAM3C concentrations were detected in EVs extracted from plasma samples of NSCLC patients compared to those of healthy subjects. More importantly, we defined a hitherto-unknown mode of microenvironmental crosstalk involving FAM3C in EVs, whereby the delivery and uptake of FAM3C via TDEs enhances oncogenic signaling - in recipient cells that phenocopies the cell-endogenous overexpression of FAM3C. The oncogenicity transduced by FAM3C is executed via a novel interaction with the Ras-related protein RalA, triggering the downstream activation of the Src/Stat3 signaling cascade. Conclusions: Our study describes a novel mechanism for FAM3C-driven carcinogenesis and shed light on EV FAM3C as a driver for metastatic lung tumors that could be exploited for cancer therapeutics.

Co-prevalence and incidence of myocardial infarction and/or stroke in patients with depression and/or anxiety: A systematic review and meta-analysis.

OBJECTIVE: Co-prevalence and incidence of depression and/or anxiety with stroke and myocardial infarction are currently unclear. This paper explores the relationships, as these are important comorbidities affecting patient outcomes. METHODS: A systematic search across five databases (PubMed, Scopus, PsycINFO, Embase, Cochrane) was conducted for observational studies reporting co-prevalence of depression or anxiety with stroke or myocardial infarction. We used random-effects models in all meta-analyses and evaluated heterogeneity using I2. RESULTS: This analysis included 48 studies with a total of 57,342 patients. In patients with depression, the pooled prevalence of stroke was 5.9% (95% CI = 5.53-6.37). In patients with myocardial infarction, the pooled prevalence of anxiety and depression was 9.1% (95% CI = 7.07-11.40, I2 = 85.6%) and 25.9% (95% CI = 18.46-34.12, I2 = 99.1%), respectively, and the pooled cumulative incidence of depression at one year was 20.5% (95% CI = 18.36-22.79). The pooled prevalence of anxiety and depression in patients with stroke was 13.5% (95% CI = 7.67-22.66, I2 = 96.9%) and 23.0% (95% CI = 17.93-28.99, I2 = 96.7%), respectively. The pooled cumulative incidences of depression at two weeks, three months, six months, and one year, were 29.1% (95% CI = 26.60-31.81), 17.0% (95% CI = 10.74-25.92, I2 = 98.0%), 7.4% (95% CI = 6.52-8.49), and 9.1% (95% CI = 3.71-20.79, I2 = 99.8%), respectively. CONCLUSIONS: This meta-analysis outlines the co-morbid burden between depression/anxiety and stroke/myocardial infarction. Future research should be done to evaluate the effectiveness of screening anxiety/depression in myocardial infarction/stroke.

Impact of tumor size on the difficulty of laparoscopic left lateral sectionectomies.

BACKGROUND: Tumor size (TS) represents a critical parameter in the risk assessment of laparoscopic liver resections (LLR). Moreover, TS has been rarely related to the extent of liver resection. The aim of this study was to study the relationship between tumor size and difficulty of laparoscopic left lateral sectionectomy (L-LLS). METHODS: The impact of TS cutoffs was investigated by stratifying tumor size at each 10 mm-interval. The optimal cutoffs were chosen taking into consideration the number of endpoints which show a statistically significant split around the cut-points of interest and the magnitude of relative risk after correction for multiple risk factors. RESULTS: A total of 1910 L-LLS were included. Overall, open conversion and intraoperative blood transfusion were 3.1 and 3.3%, respectively. The major morbidity rate was 2.7% and 90-days mortality 0.6%. Three optimal TS cutoffs were identified: 40-, 70-, and 100-mm. All the selected cutoffs showed a significant discriminative power for the prediction of open conversion, operative time, blood transfusion and need of Pringle maneuver. Moreover, 70- and 100-mm cutoffs were both discriminative for estimated blood loss and major complications. A stepwise increase in rates of open conversion rate (Z = 3.90, P < .001), operative time (Z = 3.84, P < .001), blood loss (Z = 6.50, P < .001), intraoperative blood transfusion rate (Z = 5.15, P < .001), Pringle maneuver use (Z = 6.48, P < .001), major morbidity(Z = 2.17, P = .030) and 30-days readmission (Z = 1.99, P = .047) was registered as the size increased. CONCLUSION: L-LLS for tumors of increasing size was associated with poorer intraoperative and early postoperative outcomes suggesting increasing difficulty of the procedure. We determined three optimal TS cutoffs (40-, 70- and 100-mm) to accurately stratify surgical difficulty after L-LLS.