Risk factors for post-operative VTE following colorectal surgery: Is caprini score enough?

BACKGROUND: Post-operative colorectal venous thromboembolism (VTE) rates range between 1 and 3%. Often, surgeons utilize risk assessment models, like the modified Caprini, to determine need for prophylaxis. However, studies reveal additional unaccounted risk factors like preoperative serum albumin level, perioperative blood transfusion, emergency surgery, and preoperative steroid use. METHODS: This was a multicenter, retrospective study conducted between January 2021-December 2021. The primary endpoint was to assess the VTE rate within 30 days post-operatively. RESULTS: Overall, incidence rate was 1.75%. Of these, 53% underwent urgent/emergent surgery and 60% had perioperative blood transfusions. Twelve patients had a known preoperative serum albumin level, with 66% being less than 3.5 â€‹g/dL. Only 30% of patients had a high Caprini risk score. No patient had preoperative steroid use. CONCLUSION: The study suggests considering urgent/emergent surgeries, low preoperative albumin levels, and blood transfusions for enhanced VTE screening and prophylaxis in post-operative colorectal patients.

Anomalous Mechanical and Electrical Interplay in a Covalent Organic Framework Monolayer Membrane.

Ion transport through nanoconfinement, driven by both electrical and mechanical forces, has drawn ever-increasing attention, due to its high similarity to stress-sensitive ion channels in biological systems. Previous studies have reported only pressure-induced enhancement in ion conductance in low-permeable systems such as nanotubes, nanoslits, or single nanopores. This enhancement is generally explained by the ion accumulation caused by the capacitive effect in low-permeable systems. Here, we fabricate a highly permeable COF monolayer membrane to investigate ion transport behavior driven by both electrical and mechanical forces. Our results show an anomalous conductance reduction activated by external mechanical force, which is contrary to the capacitive effect-dominated conductance enhancement observed in low-permeable nanopores or channels. Through simulations, we uncovered a distinct electrical-mechanical interplay mechanism that depends on the relative rate between the ion diffusion from the boundary layer to the membrane surface and the ion transport through the membrane. The high pore density of the COF monolayer membrane reduces the charge accumulation caused by the capacitive effect, resulting in fewer accumulated ions near the membrane surface. Additionally, the high membrane permeability greatly accelerates the dissipation of the accumulated ions under mechanical pressure, weakening the effect of the capacitive layer on the streaming current. As a result, the ions accumulated on the electrodes, rather than in the capacitive layer, dominating the streaming current and giving rise to a distinct electrical-mechanical interplay mechanism compared to that in low-permeable nanopores or channels. Our study provides new insights into the interplay between electrical and mechanical forces in ultra-permeable systems.

A Risk-Prediction Platform for Acute Kidney Injury and 30-Day Readmission After Colorectal Surgery.

INTRODUCTION: Few known risk factors for certain surgical complications are prospectively analyzed to ascertain their influence on outcomes. Health systems can use integrated machine-learning-derived algorithms to provide information regarding patients' risk status in real time and pair this data with interventions to improve outcomes. The purpose of this work was to evaluate whether real-time knowledge of patients' calculated risk status paired with a stratified intervention was associated with a reduction in acute kidney injury and 30-d readmission following colorectal surgery. METHODS: Unblinded, retrospective study, evaluating the impact of an electronic health record-integrated and autonomous algorithm-based clinical decision support tool (KelaHealth, San Francisco, California) on acute kidney injury and 30-d readmission following colorectal surgery at a single academic medical center between January 1, 2020, and December 31, 2020, relative to a propensity-matched historical cohort (2014-2018) prior to algorithm integration (January 11, 2019). RESULTS: 3617 patients underwent colorectal surgery during the control period and 665 underwent surgery during the treatment period; 1437 historical control patients were matched to 479 risk-based patients for the study. Utilization of the risk-based management platform was associated with a 2.5% decrease in the rate of acute kidney injury (11.3% to 8.8%) and 3.1% decrease in rate of readmissions (12% to 8.9%). CONCLUSIONS: In this study, we found significant reductions in postoperative acute kidney injury (AKI) and unplanned readmissions after the implementation of an algorithm based clinical decision support tool that risk-stratified populations and offered stratified interventions. This opens up an opportunity for further investigation in translating similar risk platform approaches across surgical specialties.

Implications of radiofrequency ablation in patients undergoing thyroid surgery for benign disease in the United States.

BACKGROUND: Radiofrequency ablation is an alternative strategy for the management of benign thyroid conditions. We analyzed the proportion of patients who underwent thyroid surgery for benign conditions who would be potentially eligible for radiofrequency ablation. METHODS: We identified patients who underwent thyroid surgery from 2015 to 2019 at the study institution for Bethesda II cytopathology or toxic adenoma. Patients were considered potentially eligible for radiofrequency ablation if they had a dominant nodule >2 cm with or without compression symptoms, a dominant nodule <2 cm with compression symptoms, or a toxic adenoma. RESULTS: Of 411 patients in total, 284 (69.1%) would be eligible to consider thyroid radiofrequency ablation. In the radiofrequency ablation-eligible group, 20 (7.0%) experienced voice change after surgery, and 2 (0.7%) were dissatisfied or concerned about their scar. In the radiofrequency ablation-eligible group, 70 patients (24.6%) had malignancy diagnosed by final pathology, and 23 patients (8.1%) had cancers that were equal to or larger than 1 cm in size. CONCLUSION: Many patients who undergo surgery for benign thyroid disease could be considered for radiofrequency ablation as an alternative treatment modality. Given the rate of occult malignancy, optimal evaluation of nondominant nodules before radiofrequency ablation and long-term thyroid surveillance for patients who undergo radiofrequency ablation should be further studied.

Effect of High-Temperature Nitridation and Buffer Layer on Semi-Polar (10-13) AlN Grown on Sapphire by HVPE.

We have investigated the effect of high-temperature nitridation and buffer layer on the semi-polar aluminum nitride (AlN) films grown on sapphire by hydride vapor phase epitaxy (HVPE). It is found the high-temperature nitridation and buffer layer at 1300 °C are favorable for the formation of single (10-13) AlN film. Furthermore, the compressive stress of the (10-13) single-oriented AlN film is smaller than polycrystalline samples which have the low-temperature nitridation layer and buffer layer. On the one hand, the improvement of (10-13) AlN crystalline quality is possibly due to the high-temperature nitridation that promotes the coalescence of crystal grains. On the other hand, as the temperature of nitridation and buffer layer increases, the contents of N-Al-O and Al-O bonds in the AlN film are significantly reduced, resulting in an increase in the proportion of Al-N bonds.

Hospital-level compliance with the commission on cancer's quality of care measures and the association with patient survival.

BACKGROUND: Quality measurement has become a priority for national healthcare reform, and valid measures are necessary to discriminate hospital performance and support value-based healthcare delivery. The Commission on Cancer (CoC) is the largest cancer-specific accreditor of hospital quality in the United States and has implemented Quality of Care Measures to evaluate cancer care delivery. However, none has been formally tested as a valid metric for assessing hospital performance based on actual patient outcomes. METHODS: Eligibility and compliance with the Quality of Care Measures are reported within the National Cancer Database, which also captures data for robust patient-level risk adjustment. Hospital-level compliance was calculated for the core measures, and the association with patient survival was tested using Cox regression. RESULTS: Seven hundred sixty-eight thousand nine hundred sixty-nine unique cancer cases were included from 1323 facilities. Increasing hospital-level compliance was associated with improved survival for only two measures, including a 35% reduced risk of mortality for the gastric cancer measure G15RLN (HR 0.65, 95% CI 0.58-0.72) and a 19% reduced risk of mortality for the colon cancer measure 12RLN (HR 0.81, 95% CI 0.77-0.85). For the lung cancer measure LNoSurg, increasing compliance was paradoxically associated with an increased risk of mortality (HR 1.14, 95% CI 1.08-1.20). For the remaining measures, hospital-level compliance demonstrated no consistent association with patient survival. CONCLUSION: Hospital-level compliance with the CoC's Quality of Care Measures is not uniformly aligned with patient survival. In their current form, these measures do not reliably discriminate hospital performance and are limited as a tool for value-based healthcare delivery.

Deep Learning-Based Risk Model for Best Management of Closed Groin Incisions After Vascular Surgery.

BACKGROUND: Reduced surgical site infection (SSI) rates have been reported with use of closed incision negative pressure therapy (ciNPT) in high-risk patients. METHODS: A deep learning-based, risk-based prediction model was developed from a large national database of 72,435 patients who received infrainguinal vascular surgeries involving upper thigh/groin incisions. Patient demographics, histories, laboratory values, and other variables were inputs to the multilayered, adaptive model. The model was then retrospectively applied to a prospectively tracked single hospital data set of 370 similar patients undergoing vascular surgery, with ciNPT or control dressings applied over the closed incision at the surgeon's discretion. Objective predictive risk scores were generated for each patient and used to categorize patients as "high" or "low" predicted risk for SSI. RESULTS: Actual institutional cohort SSI rates were 10/148 (6.8%) and 28/134 (20.9%) for high-risk ciNPT versus control, respectively (P < 0.001), and 3/31 (9.7%) and 5/57 (8.8%) for low-risk ciNPT versus control, respectively (P = 0.99). Application of the model to the institutional cohort suggested that 205/370 (55.4%) patients were matched with their appropriate intervention over closed surgical incision (high risk with ciNPT or low risk with control), and 165/370 (44.6%) were inappropriately matched. With the model applied to the cohort, the predicted SSI rate with perfect utilization would be 27/370 (7.3%), versus 12.4% actual rate, with estimated cost savings of $231-$458 per patient. CONCLUSIONS: Compared with a subjective practice strategy, an objective risk-based strategy using prediction software may be associated with superior results in optimizing SSI rates and costs after vascular surgery.

Preoperative radiation therapy in the surgical management of gastric and junctional adenocarcinoma: Should lymph node retrieval guidelines be altered?

BACKGROUND: Although surgery remains the cornerstone of gastric cancer therapy, the use of radiation therapy (RT) is increasingly being employed to optimize outcomes. We sought to assess outcomes following use of RT for the treatment of gastric adenocarcinoma. METHODS: Using the National Cancer Data Base (NCDB) from 1998 to 2012, all patients with resected gastric adenocarcinoma were identified. Patients were stratified into four groups based on preoperative therapy: RT alone, chemotherapy only, chemoradiotherapy (CRT), and no preoperative therapy. Overall survival was estimated using multivariate Cox proportional hazards model. Adjusted secondary outcomes include margin positivity, lymph node harvest, LOS, 30-day readmission and mortality. RESULTS: A total of 10 019 patients met study criteria. In the unadjusted analysis, patients undergoing CRT compared to chemotherapy alone had fewer positive margins (7.9% vs 15.9%; P < 0.001), increased negative LNs (54.6% vs 37.7%; P < 0.001) with reduced LN retrieval (mean: 13.5 vs 19.6; P < 0.01). After multivariate adjustment, there was no survival benefit to any preoperative therapy; however, preoperative RT/CRT remained associated with decreased LN retrieval. CONCLUSIONS: The results support previous reports on preoperative RT resulting in decreased margin positivity. This study highlights the need to reconsider practice guidelines regarding appropriate lymphadenectomy in the setting of preoperative RT given reduced LN retrieval.

Open versus laparoscopic portal lymphadenectomy in gallbladder cancer: is there a difference in lymph node yield?

BACKGROUND: Gallbladder cancer (GBC) is the most common biliary tract malignancy. Because it commonly metastasizes via lymphatics, portal lymphadenectomy should be included in oncologic resections. This study aimed to compare the oncologic equivalence of the laparoscopic versus open technique by evaluating lymph node (LN) yield. METHODS: The 2010-2012 National Cancer Data Base identified patients who underwent laparoscopic or open resection of GBC with dedicated lymphadenectomy. LN yield was compared by resection method. Variables associated with LN yield ≥3 were identified. RESULTS: Of 1524 patients identified, 52% were intended to undergo laparoscopic surgery, with 20% of these patients converted to open. Collection of ≥3 LNs following open resection (47%) was higher than for laparoscopic resection (34%), p < 0.001. Operations performed at high-volume (aOR:1.74, p < 0.001) and/or academic centers (aOR:1.70, p = 0.024) had superior LN yield. LN yield was not associated with overall survival (aHR:0.93, p = 0.493). CONCLUSIONS: In this analysis of national data, LN yield following laparoscopic resection for GBC was significantly lower than following open resection. Open resection is more frequently performed at academic centers, possibly to assure adequate oncologic resection. Enforcing consensus guidelines for lymphadenectomy in gallbladder cancer will optimize outcomes as minimally invasive approaches evolve.

Delay in Adjuvant Chemotherapy and Survival Advantage in Stage III Colon Cancer.

BACKGROUND: Adjuvant chemotherapy after resection is the standard of care for stage III colon cancer, yet many patients omit chemotherapy. We aimed to describe the impact of delayed chemotherapy on overall survival across multiple time points. STUDY DESIGN: The 2006 to 2014 National Cancer Data Base (NCDB) was queried for patients with single primary stage III adenocarcinoma of the colon. Patients were grouped by receipt and timing of chemotherapy from resection date: chemotherapy omitted, <6 weeks, 6 to 8 weeks, 8 to 12 weeks, 12 to 24 weeks, and >24 weeks. Subgroup analyses were performed for those with comorbidities and those who had postoperative complications. Overall survival was compared using Cox proportional hazard modeling, adjusting for patient, tumor, and facility characteristics. RESULTS: In total, 72,057 patients were included; 20,807 omitted chemotherapy, 22,705 received it at <6 weeks, 15,412 between 6 and 8 weeks, 9,049 between 8 and 12 weeks, 3,595 between 12 and 24 weeks, and 489 at >24 weeks after resection. Compared with patients who omitted chemotherapy, patients who received chemotherapy at <6 weeks (hazard ratio [HR] 0.44), 6 to 8 weeks (HR 0.45), 8 to 12 weeks (HR 0.52), 12 to 24 weeks (HR 0.61), and >24 weeks (HR 0.68) had superior overall survival (p < 0.001). This survival benefit was preserved across subgroups (p < 0.001). CONCLUSIONS: After resection of stage III colon cancer, patients should receive adjuvant chemotherapy within 6 to 8 weeks for maximal benefit. However, chemotherapy should be offered to patients who are outside the optimal window, who have significant comorbidities, or who have had a complication more than 24 weeks from resection to improve the overall survival compared with omitting chemotherapy.

The appropriateness of 30-day mortality as a quality metric in colorectal cancer surgery.

BACKGROUND: Our study compares 30-day vs. 90-day mortality following colorectal cancer surgery (CRS), and examines hospital performance ranking based on this assessment. METHODS: Mortality rates were compared between 30 vs. 90 days following CRS for patients with stage I-III colorectal cancers from the National Cancer Database (2004-2012). Risk-adjusted hierarchical regression models evaluated hospital performance based on mortality. Hospitals were ranked into top (10%), middle (80%), and lowest (10%) performance groups. RESULTS: Among 185,464 patients, 90-day mortality was nearly double the 30-day mortality (4.4% vs. 2.5%). Following risk adjustment 176 hospitals changed performance ranking: 39% in the top 30-day mortality group changed ranking to the middle group; 37% of hospitals in the lowest 30-day group changed ranking to the middle 90-day group. CONCLUSIONS: Evaluation of hospital performance based on 30-day mortality is associated with misclassification for 15% of hospitals. Ninety-day mortality may be a better quality metric in oncologic CRS.

Resected irradiated rectal cancers: Are twelve lymph nodes really necessary in the era of neoadjuvant therapy?

BACKGROUND: Our study aims to identify the minimum number of lymph nodes (LN) associated with improved survival in patients who underwent NRT for stage II-III rectal cancer. METHODS: Adults with clinical stage II and III rectal adenocarcinoma in the National Cancer Data Base were stratified by NRT. Multivariable Cox regression modeling with restricted cubic splines was used to determine the minimum number of LNs associated with improved survival. RESULTS: Of 38,363 patients, 76% received NRT. After adjustment, a LNY≥12 was associated with improved survival among patients receiving NRT (HR 0.79, p < 0.0001) and those without NRT (HR 0.88, p = 0.04). Among patients receiving NRT, factors independently associated with LNY≥12 were younger age, private insurance, low comorbidity score, a recent year of diagnosis, higher T stage and grade, APR resection, and academic institution. CONCLUSIONS: A minimum LNY of 12 confers a survival benefit for rectal cancer patients regardless of receiving neoadjuvant radiation therapy.

Solid Pseudopapillary Neoplasm of the Pancreas in Children and Adults: A National Study of 369 Patients.

BACKGROUND: Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare tumor in children, with current evidence limited to single-center studies. We examined treatment and clinical outcomes for pediatric and adult SPN with a national data set. METHODS: The 2004 to 2013 National Cancer Data Base was queried to identify all patients diagnosed with SPN. The cohort was stratified by age (pediatric and adult) defined as below 18 years and 18 years and above, respectively. Baseline characteristics and unadjusted outcomes were compared. RESULTS: We identified 21 pediatric and 348 adult patients with SPN. Both groups displayed similar demographic composition. Patients were commonly female (90.5% [pediatric] vs. 85.9% [adult], P=0.56) and white (66.7% vs. 68.3%, P=0.74). Tumor location was similar between adults and children. Median tumor size was similar between children and adults (5.9 vs. 4.9 cm, P=0.41). Treatment strategies did not vary between groups. Partial pancreatectomy was the most common resection strategy (71.4% vs. 53.1%, P=0.80). Both groups experienced low mortality (0.0% vs. 0.7% at 5 y, P=0.31). CONCLUSIONS: This study provides the largest comparison of pediatric and adult SPN to date. Children with SPN have similar disease severity at presentation, receive similar treatments, and demonstrate equivalent postoperative outcomes compared with their adult counterparts.

Adjuvant Chemotherapy After Preoperative Chemoradiation Improves Survival in Patients With Locally Advanced Rectal Cancer.

BACKGROUND: Practice guidelines differ in their support of adjuvant chemotherapy use in patients who received preoperative chemoradiation for rectal cancer. OBJECTIVE: The purpose of this study was to evaluate the impact of adjuvant chemotherapy among patients with locally advanced rectal cancer who received neoadjuvant chemoradiation and surgery. DESIGN: This was a retrospective study. Multivariable Cox proportional hazard modeling was used to evaluate the adjusted survival differences. SETTINGS: Data were collected from the National Cancer Database. PATIENTS: Adults with pathologic stage II and III rectal adenocarcinoma who received neoadjuvant chemoradiation and surgery were included. MAIN OUTCOME MEASURES: Overall survival was measured. RESULTS: Among 12,696 patients included, 4023 (32%) received adjuvant chemotherapy. The use of adjuvant chemotherapy increased over the study period from 23% to 36%. Although older age and black race were associated with a lower likelihood of receiving adjuvant chemotherapy, patients with higher education level and stage III disease were more likely to receive adjuvant chemotherapy (all p < 0.05). At 7 years, overall survival was improved among patients who received adjuvant chemotherapy (60% vs. 55%; p < 0.001). After risk adjustment, the use of adjuvant chemotherapy was associated with improved survival (HR = 0.81 (95% CI, 0.72-0.91); p < 0.001). In the subgroup of patients with stage II disease, survival was also improved among patients who received adjuvant chemotherapy (68% vs 58% at 7 y; p < 0.001; HR = 0.70 (95% CI, 0.57-0.87); p = 0.002). Among patients with stage III disease, the use of adjuvant chemotherapy was associated with a smaller but persistent survival benefit (56% vs 51% at 7 y; p = 0.017; HR = 0.85 (95% CI, 0.74-0.98); p = 0.026). LIMITATIONS: The study was limited by its potential for selection bias and inability to compare specific chemotherapy regimens. CONCLUSIONS: The use of adjuvant chemotherapy among patients with rectal cancer who received preoperative chemoradiation conferred a survival benefit. This study emphasizes the importance of adjuvant chemotherapy in the management of rectal cancer and advocates for its increased use in the setting of neoadjuvant therapy. See Video Abstract at http://link.lww.com/DCR/A428.

Enhanced recovery protocols for colorectal surgery and postoperative renal function: a retrospective review.

BACKGROUND: While enhanced recovery protocols (ERPs) reduce physiologic stress and improve outcomes in general, their effects on postoperative renal function have not been directly studied. METHODS: Patients undergoing major colorectal surgery under ERP (February 2010 to March 2013) were compared with a traditional care control group (October 2004 October 2007) at a single institution. Multivariable regression models examined the association of ERP with postoperative creatinine changes and incidence of postoperative acute kidney dysfunction (based on the Risk, Injury, Failure, Loss, and End-stage renal disease criteria). RESULTS: Included were 1054 patients: 590 patients underwent surgery with ERP and 464 patients without ERP. Patient demographics were not significantly different. Higher rates of neoplastic and inflammatory bowel disease surgical indications were found in the ERP group (81 vs. 74%, p = 0.045). Patients in the ERP group had more comorbidities (ASA ≥ 3) (62 vs. 40%, p < 0.001). In unadjusted analysis, postoperative creatinine increase was slightly higher in the ERP group compared with control (median 0.1 vs. 0 mg/dL, p < 0.001), but levels of postoperative acute kidney injury were similar in both groups (p = 0.998). After adjustment with multivariable regression, postoperative changes in creatinine were similar in ERP vs. control (p = 0.25). CONCLUSIONS: ERP in colorectal surgery is not associated with a clinically significant increase in postoperative creatinine or incidence of postoperative kidney injury. Our results support the safety of ERPs in colorectal surgery and may promote expanding implementation of these protocols. TRIAL REGISTRATION: Not applicable, prospective data collection and retrospective chart review only.

Minimally invasive gastrectomy for gastric cancer: A national perspective on oncologic outcomes and overall survival.

BACKGROUND: Minimally invasive (MI) gastrectomy has become increasingly common as a resection technique for gastric cancer; however, data are limited regarding peri-operative morbidity, oncologic outcomes and long-term survival, particularly in the Western patient population. STUDY DESIGN: The 2010-2012 National Cancer Data Base was queried for adult patients who underwent gastrectomy for localized, intestinal-type gastric adenocarcinoma. Patients were classified by surgical approach (MI vs. open gastrectomy) on an intent-to-treat basis. Groups were propensity score matched using a 1:1 nearest neighbor algorithm, and outcomes were compared. Survival was estimated using the Kaplan-Meier method. RESULTS: Among 5420 patients, 1423 (26%) underwent MI gastrectomy. Following adjustment with propensity matching, all baseline characteristics were highly similar between 1175 patients in each treatment group. Between propensity-matched groups, MI gastrectomy patients had similar rates of margin-negative resections (91 vs. 90%, p = 0.447), median lymph node harvest (16 vs. 15, p = 0.104), and utilization of adjuvant therapies (28 vs. 28%, p = 0.748). MI gastrectomy was associated with shorter hospital stay (8 vs. 9 days, p < 0.001) without an increase in unplanned readmissions (7 vs. 6%, p = 0.456) or 30-day mortality (2 vs. 3%, p = 0.655). There was no difference in 3-year overall survival (50 vs. 55%, p = 0.359). CONCLUSIONS: On a national level, MI gastrectomy for gastric cancer appears to be associated with similar perioperative and long-term outcomes compared to the traditional open approach. While prospective studies remain essential, these data provide greater equipoise for ongoing trials and institutional efforts to further implement and evaluate this technique.

Surgical resection after neoadjuvant chemoradiation for oesophageal adenocarcinoma: what is the optimal timing?

OBJECTIVES: The purpose of this study was to determine the optimal timing of surgical resection of oesophageal adenocarcinoma following neoadjuvant chemoradiotherapy (nCRT). METHODS: nCRT before resection of oesophageal adenocarcinoma yields improved overall and progression-free survival. Despite the wide acceptance of tri-modal therapy, the optimal timing of surgical resection after nCRT is not well defined and existing studies are limited. Adults with Stage II/III oesophageal adenocarcinoma undergoing nCRT before surgery were identified from the National Cancer Database. Multivariable analysis using restricted cubic splines was used to identify an inflection point in clinical outcomes as a function of time between nCRT and surgery, dividing the cohort into short- and long-interval treatment groups, which were then compared. Adjusted rates of survival and margin status were compared between groups using multivariable analysis. RESULTS: Among 2444 patients, restricted cubic splines identified an inflection point at 56 days, dividing our cohort into 1533 short-interval and 911 long-interval patients. Long-interval patients had a higher adjusted incidence of pathologic downstaging (odds ratio 1.38, confidence interval 1.02-1.85, P = 0.04) but no difference in margin positivity compared with short-interval patients (odds ratio 0.91, confidence interval 0.56-1.47, P = 0.69). Worse overall survival was noted in the long-interval subgroup (hazard ratio 1.44, confidence interval 1.22-1.71, P < 0.001), but 30-day postoperative mortality was not statistically different (odds ratio 1.56, confidence interval 0.9-2.72, P = 0.12). CONCLUSIONS: Restricted cubic splines provides an objective mechanism to more accurately delineate optimum timing between nCRT and surgical resection. A time interval of 56 days represents an interval where increased pathologic downstaging is balanced by decreased overall survival.