Recurrence-free survival dynamics following adjuvant chemotherapy for resected colorectal cancer: A systematic review of randomized controlled trials.

BACKGROUND: Several cytotoxic chemotherapies have demonstrated efficacy in improving recurrence-free survival (RFS) following resection of Stage II-IV colorectal cancer (CRC). However, the temporal dynamics of response to such adjuvant therapy have not been systematically quantified. METHODS: The Cochrane Central Register of Trials, Medline (PubMed) and Web of Science were queried from database inception to February 23, 2023 for Phase III randomized controlled trials (RCTs) where there was a significant difference in RFS between adjuvant chemotherapy and surgery only arms. Summary data were extracted from published Kaplan-Meier curves using DigitizeIT. Absolute differences in RFS event rates were compared at matched intervals using multiple paired t-tests. RESULTS: The initial search yielded 1469 manuscripts. After screening, 18 RCTs were eligible (14 Stage II/III; 4 Stage IV), inclusive of 16,682 patients. In the absence of adjuvant chemotherapy, the greatest rate of recurrence was observed in the first year (mean RFS event rate; 0-0.5 years: 0.22 ± 0.21; 0.5-1 years: 0.20 ± 0.09). Adjuvant chemotherapy was associated with significant decreases in the RFS event rates for the intervals 0-0.5 years (0.09 ± 0.09 vs. 0.22 ± 0.21, p < 0.001) and 0.5-1 years (0.14 ± 0.11 vs. 0.20 ± 0.09, p = 0.001) after randomization, but not at later intervals (1-5 years). In Stage IV trials, RFS event rates significantly differed for the interval 0-0.5 years (p = 0.012), corresponding with adjuvant treatment durations of 6 months. In Stage II/III trials, which included therapies of 6-24 months duration, there were marked differences in the RFS event rates between surgery and chemotherapy arms for the intervals 0-0.5 years (p < 0.001) and 0.5-1 years (p < 0.001) with smaller differences in the RFS event rates for the intervals 1-2 years (p = 0.012) and 2-3 years (p = 0.010). CONCLUSIONS: In a systematic review of positive RCTs comparing adjuvant chemotherapy to surgery alone for Stage II-IV CRC, observed RFS improvements were driven by early divergences that occurred primarily during active cytotoxic chemotherapy. Late recurrence dynamics were not influenced by adjuvant therapy use. Such observations may have implications for the use of chemotherapy for micrometastatic clones detectable by cell-free DNA-based methodologies.

Pancreatectomy for intraductal papillary mucinous neoplasm: has anything changed in North America?

BACKGROUND: Multiple guidelines on the management of intraductal papillary mucinous neoplasm (IPMN) have been published over the past decade. However, practice data are lacking. This study aims to determine whether pancreatectomy procedures, IPMN pathology, or outcomes have changed. METHODS: ACS-NSQIP Procedure Targeted Pancreatectomy database was queried for patients with IPMN from 2014 to 2019. Cases were stratified by pathology, tumor stage/cyst size and procedure. Pancreatectomies for IPMN by year, 30-day morbidity, and clinically relevant postoperative pancreatic fistula (CR-POPF) were quantified. Mann-Kendall trend tests were performed to assess surgical trends and associated outcomes over time. RESULTS: 3912 patients underwent pancreatectomy for IPMN. 21% demonstrated malignancy and 79% were benign. Morbidity and mortality occurred in 29.7% and 1.5% of cases, respectively. Over time, no change was observed in use of pancreatectomy for IPMN (10%) or in benign/malignant pathology, or cyst size. Robotic approach increased from 9.1% to 16.5% with decreases in laparoscopic (19.5%-15.0%) and open interventions (71.5%-68.1%, p = 0.016). No change was observed over time in morbidity or mortality; however, rates of CR-POPF decreased (18.8%-13.8%, p < 0.001). CONCLUSIONS: Practice patterns in treatment of IPMN have not changed significantly in North America. More patients are undergoing robotic pancreatectomy, and postoperative pancreatic fistula rates are improving.

COVID-19 Effect on Surgery for Gastrointestinal Malignancies: Have Operative Volumes Recovered?

BACKGROUND: COVID-19 disrupted elective operations, cancer screening, and routine medical care while simultaneously overwhelming hospital staff and supplies. Operations for gastrointestinal (GI) malignancies rely on endoscopic screening, staging, and neoadjuvant therapy (NAT), each of which was disrupted by the pandemic. The aim was to evaluate the effect of the COVID-19 pandemic on the US national rates of gastrointestinal oncologic operations. METHODS: The Vizient Clinical Data Base® was queried for oncologic operations for esophageal, gastric, and colorectal malignancies with and without NAT from March 2019 to March 2022. Control chart analysis examined operative volume over time while Wilcoxon rank sum tests were used to compare mean monthly volume before and during the pandemic. RESULTS: A total of 95,912 patients were identified over 36 months; 5.8% esophageal, 6.3% gastric, 77.5% colonic, and 10.4% rectal operations. Esophageal operative volume decreased for 9 months during the pandemic and was significantly lower during than before the pandemic (p=0.002). Gastric operations decreased for 10 months early in the pandemic, but rebounded so that after 2 years volumes were unchanged (p=0.49). Colonic operations experienced a sharp decrease for 4 months at the beginning of the pandemic, but volumes quickly increased and overall were unchanged (p=0.29). Rectal operations decreased for 13 months and were significantly lower during than before the pandemic (p=0.018). Oncologic operations for patients receiving NAT varied. CONCLUSION: COVID-19 significantly disrupted the volume of gastrointestinal oncologic operations in the USA. Esophageal and rectal oncologic operations experienced prolonged and significant reductions while gastric and colonic oncologic operations transiently decreased but rebounded during the pandemic.

Chronologic Age, Independent of Frailty, is the Strongest Predictor of Failure-to-Rescue After Surgery for Gastrointestinal Malignancies.

BACKGROUND: Prior studies of older cancer patients undergoing large operations have reported similar rates of complications to the general population but higher rates of mortality, suggesting higher rates of failure-to-rescue (FTR) with advanced age. Whether age is a marker for frailty, or an independent predictor of FTR, is not clear. METHODS: The ACS-NSQIP database was queried from 2015-19 for patients undergoing surgery for gastrointestinal (GI) malignancy. Patients were divided into age-stratified cohorts: C1 (18-55), C2 (56-65), C3 (66-75), C4 (76-89). Adjusted odds ratios (aOR) were computed to assess the relationship of the FTR rate and age, while controlling for potential confounders. A second analysis was specified with all covariates converted to Z-scores, which generated scaled adjusted odds ratios (saOR) to determine the strongest predictor of FTR. RESULTS: Multivariable analysis suggests that age is an independent predictor of FTR: C2:C1 aOR = 1.87 (p < 0.001); C3:C1 aOR = 3.33 (p < 0.001); C4:C1 aOR = 5.71 (p < 0.001). The scaled analysis demonstrated that age is the strongest predictor of FTR (saOR = 1.92, p < 0.001); a one standard deviation increase in age was associated with a 92% increased odds of FTR. The saOR for frailty (1.18, p < 0.001) and for number of comorbidities (1.10, p = 0.005) also were statistically significant. CONCLUSIONS: Chronologic age was independently associated with increased FTR after surgery for GI malignancy and was the strongest predictor of FTR. These results suggest that chronologic age must be carefully considered when evaluating the fitness of a patient for GI cancer surgery.

Does Neoadjuvant Radiation Therapy Contribute to the Incidence of Pulmonary Complications Following Esophagectomy for Malignant Neoplasm?

BACKGROUND: Post-operative pulmonary complications (POPC) are common in patients undergoing esophagectomy and neoadjuvant radiotherapy may exacerbate POPC. This study assessed whether neoadjuvant radiation increases the incidence of POPC in patients undergoing esophagectomy for malignancy. METHODS: The American College of Surgeons-National Surgical Quality Improvement Program database files from 2016 to 2018 were queried for patients undergoing esophagectomy for malignancy. Inverse probability treatment weighting (IPTW) was used to create balanced cohorts in which the control group received neoadjuvant chemotherapy (nCT) and the treatment cohort received neoadjuvant chemoradiotherapy (nCRT). A subset analysis was performed on patients with pre-existing pulmonary disease (PEPD). Primary outcomes were POPC and 30-day mortality. RESULTS: The all-patient analysis did not demonstrate a consistent association between neoadjuvant radiation and POPC. However, in patients with PEPD, POPC occurred more often in the nCRT cohort. Comparing nCRT to nCT and after IPTW adjustment for confounders, there was higher odds of pneumonia (aOR = 3.0, P = .002), unplanned intubation (aOR = 2.0, P = .03), and extended mechanical ventilation (aOR = 3.6, P = .002). DISCUSSION: In esophageal cancer patients with PEPD that undergo nCRT vs nCT prior to esophagectomy, the greater risk of POPCs must be weighed against the potential for improved oncologic outcomes.

Robotic pancreatoduodenectomy: trends in technique and training challenges.

BACKGROUND: More complex cases are being performed robotically. This study aims to characterize trends in robotic pancreatoduodenectomy (RPD) over time and assess opportunities for advanced trainees. METHODS: Using the ACS-NSQIP database from 2014 to 2019, PD cases were characterized by operative approach (open-OPN, laparoscopic-LAP, robotic-ROB). Proficiency and postoperative outcomes were described by approach over time. RESULTS: 24,268 PDs were identified, with the ROB approach increasing from 2.8% to 7.5%. Unplanned conversion increased over time for LAP (27.7-39.0%, p = 0.003) but was unchanged for ROB cases (14.8-14.7%, p = 0.257). Morbidity increased for OPN PD (35.5-36.8%, p = 0.041) and decreased for ROB PD (38.7-30.3%, p = 0.010). Mean LOS was lower in ROB than LAP/OPN (9.5 vs. 10.9 vs. 10.9 days, p < 0.00001). Approximately, 100 AHPBA, SSO, and ASTS fellows are being trained each year in North America; however, only about 5 RPDs are available per trainee per year which is far below that recommended to achieve proficiency. CONCLUSION: Over a 6-year period, a significant increase was observed in the use of RPD without a concomitant increase in conversion rates. RPD was associated with decreased morbidity and length of stay. Despite this shift, the number of cases being performed is not adequate for all fellows to achieve proficiency before graduation.

Virtual Tumor Board Increases Provider Attendance and Case Presentations.

PURPOSE: Many cancer centers engage in multidisciplinary tumor board meetings to determine the optimal approach to complex cancer care. With the onset of the COVID-19 pandemic, many institutions changed the format of these meetings from in-person to virtual. The aim of this study was to determine if the change to a virtual meeting format had an impact on attendance and cases presented. METHODS: Tumor board records were analyzed to obtain attendance and case presentation information at a National Cancer Institute-designated Comprehensive Cancer Center. Twelve-month in-person tumor board data were compared with 12-month virtual tumor board data to assess for difference in attendance and case presentation patterns. RESULTS: Seven separate weekly tumor board meetings at the beginning of the study (breast, GI, gynecology, liver, lung, melanoma, and urology) were expanded to nine meetings on the virtual platform (+endocrine and pancreas). Overall attendance increased by 46% on the virtual platform compared with in-person meetings (4,030 virtual attendances v 2,753 in-person, P < .001). Increased attendance was present across all specialties on the virtual platform. In addition, the number of patient cases discussed increased from 2,127 in in-person meeting to 2,656 on the virtual platform (a 20% increase, P < .001). CONCLUSION: A significant increase was observed in overall tumor board attendance and in case presentations per meeting, requiring the expansion of additional weekly meetings. Furthermore, in a major cancer center with multiple community affiliates, virtual tumor boards may encourage increased participation from remote sites with the benefit of obtaining expert specialist advice as compared with geographically challenging in-person meetings.

The Impact of Venous Thromboembolism on Mortality and Morbidity During Nephrectomy for Renal Mass.

OBJECTIVE: To determine the morbidity, mortality, and costs associated with having concurrent venous thromboembolism (VTE) at the time of surgical resection of a renal mass. PATIENTS AND METHODS: We identified 108,430 patients undergoing elective partial or radical nephrectomy for a renal mass from 2013 to 2017 using the Premier Healthcare database. The association of VTE with 90-day complication rates, mortality, ICU admission, readmission, and direct hospital costs (2019 US dollars) was determined with multivariable logistic regression and quantile regression models, respectively. RESULTS: Of the 108,430 patients who underwent elective partial or radical nephrectomy, 1.2% (n = 1301) of patients were diagnosed with a preoperative VTE. Patients with preoperative VTE have higher rates of minor (odds ratio [OR] 1.47, 95% confidence inteval [CI] 1.34-1.62, P < .0001) and major complications (OR 2.53, 95% CI 2.23-2.86, P < .0001), mortality (OR 2.03, 95% CI 1.6-2.57, P < .0001), and readmissions (OR 1.73, 95% CI 1.57-1.90, P < .0001) compared to patients without preoperative VTE at the time of nephrectomy. Notably, the predicted probability for a major complication was significantly higher among patients with preoperative VTE who underwent either partial or radical nephrectomy, irrespective of the surgical approach utilized. Furthermore, rates of all types of complications except endocrine and soft tissue were significantly increased in patients undergoing nephrectomy with preoperative VTE compared to those without VTE. CONCLUSION: VTE at the time of nephrectomy is associated with significantly higher rates of major complications, increased mortality, and higher overall costs. Taken together, these findings have important implications for the counseling and management of renal masses in presence of VTE.

Surgery is Associated With Improved Overall Survival in Patients With Metastatic Gastric Cancer: A National Cancer Database Analysis.

BACKGROUND: The 5-year overall survival (OS) rate for patients with metastatic gastric cancer (mGC) is 5.3%. Surgery for mGC is controversial. METHODS: We identified all mGC patients who received chemotherapy using the National Cancer Database (2004-2015). Patients were grouped according to surgery of: (1) the primary site (PS) only, (2) primary and distant sites (PDS), (3) distant site only (DS), or (4) no surgery (NS). A propensity score adjustment and multivariate regression was used to compare OS. RESULTS: Overall, 18,772 patients met the inclusion criteria: (1) PS (n = 962, 5.1%), (2) PDS (n = 380, 2.1%), (3) DS (n = 984, 5.2%), and 16,446 NS (87.6%). Surgery was associated with improved OS in the PS and PDS groups (hazard ratios: .489 (95% CI: .376-.636); .583 (95% CI: .420-.811), P < .001) (median OS 15.8 and 15.9 months vs 8.6 for NS patients, respectively). CONCLUSIONS: Gastrectomy with or without metastasectomy is associated with improved survival in stage IV gastric cancer patients receiving chemotherapy. This warrants further prospective studies.

Pancreatoduodenectomy: the Metabolic Syndrome is Associated with Preventable Morbidity and Mortality.

BACKGROUND: Patients with metabolic syndrome (MS) may have increased perioperative morbidity and mortality. The aim of this analysis was to investigate the association of MS with mortality, serious morbidity, and pancreatectomy-specific outcomes in patients undergoing pancreatoduodenectomy (PD). METHODS: Patients with MS who underwent PD were selected from the 2014-2018 ACS-NSQIP pancreatectomy-specific database. MS was defined as obesity (BMI ≥ 30 kg/m2), diabetes, and hypertension. Demographics and outcomes were compared by χ2 and Mann-Whitney tests, and adjusted odds ratios from multivariable logistic regression assessed the association between MS and primary outcomes. RESULTS: Of 19,054 patients who underwent PD, 7.3% (n = 1388) had MS. On univariable analysis, patients with MS had significantly worse outcomes (p < 0.05): 30-day mortality (3% vs 1.8%), serious morbidity (26% vs 23%), re-intubation (4.9% vs 3.5%), pulmonary embolism (2.0% vs 1.1%), acute renal failure (1.5% vs 0.9%), cardiac arrest (1.9% vs 1.0%), and delayed gastric emptying (18% vs 16.5%). On multivariable analysis, 30-day mortality was significantly increased in patients with MS (aOR: 1.53, p < 0.01). CONCLUSION: Metabolic syndrome is associated with increased morbidity and mortality in patients undergoing pancreatoduodenectomy. The association with mortality is a novel observation. Perioperative strategies aimed at reduction and/or mitigation of cardiac, pulmonary, thrombotic, and renal complications should be employed in this population given their increased risk.

Propensity score methods in the surgical oncology literature.

The use of propensity score methods in the surgical literature is increasing. Randomized, controlled clinical trials are the gold standard of medical research, allowing for accurate measurement and analysis of treatment effects. Use of propensity score methods allows researchers to mimic randomization when true randomization may not be possible. When used properly, these methods are a powerful tool for the medical researcher, allowing more rigorous conclusions to be drawn from retrospective data. With the increasing prevalence of propensity methods, it is important that these methods are used correctly, lest researchers be led to misleading conclusions based on poor statistical study design and analysis. The objective of this review is to analyze and evaluate the use of propensity score methods in the surgical oncology literature. We critique the current state of the use of propensity scores in the surgical oncology literature and offer recommendations to assure appropriate usage of propensity score methods.

Neoadjuvant Therapy for Pancreatic Cancer: Increased Use and Improved Optimal Outcomes.

BACKGROUND: The introduction of more effective chemotherapy a decade ago has led to increased use of neoadjuvant therapy (NAT) in patients with pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to assess the evolving use of NAT in individuals with PDAC undergoing pancreatoduodenectomy (PD) and to compare their outcomes with patients undergoing upfront operation. STUDY DESIGN: The American College of Surgeons NSQIP Procedure Targeted Pancreatectomy database was queried from 2014 to 2019. Patients undergoing pancreatoduodenectomy were evaluated based on the use of NAT versus upfront operation. Multivariable analysis was performed to determine the effect of NAT on postoperative outcomes, including the composite measure optimal pancreatic surgery (OPS). Mann-Kendall trend tests were performed to assess the use of NAT and associated outcomes over time. RESULTS: A total of 13,257 patients were identified who underwent PD for PDAC between 2014 and 2019. Overall, 33.6% of patients received NAT. The use of NAT increased steadily from 24.2% in 2014 to 42.7% in 2019 (p < 0.0001). On multivariable analysis, NAT was associated with reduced serious morbidity (odds ratio [OR] 0.83, p < 0.001), clinically relevant pancreatic fistulas (OR 0.52, p < 0.001), organ space infections (OR 0.74, p < 0.001), percutaneous drainage (OR 0.73, p < 0.001), reoperation (OR 0.76, p = 0.005), and prolonged length of stay (OR 0.63, p < 0.001). OPS was achieved more frequently in patients undergoing NAT (OR 1.433, p < 0.001) and improved over time in patients receiving NAT (50.7% to 56.6%, p < 0.001). CONCLUSION: NAT before pancreatoduodenectomy increased more than 3-fold over the past decade and was associated with improved optimal operative outcomes.

Molecular weaving.

Historically, the interlacing of strands at the molecular level has mainly been limited to coordination polymers and DNA. Despite being proposed on a number of occasions, the direct, bottom-up assembly of molecular building blocks into woven organic polymers remained an aspirational, but elusive, target for several decades. However, recent successes in two-dimensional and three-dimensional molecular-level weaving now offer new opportunities and research directions at the interface of polymer science and molecular nanotopology. This Perspective provides an overview of the features and potential of the periodic nanoscale weaving of polymer chains, distinguishing it from randomly entangled polymer networks and rigid crystalline frameworks. We review the background and experimental progress so far, and conclude by considering the potential of molecular weaving and outline some of the current and future challenges in this emerging field.

Timing of oral intake after esophagectomy: A narrative review of the literature and case report.

Esophagectomy, a treatment modality for esophageal cancer, is associated with high rates of morbidity, the most common being anastomotic leaks and pulmonary complications. The current standard of care for nutrition support after esophagectomy includes a period of nothing by mouth with enteral nutrition support via jejunostomy tube owing to the concern of increasing the risk of anastomotic leak as a result of early postoperative oral intake. However, the optimal timing of oral diet initiation remains controversial. This narrative review presents a patient who incurred an anastomotic leak following esophagectomy after initiation of oral intake on postoperative day 5 and evaluates the current literature on the timing of oral diet initiation after esophagectomy. A systematic literature search was performed to assess current evidence evaluating early oral diet (EOD) initiation after esophagectomy. Over the past 5 years, 11 studies have evaluated the impact of EOD initiation after esophagectomy in comparison with a conventional feeding regimen, including a period of nothing by mouth with enteral or parenteral nutrition support. The available evidence suggests that EOD initiation does not increase rates of complications after esophagectomy. However, the evidence is limited by the lack of a standardized definition of what constitutes EOD initiation, patient selection bias, variations in nutrition support provided in the studies, and lack of statistical analyses evaluating the impact of potential confounding variables. Additional research with larger, high-quality randomized controlled trials is needed to determine the optimal timing of diet initiation after esophagectomy.

Adverse perioperative outcomes among patients undergoing gastrointestinal cancer surgery: Quantifying attributable risk from malnutrition.

BACKGROUND: Preoperative malnutrition adversely impacts perioperative outcomes among patients with gastrointestinal (GI) cancer. The attributable risk (AR) that nutrition status contributes towards negative outcomes is poorly understood. METHODS: Adults undergoing GI cancer surgeries were identified within the American College of Surgeons National Surgical Quality Improvement Program database (2005-2017). Emergency surgeries, outpatients, and cases with an American Society of Anesthesiologists status above III were excluded. Adjusted multivariable models were constructed to determine the associations between markers of nutrition status (body mass index, >10% weight loss in last 6 months, functional status, and serum albumin level) and adverse perioperative outcomes (presence and number of complications, death, 30-day readmission, and length of stay). Predictive accuracy statistics and population AR (PAR) were determined. RESULTS: The final sample included 78,662 cases. Patients with >10% weight loss 6 months preceding surgery (compared with those who did not), had a significantly increased risk of complications (Relative Risk = 1.28; 95% CI, 1.20-1.37) and odds of death (odds ratio [OR] = 1.37; 95% CI, 1.18-1.59). A totally dependent functional status (compared with independent status) was associated with a 3.3-times higher odds of death (OR = 3.30; 95% CI, 1.53-7.15). Multivariable models were not predictive of adverse outcomes; PAR from the markers ranged 1%-2%. CONCLUSION: Ten percent weight loss in preceding 6 months was associated with increased risk of adverse perioperative outcomes among adults undergoing GI cancer surgery. The contribution of nutrition status markers to surgical outcomes as assessed by PAR was small (1%-2%), a finding not previously reported. Future intervention studies should include validated nutrition risk markers, control for effects of perioperative variables, and evaluate PAR within the immediate/long-term postoperative periods.

Delayed cytokine release syndrome after neoadjuvant nivolumab: a case report and literature review.

Aim: Cytokine release syndrome (CRS) is an infrequently described immune-related adverse event of checkpoint inhibitors (CPI). CPI-induced CRS typically presents with fevers, hemodynamic instability and organ dysfunction within 2 weeks of the last treatment cycle. Case study: We report an unusual case of delayed and severe CRS occurring postoperatively in a patient with hepatic-limited metastatic colorectal cancer who received neoadjuvant immunotherapy. After a negative workup for alternative causes, he received prolonged corticosteroid treatment with symptom resolution. Conclusion: CPI-induced CRS can mimic sepsis and clinicians should maintain a high-index of suspicion to diagnose this immune-related adverse event early and initiate appropriate treatment. As use of perioperative immunotherapy increases, the potential role of surgery to trigger CRS in this case warrants further investigation.

Lay abstract Aim: Cytokine release syndrome (CRS) is a rare but potentially serious side effect of a class of immunotherapy drugs called checkpoint inhibitors (CPI). CRS typically presents with fevers and low blood pressure and can cause damage to organs including the kidneys and liver. Case study: We report an unusual case of severe CRS occurring after surgery in a patient who had received prior CPI therapy. After a thorough evaluation for alternative causes, he was diagnosed with CRS and treated successfully with steroids. Conclusion: It is important for medical providers to consider this potential side effect when treating patients with CPI. Further research is needed to clarify the role of surgery in CPI-induced CRS.

Cannabinoid use for appetite stimulation and weight gain in cancer care: Does recent evidence support an update of the European Society for Clinical Nutrition and Metabolism clinical guidelines?

Cannabinoids have been used medicinally for thousands of years. Clinical trials support their use for treatment of chemotherapy-induced nausea and vomiting and HIV- and AIDS-related anorexia. Cancer anorexia cachexia syndrome (CACS) is a common debilitating condition and is associated with poor prognosis. The 2016 European Society for Parenteral and Enteral Nutrition clinical guidelines on nutrition in cancer patients concluded that "there are insufficient consistent clinical data to recommend cannabinoids to improve taste disorders or anorexia in cancer patients." The increased attention that cannabinoids have received in recent years warrants an updated evaluation of the literature on this topic, as practitioners are likely to encounter cancer patients interested in cannabinoid use. A systematic literature search was performed to assess the current body of evidence concerning cannabinoid use for the stimulation of appetite and oral intake by cancer patients. Over the past 20 years, 6 randomized controlled trials have evaluated the impact of cannabinoids on appetite-related outcomes in oncology patients in comparison with a control group or placebo. Based on this literature, cannabinoids do not appear to improve appetite, oral intake, weight, chemosensory function, or appetite-related quality of life. Limitations of the literature include small sample sizes, lack of adjustment for confounding variables, and difficulties conducting true placebo-controlled trials with a drug that may result in psychoactive side effects. Further exploration of the impact of cannabinoid use on CACS by using large, well-designed clinical trials is needed.

A Chiral Cyclometalated Iridium Star of David [2]Catenane.

Although circular helicates can be assembled with a range of labile transition-metal centers, solely "chiral-at-metal" examples (i.e., systems without chiral ligands) and heterometallic (i.e., mixed metal systems, racemic or chiral) circular helicates both remain unexplored. Here, we report on the enantioselective synthesis of a heterometallic (Ir2Zn4) hexameric circular helicate and its elaboration into the corresponding triply interlocked Star of David [2]catenane. The relative inertness of Ir(III) enables enantiospecific synthesis of the hexameric circular helicate using chiral-at-metal building blocks. The resulting Star of David [2]catenane, which is a chiral 6-2-1 link, is formed as a single topological enantiomer. The X-ray crystal structure of the (Ir2Zn4)-catenane shows each of the two 95-atom-long macrocycles entwined around the six metal octahedral metal ions and each other, forming a triply interlocked circular double helix. Two PF6- anions reside above and below the central cavity. The Star of David [2]catenane, both with and without coordinated Zn(II) ions, retains the photophysical properties characteristic of cyclometalated Ir(III) complexes. The synthetic strategy opens up new research directions and opportunities for the assembly of other chiral knots, links, and heterometallic circular helicates.