Unveiling the anticancer potential of novel spirooxindole-tethered pyrazolopyridine derivatives.

In the current medical era, human health is confronted with various challenges, with cancer being a prominent concern. Therefore, enhancing the therapeutic arsenal for cancer with a constant influx of novel molecules that selectively target tumor cells while displaying minimal toxicity toward normal cells is imperative. This study delves into the antiproliferative and EGFR kinase inhibitory activities of newly reported spirooxindole-pyrazolo[3,4-b]pyridine derivatives 8a-h and 10a-h. The inhibitory effects on the growth of human cancer cell lines A-549 (lung carcinoma), Panc-1 (pancreatic carcinoma), and A-431 (skin epidermoid carcinoma) were evaluated, and the SAR has been clarified through analysis. With IC50 values in the single-digit micromolar range, compounds 8b, 8d, 10a-b, and 10d were shown to be the most effective antiproliferative candidates against the studied cancer cell lines. They also exerted negligible cytotoxicity (with selectivity scores between 8.63 and 30.02) against the human lung MRC5 cell line. Additionally, we investigated the potential inhibitory action of compounds 8b, 8d, 10a-b, and 10d on EGFR and VEGFR-2. 10a was this investigation's most effective EGFR inhibitor, with an IC50 value of 0.54 µM. Ultimately, the molecular docking analysis of congener 10a highlighted its effective suppression of EGFR by examining its binding mode and docking score compared to Erlotinib. These findings underscore the potential of spirooxindole-pyrazolo[3,4-b]pyridine derivatives as promising anticancer agents targeting EGFR kinase.

Identification of indole-grafted pyrazolopyrimidine and pyrazolopyridine derivatives as new anti-cancer agents: Synthesis, biological assessments, and molecular modeling insights.

In the current medical era, developing new PIM-1 inhibitors stands as a significant approach to cancer management due to the pivotal role of PIM-1 kinase in promoting cell survival, proliferation, and drug resistance in various cancers. This study involved designing and synthesizing new derivatives of pyrazolo[1,5-a]pyrimidines (6a-i) and pyrazolo[3,4-b]pyridines (10a-i) as potential anti-cancer agents targeting PIM-1 kinase. The cytotoxicity was screened on three cancer cell lines: A-549 (lung), PANC-1 (pancreatic), and A-431 (skin), alongside MRC5 normal lung cells to assess selectivity. Several pyrazolo[1,5-a]pyrimidines (6b, 6c, 6g, 6h, and 6i) and pyrazolo[3,4-b]pyridine (10f) demonstrated notable anticancer properties, particularly against A-549 lung cancer cells (IC50 range: 1.28-3.52 µM), also they exhibited significantly lower toxicity towards MRC5 normal cells. Thereafter, the compounds were evaluated for their inhibitory activity against PIM-1 kinase. Notably, 10f, bearing a 4-methoxyphenyl moiety, demonstrated good inhibition of PIM-1 with an IC50 of 0.18 µM. Additionally, 10f induced apoptosis and arrested cell cycle progression in A-549 cells. Molecular docking and dynamics simulations provided insights into the binding interactions and compounds' stability with PIM-1 kinase. The results highlight these compounds, especially 10f, as promising selective anticancer agents targeting PIM-1 kinase.

5-year oncological outcomes in left-sided malignant colonic obstruction: stent as bridge to surgery.

BACKGROUND: A considerable number of patients with colon cancer present with a colonic obstruction. The use of self-expanding metallic stents (SEMS) as a bridge to surgery (BTS) in potential curative patients with left-sided colonic cancer obstruction remains debatable. Therefore, this study aimed to investigate the 5-year oncological outcomes of using a SEMS as a BTS. METHODS: All patients with left-sided malignant colon obstruction who underwent curative surgery with no metastasis upon presentation between March 2009 and May 2013 were retrospectively reviewed and analyzed. RESULTS: A total of 45 patients were included, 28 patients underwent upfront surgery, and 17 patients had a stent as a bridge to surgery. T4 stage was statistically significantly higher in patients who had a SEMS as a BTS (35.3% vs. 10.7%) (p-value 0.043). The mean duration in days of the SEMS to surgery was 13.76 (SD 10.08). TNM stage 3 was a prognostic factor toward distant metastasis (HR 5.05). When comparing patients who had upfront surgery to those who had a SEMS as a BTS, higher 5-year disease-free survival (75% vs. 72%) and 5-year overall survival (89% vs. 82%) were seen in patients who had upfront surgery. However, both were statistically insignificant. CONCLUSION: Using self-expanding metallic stents as a bridge to surgery yields comparable 5-year survival and disease-free survival rates to upfront emergency surgery. The decision to use SEMS versus opting for emergency surgery should be made after careful patient selection and with the assistance of experienced endoscopists. TRIAL REGISTRATION: N/A.

Clinical outcomes of lower gastrointestinal bleeding in patients managed with lower endoscopy: A tertiary center results.

BACKGROUND: Lower gastrointestinal bleeding (LGIB) is an urgent presentation with increasing prevalence and remains a common cause of hospitalization. The clinical outcome can vary based on several factors, including the cause of bleeding, its severity, and the effectiveness of management strategies. The aim of this study is to provide a comprehensive report on the clinical outcomes observed in patients with LGIB who underwent lower endoscopy. METHODS: All patients who underwent emergency lower endoscopy for fresh bleeding per rectum, from May 2015 to December 2021, were included. The primary outcome was to identify the rate of rebleeding after initial control of bleeding. The second was to measure the clinical outcomes and the potential predictors leading to intervention and readmission. RESULTS: A total of 84 patients were included. Active bleeding was found in 20% at the time of endoscopy. Rebleeding within 90 days occurred in 6% of the total patients; two of which (2.38%) were within the same admission. Ninety-day readmission was reported in 19% of the cases. Upper endoscopy was performed in 32.5% of the total cases and was found to be a significant predictor for intervention (OR 4.1, P = 0.013). Personal history of inflammatory bowel disease (IBD) and initial use of sigmoidoscopy were found to be significant predictors of readmission [(OR 5.09, P = 0.008) and (OR 5.08, P = 0.019)]. CONCLUSIONS: LGIB is an emergency that must be identified and managed using an agreed protocol between all associated services to determine who needs upper GI endoscopy, ICU admission, or emergency endoscopy within 12 hours.

Surgical outcomes and stoma-related complications in inflammatory bowel disease in Saudi Arabia: a retrospective study.

BACKGROUND: The prevalence of inflammatory bowel diseases (IBD), Crohn's (C) and ulcerative colitis (UC) has increased in Saudi Arabia during the past decade. Even though medical treatment is first-line therapy, most patients require surgery during the course of the disease. Stoma creation complications in IBD are underreported in the literature of the Middle East and especially in Saudi Arabia. OBJECTIVES: Report the postoperative, stoma and peristomal complications following stoma creation in (C) versus UC. DESIGN: Retrospective cohort study. SETTINGS: Tertiary care center. PATIENTS AND METHODS: Patients with IBD who underwent stoma creation for either UC or CD between August 2015 and July 2020 were included. The diseases were compared to assess their characteristics and association to postoperative, stoma and peristomal complications. All complications were reported over a 90-day duration from the surgery. Patients younger than 14 years of age were excluded. MAIN OUTCOME MEASURES: Postoperative complications, stoma and peristomal complications in IBD patients who underwent stoma creation. SAMPLE SIZE: 50. RESULTS: Of 50 IBD patients underwent stoma creation, 32 patients (64%) were diagnosed with CD and 18 patients (36%) with UC. Most of the procedures in both groups were laparoscopic and elective. Low BMI and serum albumin were more prevalent in the CD group. Postoperative complications were higher in the CD patients compared to the UC patients (CD 40.6% vs UC 11.1%, P=.028) with the most common complication being abdominal collection[a]. Stoma complications were comparable between the two groups (UC 16.7% vs CD 15.6%). However, peristomal complications were higher clinically in UC patients in comparison with the CD patients (UC 61.1% vs CD 37.5% P=.095) with the most common complication being skin excoriation (UC 44.4% vs CD 37.5%). CONCLUSIONS: CD has significantly higher postoperative complications compared to UC. Peristomal complications were high in both groups and had a negative impact on quality of life. Therefore, comprehensive stoma education and regular outpatient follow ups are recommended to improve the overall outcomes. LIMITATIONS: Retrospective and conducted in one academic institution with a small sample size.

The impact of preoperative total parenteral nutrition on the surgical complications of Crohn's disease: A retrospective cohort study.

Background: Crohn's disease (CD) is associated with malnutrition, an independent risk factor for surgical morbidity and mortality in more than 65% of patients, with a significant impact on disease outcomes. In this single-center retrospective cohort study, we aimed to investigate the impact of total parenteral nutrition (TPN) on the surgical outcomes of patients with CD. Methods: This study included patients with CD who underwent abdominal surgery. We compared patients who received preoperative total parenteral nutrition (TPN group) to those who did not (non-TPN group). Prolonged oral intolerance, albumin level <30 g/L, and body mass index <18.5 were the main indications for TPN. We evaluated postoperative surgical complications in both groups. Results: Between January 2010 and October 2018, 169 eligible patients underwent abdominal surgery. The TPN and non-TPN groups included 40 and 129 patients, respectively. The mean albumin level was significantly lower in the TPN group (P = 0.013). Laparoscopic surgery was performed in 76.9% of the patients, with a conversion rate of 11.6%. Infectious and non-infectious complications developed in 8.9% and 16% of patients, respectively. Surgical complications were comparable between the groups (P >0.05). Conclusions: Despite oral intake intolerance and severe disease in the TPN group, the surgical complications were comparable between the groups.

Oncological outcomes of elective versus emergency surgery for colon cancer: A tertiary academic center experience.

Background: In this study, we aimed to identify the oncological outcomes in colon cancer patients who underwent elective versus emergency curative resection. Methods: All patients who underwent curative resection for colon cancer between July 2015 and December 2019 were retrospectively reviewed and analyzed. Patients were divided into two groups based on the presentation into elective and emergency groups. Results: A total of 215 patients with colon cancer were admitted and underwent curative surgical resection. Of those, 145 patients (67.4%) were elective cases, and 70 (32.5%) were emergency cases. Family history of malignancy was positive in 44 patients (20.5%) and significantly more common in the emergency group (P = 0.016). The emergency group had higher T and TNM stages (P = 0.001). The 3-year survival rate was 60.9% and significantly less in the emergency group (P = 0.026). The mean duration from surgery to recurrence, 3-year disease-free survival, and overall survival were 1.19, 2.81, and 3.11, respectively. Conclusion: Elective group was associated with better 3-year survival, longer overall, and 3-year disease-free survival compared to the emergency group. The disease recurrence rate was comparable in both groups, mainly in the first two years after curative resection.

The Anticancer Effects of the Pro-Apoptotic Benzofuran-Isatin Conjugate (5a) Are Associated With p53 Upregulation and Enhancement of Conventional Chemotherapeutic Drug Efficiency in Colorectal Cancer Cell Lines.

The present study aimed to investigate in-depth a cytotoxic novel benzofuran-isatin conjugate (5a, 3-methyl-N'-(2-oxoindolin-3-ylidene)benzofuran-2-carbohydrazide) with promising potential anticancer activities in colorectal adenocarcinoma HT29 and metastatic colorectal cancer (CRC) SW620 cell lines. Thus, the primary cell events involved in tumorigenicity, tumor development, metastasis, and chemotherapy response were explored. Both CRC cell lines were exposed to different concentrations of Compound 5a and then subjected to real-time cell viability, migration, and invasion assays, colony formation and cytotoxicity assays, and flow cytometry for cell cycle analysis and apoptosis determination. Western blot and RT-qPCR were performed to assess the protein and transcript expression levels of epithelial-mesenchymal transition (EMT), cell cycle, and apoptosis markers. We showed that the Compound 5a treatment exhibited anticancer effects through inhibition of HT29 and SW620 cell viability, migration, and invasion, in a dose-dependent manner, which were associated with the upregulation of the tumor suppressor p53. Compound 5a also inhibited the colony formation ability of HT29 and SW620 cells and reversed EMT markers E-cadherin and N-cadherin expression. CRC cell exposure to Compound 5a resulted in a cell cycle arrest at the G1/G0 phase in HT29 cells and at the G2/M phase in SW620 cells, along with the downregulation of cyclin A1 expression, described to be involved in the S phase entry. Furthermore, Compound 5a-induced apoptosis was associated with the downregulation of the anti-apoptotic Bcl-xl marker, upregulation of pro-apoptotic Bax and cytochrome c markers, and increased mitochondrial outer membrane permeability, suggesting the involvement of mitochondria-dependent apoptosis pathway. In addition, the combination studies of Compound 5a with the main conventional chemotherapeutic drugs 5-fluorouracil, irinotecan, and oxaliplatin showed a more potent cytotoxic effect in both CRC cells than a single treatment. In conclusion, our findings described the interesting in vitro anticancer properties of Compound 5a, shown to have possible antitumor, antimetastatic, and pro-apoptotic activities, with the enhancement of the cytotoxic efficiency of conventional chemotherapeutic drugs. In vivo studies are requested to confirm the promising anticancer potential of Compound 5a for CRC therapy.

The attitude and practice of general surgeons toward cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: A cross-sectional study.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) mandate well-established HIPEC and oncology centers, which are not available in many medical institutions. This study assessed the knowledge, attitude, and practice toward CRS and HIPEC of general surgeons in Riyadh, Saudi Arabia. PATIENTS AND METHODS: General surgeons (n = 266) from nine hospitals who treat patients with gastrointestinal cancer were surveyed. The responses of surgeons who work in HIPEC and academic centers (Group A) and surgeons working in tertiary and secondary hospitals (Group B) were compared. The survey response rate was 48.1% (128/266). RESULTS: Surgeons in group B treated significantly more patients with peritoneal carcinomatosis per year than surgeons in group A (P = .001). Group B reported having a HIPEC specialist at their hospital, and 71.4% reported that the nearest HIPEC center was within 30 miles, compared to 4.5% of respondents in group A (P = .001). Lack of access to a HIPEC specialist was reported by 15.5% of surgeons in group B and 0% of surgeons in group A (P = .006). HIPEC as a possible therapeutic option for appendiceal cancer was cited by 60.7% of surgeons in group B compared to 84.1% of surgeons in group A (P = .007) and as a therapeutic option for ovarian cancer by 52.4% of surgeons in group B and 81.8% of surgeons in group A (P = .001). CONCLUSION: New strategies are needed to improve the knowledge and implementation of the referral system for HIPEC among general surgeons. Our study was limited by a low response rate.

Impact of COVID-19 pandemic on patient satisfaction and surgical outcomes: A retrospective and cross sectional study.

OBJECTIVE: The objective of this study was to evaluate the impact of the COVID-19 pandemic on patient satisfaction and surgical outcomes at King Khalid University Hospital in Saudi Arabia. BACKGROUND: The COVID-19 pandemic has greatly affected health care systems across developing and developed countries. Therefore, it is important to understand its impact on various parameters of patient care as regards revised infrastructure and policies in hospitals during the pandemic. METHOD: It is a retrospective cross-sectional study was conducted from 13-3-2020 to 26-4-2020 at King Khalid University Hospital in Saudi Arabia. Patient satisfaction and surgical outcomes were the main outcome measures. RESULTS: 331 participants were included in the study (median age: 53 years; 70% female), and 223 completed the patient's satisfaction survey. 260 of the surgeries were non-oncolog cases (78.6%) compared to 71 oncology cases (21.4%). With respect to the surgical outcomes, 12% of the patients required admission to the ICU, and 10.9% developed postoperative complications, most of which were infectious complications. Only 1.8% (6 patients) were re-admitted to the hospital. Three patients died within 30 days post-op (0.9%), all had emergency surgery. Regarding patient satisfaction, 77.6% and 93% of the patients reported that nurses and doctors, respectively, treated them with courtesy and respect, listened to them carefully, and provided clear explanations to them. 90.3% were satisfied with the hospital sanitary measures. 64.1% stated that they got written instructions at the time of discharge. CONCLUSION: The satisfaction level of patients was high for all the studied domains, and there were a small number of complications with overall good surgical outcomes. That indicates that all the actions and policies that were implemented during the pandemic were proven beneficial for the patients. It is recommended to continue those measures until the COVID-19 pandemic is over.