Univariate Cox Proportional Hazards Analyses Research Articles

Platelets as a prognostic factor for patients with adenocarcinoma of the gastroesophageal junction

ObjectiveThe aim of this study was to investigate the prognostic role of plasma platelet count (PLT), mean platelet volume (MPV), and the combined COP-MPV score in patients with resectable adenocarcinomas of the gastroesophageal junction.BackgroundPlatelet activation, quantified by PLT and elevated MPV, plays an essential part in the biological process of carcinogenesis and metastasis. An increased preoperative COP-MPV is associated with poor survival in various tumor entities.MethodsData of 265 patients undergoing surgical resection for adenocarcinoma of the gastroesophageal junction were abstracted. COP-MPV score was defined for each patient. Utilizing univariate and multivariate Cox proportional hazard analyses, survival was determined.ResultsIn univariate analysis, elevated PLT (HR 3.58, 95% CI 2.61–4.80, p<0.001) and increased COP-MPV (HR 0.27, 95% CI 0.17–0.42, p<0.001 and HR 0.42, 95% CI 0.29–0.60, p<0.001) significantly correlated with shorter patients’ overall and disease-free survival, for all 256 patients, as well as in the subgroups of neoadjuvantly treated (p<0.001) and primarily resected patients (p<0.001). COP-MPV remained a significant prognostic factor in multivariate analysis for OS. However, PLT alone showed significant diminished OS and DFS in all subgroups (p<0.001) in univariate and multivariate analysis.ConclusionPLT is a potent independent prognostic biomarker for survival in a large prospective cohort of patients with resectable adenocarcinoma of the gastroesophageal junction. Additionally, we confirm that the COP-MPV score is significantly associated with worse outcome in these patients, but has no benefit in comparison to PLT.

Radiation dose is associated with improved local control for large, but not small, hepatocellular carcinomas

BackgroundWith advances in understanding liver tolerance, conformal techniques, image guidance, and motion management, dose-escalated radiotherapy has become a potential treatment for inoperable hepatocellular carcinoma (HCC). We aimed to evaluate the possible impact of biologically effective dose (BED) on local control and toxicity among patients with HCC.Methods and materialsPatients treated at our institution from 2009 to 2018 were included in this retrospective analysis if they received definitive-intent radiotherapy with a nominal BED of at least 60 Gy. Patients were stratified into small and large tumors using a cutoff of 5 cm, based on our clinical practice. Toxicity was assessed using ALBI scores and rates of clinical liver function deterioration.ResultsOne hundred and twenty-eight patients were included, with a mean follow-up of 16 months. The majority of patients (90.5%) had a good performance status (ECOG 0–1), with Child-Pugh A (66.4%) and ALBI Grade 2 liver function at baseline (55.4%). Twenty (15.6%) patients had a local recurrence in the irradiated field during the follow-up period. Univariate and multivariate Cox proportional hazard analyses showed that only BED significantly predicted local tumor recurrence. Higher BED was associated with improved local control in tumors with equivalent diameters over 5 cm but not in smaller tumors. There was no difference in liver toxicity between the low and high-dose groups.ConclusionsHigher radiotherapy dose is associated with improved local control in large tumors but not in tumors smaller than 5 cm in diameter. High-dose radiotherapy was not associated with increased liver toxicity.

Clinical features and outcomes analysis of Gallbladder neuroendocrine carcinoma.

Gallbladder neuroendocrine carcinoma (GB-NEC) is an uncommon and highly malignant tumor. This research aimed to investigate the clinical characteristics and prognostic factors of GB-NEC. Our survey of case reports from January 2000 to May 2022 screened a total of 84 patients with complete data who received surgical resection for gallbladder NEC. Log-rank generated survival curves using the Kaplan-Meier method for univariate survival analysis. To identify GB-NEC independent prognostic indicators for overall survival (OS), univariate and multivariate Cox proportional hazard analyses were conducted. These patients consisted of 25 men and 59 women, with an average age of 60 (range 29-85). Patients under 60 years old made up 44% of the population, while patients over 60 made up 56%. Fifty-three tumors were advanced pathologic TNM stage III and IV. After surgery, 44 patients underwent chemotherapy or radiotherapy. The median OS of 84 patients with GB-NEC was 16.8 months. In univariate and multivariate analysis, tumor size (diameter ≥5 cm), TNM tumor stage, and the receipt of postoperative adjuvant chemotherapy are independent factors influencing the prognosis of patients with GB-NEC. Tumor size (diameter ≥5 cm) and TNM tumor stage were independently related to a shorter OS. An enhanced OS was independently linked to receiving postoperative adjuvant chemotherapy.

Serum PLA2R antibody as a predictive biomarker for venous thromboembolism risk in primary membranous nephropathy

BackgroundPatients with nephrotic syndrome are at high risk of venous thromboembolism (VTE), especially for primary membranous nephropathy (PMN). The phospholipase A2 receptor (PLA2R) is a marker of primary membranous nephropathy activity. This study investigated the predictive value of PLA2R antibodies in PMN for VTE. MethodsIn this retrospective study, we included 97 PMN patients and evaluated the predictive value of serum PLA2R antibodies for VTE risk. Lower extremity venous ultrasound, renal vein ultrasound, or spiral computed tomography pulmonary arteriography were used to assess VTE events. Serum anti-PLA2R antibodies were detected by enzyme-linked immunosorbent assay (ELISA). The risk of VTE was stratified according to serum albumin levels. ResultsTwenty PMN patients (21%) had thromboembolic events. Eight (15%) of patients with serum albumin >25g/l developed VTE, 6 of whom were positive for serum PLA2R antibodies. Positive serum PLA2R antibodies were significantly associated with VTE events in patients with serum albumin >25g/l (p=0.01). Age, sex, blood creatinine, serum albumin, and 24-h urine protein levels were not statistically different between the two groups. Kaplan–Meier analysis using the log-rank test revealed anti-PLA2R positive membranous nephropathy patients had more probability of VTE events than anti-PLA2R negative patients. Univariate Cox proportional hazards analysis revealed that lnPLA2R-Ab is an unfavorable predictor for VTE events in patients with serum albumin >25g/l (hazard ratio (HR) 2.1, p=0.01). ConclusionsThe PLA2R antibody was a risk predictor for thromboembolic events in patients with primary membranous nephropathy with serum albumin >25g/l.

Outcomes and Treatment Algorithm in Glioblastoma Patients 80 Years and Older

The current standard of care for patients with glioblastoma (GBM) is maximal safe resection followed by adjuvant radiation therapy with concurrent temozolomide chemotherapy. Previous studies that identified this treatment regimen focused on younger patients with GBM. The proportion of patients with GBM over the age of 80 years is increasing. We investigate whether elderly patients benefit from the current standard of care with additional maximal safe resection. Clinical, operative, radiographic, demographic, genetic, and outcomes data were retrospectively collected for patients treated for histologically confirmed World Health Organization grade 4 GBM at University of Pittsburgh Medical Center from 2009 to 2020. Only patients 80 years and older were included (n= 123). Statistically significant values were set at P < 0.05. A univariate Cox proportional hazards analysis of GBM patients aged >80 years identified the use of temozolomide, radiation, Karnofsky Performance Status (KPS) > 70, and methylguanine DNA methyltransferase methylation with increased overall survival (OS). Further multivariate Cox proportional hazards model analysis showed that the variables identified in the univariate analysis passed multicollinearity testing, and that use of temozolomide, KPS >70, and gross total resection were shown to significantly impact survival. Survival analysis showed that patients with biopsy alone had a shorter median OS compared with patients who received resection, temozolomide, and radiation (P < 0.0001, median OS 1.6 vs. 7.5 months). Additionally, patients who underwent biopsy and then received temozolomide and radiation had a shorter median OS when compared with patients who received resection, temozolomide, and radiation (P= 0.0047, median OS 3.6 vs. 7.5 months). For elderly patients with KPS >70, GTR followed by radiation and temozolomide is associated with maximum OS.

The prognostic value of HALP score in predicting in-hospital mortality in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention.

Despite major advances in reperfusion therapies, morbidity and mortality rates associated with cardiovascular disorders remain high, particularly in patients with ST-segment elevation myocardial infarction (STEMI). Therefore, identifying prognostic variables that can be used to predict morbidity and mortality in STEMI patients is critical for better disease management. The HALP (hemoglobin, albumin, lymphocyte, and platelet) score, a novel index indicating nutritional status and systemic inflammation, provides information about prognosis. In this context, this study was carried out to investigate the relationship between HALP score assessed at admission and in-hospital mortality in STEMI patients. The population of this retrospective study consisted of 1307 consecutive patients diagnosed with STEMI and who underwent primary percutaneous coronary intervention (pPCI). The 1090 patients included in the study sample were divided into two groups based on the median HALP score value of 3.59. In-hospital and all-cause mortality rates during the follow-up were obtained from the registry. In-hospital mortality rate was significantly higher in patients with a HALP score of less than 3.59 compared to those with a HALP score of more than 3.59 (7.5% and 0.7%, respectively; P < 0.001). Univariate and multivariate Cox proportional hazard analyses revealed that the HALP score is independently associated with in-hospital mortality. The optimal HALP score cutoff value of <3.72 predicted in-hospital mortality with 95.56% sensitivity and 49.19% specificity. This study's findings indicate that HALP score may be a significant independent predictor of in-hospital mortality in patients with STEMI treated with pPCI.

Survival Trends and Profiling of Gastric Mixed Adenoneuroendocrine Carcinoma (gMANEC) in the Current Era

Background: Gastric mixed adenoneuroendocrine carcinoma (gMANEC) is a histopathologic diagnosis with at least 30% each of exocrine and endocrine components. Although prognosis is thought to be driven by the relative exocrine or endocrine dominance, gMANEC has been clinically treated as gastric adenocarcinoma (gAC). The overall survival of gMANEC as compared to gastric neuroendocrine carcinoma (gNEC) or gAC remains undefined. Methods: Using the National Cancer Database, patients with gastric tumors were queried from 2004 to 2016 for gMANEC, gNEC, and gAC histologies. Demographic and clinicopathologic features were recorded. Univariate and multivariate Cox proportional hazards analyses were performed to delineate factors associated with overall survival (OS). Results: Overall, 404 patients diagnosed with gMANEC were identified. Patients had a median age 68 years, were majority male, and predominantly Caucasian. Gastric MANEC was more frequently poorly differentiated (73%vs 52% (gAC) vs 20% (gNEC), P &lt; .001) with lymphovascular invasion (57%vs 38%vs 27%, P &lt; .001) and lymph node involvement (59%vs 49%vs 36%, P &lt; .001); these factors were associated with worse OS on univariable analysis. Finally, tumors &gt;5 cm and lymph node involvement were independent predictors of worse survival. The median OS of patients with gMANEC was 41.5 months. Conclusion: Gastric MANEC and gAC have a similarly dismal prognosis and thus should be continued to treat like gAC. Pathologic nodal metastasis, tumor size and grade are useful prognostic factors.

Association of lactate-to-albumin ratio with in-hospital and intensive care unit mortality in patients with intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a severe stroke subtype with a high mortality rate; the lactate-to-albumin ratio (LAR) is a new biomarker for predicting clinical outcomes in patients with ICH. However, the relationship between LAR and mortality in patients with ICH treated in the intensive care unit (ICU) remains controversial. Therefore, in this study, we aimed to investigate the association between LAR and in-hospital and ICU mortality in patients with ICH. Patients with ICH were selected from the Medical Information Mart for Intensive Care III (MIMIC-III) database; their clinical information, including baseline characteristics, vital signs, comorbidities, laboratory test results, and scoring systems, was extracted. Univariate and multivariate Cox proportional hazards analyses were used to investigate the association of LAR with in-hospital and ICU mortality. The maximum selection statistical method and subgroup analysis were used to investigate these relationships further. Kaplan-Meier (KM) analysis was used to draw survival curves. This study enrolled 237 patients with ICH whose lactate and albumin levels, with median values of 1.975 and 3.6 mg/dl, respectively, were measured within the first 24 h after ICU admission. LAR had an association with increased risk of in-hospital mortality [unadjusted hazards ratio (HR), 1.79; 95% confidence interval (CI), 1.32-2.42; p < 0.001] and ICU mortality (unadjusted HR, 1.88; 95% CI, 1.38-2.55; p < 0.001). A cut-off value of 0.963 mg/dl was used to classify patients into high LAR (≥0.963) and low LAR (<0.963) groups, and survival curves suggested that those two groups had significant survival differences (p = 0.0058 and 0.0048, respectively). Furthermore, the high LAR group with ICH had a significantly increased risk of in-hospital and ICU mortality compared to the low LAR group. Our study suggests that a high LAR is associated with an increased risk of in-hospital and ICU mortality in patients with ICH. Thus, the LAR is a useful prognostic predictor of clinical outcomes in patients with ICH.

PEDS3: Risk Factors for Thromboembolic Events in Pediatric Patients with Ventricular Assist Devices

Background: Pediatric patients on ventricular assist device (VAD) support are at risk of thromboembolic (TE) complications which include pump thrombosis, ischemic stroke, and transient ischemic attack. Methods: We conducted a retrospective chart review of pediatric patients implanted with Paracorporeal Pulsatile (PP) or Paracorporeal Continuous (PC) VADs between 2005-2022, at the Stollery Children’s Hospital (Edmonton, AB). Patients that transitioned from PC to PP were classified in a combination group. Patient and device related factors, including initial anti-coagulation strategies were collected. Kaplan Meier (KM) survival analysis was performed to determine freedom from TE event based on initial anti-coagulation strategy and VAD type. Univariate and multivariate Cox proportional hazard analysis was conducted to look for factors associated with TE events. Results: Of the 95 patients included, median age was 0.92 years (IQR 0.27, 5.37), median weight at implant was 8.4 kg (IQR 4.4, 18.0). Almost two-thirds (63%) had non congenital disease, with 47% supported on PC devices, 25% on PP devices, and 28% with a combination of devices. Initial anti-coagulation was with either Heparin (61.5%) or Bivalirudin (38.5%). Unadjusted freedom from a TE event was significantly higher in those who received Bivalirudin as their initial anti-coagulation strategy (p=0.022, Figure 1). KM analysis based on device type found that PC VADs predicted shorter freedom from TE events (p=0.012). In multivariate analysis, initial anticoagulation strategy (HR 0.359, 95% CI 0.165–0.785, p=0.01) for Bivalirudin was protective against events, while device type (HR 10.9, 95% CI 2.68–44.2, p<0.001), specifically PC devices, was found to be a predictor of TE events. Conclusions: This study suggests that device type, particularly PC, and heparin as an initial anti-coagulation strategy are risk factors TE events. Further work is needed to understand the interaction between device type and initial anti-coagulation strategy.

One-year change in the health status predicts the subsequent hospitalization and mortality in patients waitlisted for lung transplantation in Japan

BackgroundPoor health-related quality of life (HRQL) at the registration for lung transplantation is related to waitlist mortality. We investigated the relationship between 1-year change in HRQL and subsequent outcomes in patients waitlisted for lung transplantation. MethodsIn a 5-year longitudinal study, we analyzed the factors related to waitlist mortality in 197 lung transplant patients registered on the Japan Organ Transplant Network. HRQL was assessed using St. George's Respiratory Questionnaire (SGRQ), and factors related to changes in SGRQ scores were evaluated after 1 year. We assessed the relationship between the 1-year change in SGRQ score and subsequent mortality or hospitalization. ResultsAmong 197 patients, 108 remained waitlisted during the first-year assessment. During the median follow-up period of 469 d, 28 patients died, and 54 underwent lung transplantation. Univariate Cox proportional hazards analysis revealed that the changes in all components and total score of the SGRQ after 1 year were associated with waitlist mortality (p < 0.05). Stepwise multivariate analysis revealed that the 1-year changes in SGRQ scores were significantly related to waitlist mortality. Forty-three patients with worsened HRQL after 1 year had higher likelihoods of hospitalization (p = 0.038) and mortality (p = 0.026) after 1 and 4 years of follow-up, respectively, than 61 patients without worsened HRQL. ConclusionsPatients with worsened health status during the first year after registration had higher likelihoods of hospitalization and mortality after 1 and 4 years of follow-up, respectively, than those without worsened HRQL. Strategies to improve health status while waiting are needed to reduce waitlist hospitalization or mortality.

Predictors of all-cause 30-days mortality in acute decompensated heart failure patients in the emergency department setting

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Grants from Region Östergötland County Medical Research Council of South East Sweden. Introduction The use of NT-proBNP is well established in the management of heart failure (HF), and as predictor of mortality in HF patients. However, on short-term mortality in acute decompensated heart failure the evidence is scarce. Purpose We aimed to evaluate NT-proBNP as an independent predictor of 30-day all-cause mortality in acute decompensated heart failure patients, seeking emergency medical care. Methods This was an observational study including all visits to Vrinnevisjukhuset hospital emergency department during two years, where the patient was above 18 years of age, and the main diagnosis was set to HF. Appropriate data for each visit were collected from the patients’ medical records retrospectively. The Cox proportional hazards model was applied to estimate hazard ratios (HR) for 30-day mortality. Results From the 459 emergency department visits included in the study 59 patients (12,9%) reached the primary end point of all-cause mortality in 30 days. Age, body mass index (BMI), mean arterial pressure (MAP), sodium, potassium, NT-proBNP, and the presence of atrial fibrillation or flutter were variables achieving P&amp;lt;0.1 on univariate Cox proportional hazards analysis and were subsequently introduced to the multivariate model. Age (HR: 1,05; p=0,008), sodium (HR: 0,925; p=0,012), potassium (HR: 1,95; p=0,002) and MAP (HR: 0,978; p=0,009) was found to be the only independent predictors of 30-day all-cause mortality. Conclusions Our study indicates that for short-term prediction of mortality, other markers than NT-proBNP are of significance. Measurement of serum potassium might be a better tool for clinicians in identifying patients at highest risk of short-term mortality.

Incidence and risk factors of late right heart failure in chronic mechanical circulatory support.

Late right heart failure (LRHF) is a common complication during long-term left ventricular assist device (LVAD) support. We aimed to identify risk factors for LRHF after LVAD implantation. Patients undergoing primary LVAD implantation between 2006 and 2019 and surviving the perioperative period were included for this study (n = 261). Univariate Cox proportional hazards analysis was used to assess the association of clinical covariates and LRHF, stratified for device type. Variables with p < 0.10 entered the multivariable model. In a subset of patients with complete echocardiography or right catheterization data, this multivariable model was extended. Postoperative cardiopulmonary exercise test data were compared in patients with and without LRHF. Nineteen percentage of patients suffered from LRHF after a median of 12 months, of which 67% required hospitalization. A history of atrial fibrillation (AF) (HR: 2.06 [1.08-3.93], p = 0.029), a higher preoperative body mass index (BMI) (HR: 1.07 [1.01-1.13], p = 0.023), and intensive care unit (ICU) duration (HR: 1.03 [1.00-1.06], p = 0.025) were independent predictors of LHRF in the multivariable model. A significant relation between the severity of tricuspid regurgitation (TR) and LRHF (HR: 1.91 [1.13-3.21], p = 0.016) was found in patients with echocardiographic data. Patients with LRHF demonstrated a lower maximal workload and peak VO2 at 6 months postoperatively. A history of AF, BMI, and longer ICU stay may help identify patients at high risk for LRHF. Severity of TR was significantly related to LRHF in a subset of patients.

Clinical characteristics and oncological outcomes of recurrent adult granulosa cell tumor of ovary: A retrospective study of seventy patients.

This study aimed to describe the clinicopathological characteristics of recurrent adult granulosa cell tumor and identify the risk factors for recurrence. Seventy recurrent adult granulosa cell tumor patients treated in Peking Union Medical College Hospital between 2000 and 2020 were retrospectively reviewed. The primary outcomes were progression-free survival after first recurrence (PFS-R), overall survival after first recurrence (OS-R) and recurrence frequency. The Kaplan-Meier analysis, univariate and multivariate Cox proportional hazard analysis, and the Prentice, Williams and Peterson counting process (PWP-CP) model were adopted. There were 70 patients included in the study, and recurrence occurred twice in more than 71% of patients, and 49.9% of patients relapsed ≥ three times. The recurrence pattern in over half of the patients at first recurrence was multifocal and distant disease, and abdominal or pelvic mass and liver metastasis were the most common. The 5-year PFS-R was 29.3%, and the 10-year PFS-R was 11.3%; the 5-year OS-R was 94.9%, and the 10-year OS-R was 87.9%. Kaplan-Meier analysis demonstrated that patients with distant recurrence and PFS1 (PFS when first recurrence occurred) ≤60 months had worse PFS-R (p=0.017, 0.018), and patients with PFS-R ≤ 34 months had worse OS-R (p=0.023). It demonstrated that PFS1 ≤ 60 months (hazard ratio, HR 1.9, 95% confidence interval [CI]: 1.1-3.4, p=0.028) was an independent risk factor for PFS-R, and local lesion at recurrence (HR 0.488, 95% CI: 0.3-0.9, p=0.027) was an independent protective factor for PFS-R. In addition, it demonstrated that PFS-R ≤ 33 months (HR 5.5, 95% CI: 1.2-25.3, p=0.028) was an independent risk factor for OS-R. The PWP-CP analysis showed that laparoscopic operation (at each operation) could significantly increase recurrence times (p=0.002, HR=3.4), and no existence of gross residual lesion (R0) at each recurrence operation could significantly decrease recurrence frequency (p < 0.001, HR <0.001). The recurrence pattern in patients with recurrent adult granulosa cell tumor was characterized as late and repeated, multifocal, and distant relapse. It has been demonstrated that PFS1 ≤ 60 months and distant lesion at recurrence are independent risk factors for PFS-R, and PFS-R ≤ 33 months is an independent risk factor for OS-R. The PWP-CP model showed that the transabdominal approach and surgery reaching R0 could significantly decrease the recurrence frequency.

Shear Wave Dispersion Slope of the Liver Can Predict Adverse Outcomes in Patients with Pulmonary Hypertension

Pulmonary hypertension (PH) often causes right-sided heart failure (HF), inducing organ damage. Shear wave elastography (SWE) is a novel ultrasound technique for characterizing tissue. Some studies have reported that shear wave dispersion slope (SWDS) enables the assessment of early hepatic damage in HF. This study aimed to evaluate the prognostic impact of SWDS in patients with PH.This single-center cohort study enrolled 36 patients with PH who underwent SWE at Okayama University Hospital between March 2018 and April 2021. Patients were divided into 2 groups on the basis of the median value of SWDS: low SWDS group (SWDS < 12.4 m/second/kHz, n = 18) and high SWDS group (SWDS ≥ 12.4 m/second/kHz, n = 18). The primary endpoint was the complex of all-cause death or hospitalization for HF. During the follow-up of 391 ± 288 days, all-cause death or hospitalization for HF occurred in 8 patients. One patient died in the low SWDS group. Three patients died and 4 patients were hospitalized for HF in the high group. Kaplan-Meier analysis revealed that the event-free survival rate was significantly worse in the high SWDS group than in the low SWDS group (log-rank, P = 0.01). In univariate Cox proportional hazards analysis, high SWDS was associated with the events (hazard ratio 10.8; 95% confidence interval 1.89-202, P = 0.005).An elevated SWDS was associated with a high rate of events in patients with PH. SWDS has the potential to predict adverse outcomes in patients with PH.

Sporadic pancreatic neuroendocrine neoplasms: A retrospective clinicopathological and outcome analysis from a Latvian study group.

Although pancreatic neuroendocrine neoplasms (PNEN) are rare, there has been a constant increase in incidence. Furthermore, PNEN present unique clinical behaviors and long-term survival can be expected even in the presence of metastases as compared with ductal adenocarcinoma of the pancreas. Determining the best therapeutic approach and proper timing of therapy requires knowledge of reliable prognostic factors. Therefore, the aim of this study was to explore clinicopathological features, treatment, and survival outcomes of patients with PNEN based on Latvian gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) registry data. Patients with confirmed PNEN at Riga East Clinical University Hospital and Pauls Stradins Clinical University Hospital, between 2008 and 2020, were retrospectively analyzed. Data were collected and included in EUROCRINE, an open-label international endocrine surgical registry. In total, 105 patients were included. The median age at diagnosis was 64 years (IQR 53.0-70.0) for males and 61 years (IQR 52.5-69.0) for females. In 77.1% of patients, tumors were hormonally nonfunctional. Among those with functioning PNEN, 10.5% of patients presented with hypoglycemia and were diagnosed with insulinoma, 6.7% of patients presented with symptoms related to carcinoid syndrome; 30.5% of patients showed distant metastases at the time of diagnosis, and surgery was performed in 67.6% of patients. Notably, for five patients with nonfunctional PNEN <2 cm, a "watch and wait" approach was used; none of the patients developed metastatic disease. The median length of hospital stay was 8 days (IQR 5-13). Major postoperative complications were found in 7.0% of patients, and reoperation was conducted for 4.2% of patients, due to postpancreatectomy bleeding (2/71) and abdominal collection (1/71). The median follow-up period was 34 months (IQR 15.0-68.8). The OS at the last follow-up was 75.2% (79/105). The observed 1-, 5- and 10-year survival rates were 87.0, 71.2 and 58.0, respectively. Seven of the surgically treated patients had tumor recurrence. The median time of recurrence was 39 months (IQR 19.0-95.0). A univariable Cox proportional hazard analysis provided evidence that a nonfunctional tumor, a larger tumor size, the presence of distant metastases, a higher tumor grade, and the tumor stage were strong, negative predictors of OS. Our study represents the general trends of clinicopathological features and treatment of PNEN in Latvia. For PNEN patients, tumor functionality, size, distant metastases, grade, and stage may be useful to predict OS and must be confirmed in further studies. Furthermore, a "surveillance" strategy might be safe for selected patients with small asymptomatic PNEN.

The Effect of Renin–Angiotensin–Aldosterone System Inhibitors on Outcomes of Patients Treated with Immune Checkpoint Inhibitors: a Retrospective Cohort Study

AimsRenin–angiotensin–aldosterone system inhibitors (RAASi) are associated with improved survival outcomes in patients receiving immune checkpoint inhibitors (ICIs), but the data on the response to treatment and tumour-based endpoints across different tumour types are unknown. Materials and methodsWe carried out a retrospective study at two tertiary referral centres in Taiwan. All adult patients treated with ICIs between January 2015 and December 2021 were included. The primary outcome was overall survival and the secondary outcomes were progression-free survival (PFS) and clinical benefit rates. ResultsIn total, 734 patients were enrolled in our study, of which 171 were RAASi users and 563 were non-users. Compared with non-users, RAASi users had a longer median overall survival [26.8 (interquartile range 11.3–not reached) versus 15.2 (interquartile range 5.1–58.4) months, P < 0.001] and PFS [12.2 (interquartile range 3.9–34.5) versus 5.0 (interquartile range 2.2–15.2) months, P < 0.001]. In univariate Cox proportional hazard analyses, the use of RAASi was associated with a 40% reduction in the risk of mortality [hazard ratio 0.58 (95% confidence interval 0.44–0.76), P < 0.001] and disease progression [hazard ratio 0.62 (95% confidence interval 0.50–0.77), P < 0.001]. The association remained significant after adjusting for underlying comorbidities and cancer therapy in multivariate Cox analyses. A similar trend was observed for PFS. Furthermore, RAASi users experienced a greater clinical benefit rate than non-users (69% versus 57%, P = 0.006). Importantly, the use of RAASi before ICI initiation was not associated with improved overall survival and PFS. RAASi were not associated with an increased risk of adverse events. ConclusionThe use of RAASi is associated with improved survival outcomes, treatment response and tumour-based endpoints in patients undergoing immunotherapy.

The thickness of glomerular basement membrane predicts complete remission in primary membranous nephropathy

Objective Glomerular basement membrane (GBM) thickening is a typical and essential histopathological characteristic for the diagnosis of primary membranous nephropathy (PMN). The present study aimed to explore the relationship between GBM thickness and treatment response in PMN patients. Methods A total of 128 patients with nephrotic syndrome concurrent with PMN were studied. The highest GBM thickness was measured from at least five glomerular capillary loops using an electron microscope, and the mean value was obtained. Patients were categorized into three groups according to the tertiles of GBM thickness as follows: Group 1 (GBM thickness ≤ 1100 nm, n = 48), Group 2 (1100 nm < GBM thickness ≤ 1300 nm, n = 40), Group 3 (GBM thickness >1300 nm, n = 40). Clinicopathological features and treatment response were compared among the three groups. The associations of GBM thickness with complete remission (CR) were assessed by Cox proportional hazard analyses and a cubic spline curve. Results During a median follow-up period of 25.80 months, 69 (53.9%) patients achieved CR. Kaplan–Meier analysis showed that the non-CR probability was significantly higher in the highest tertile of GBM thickness (p˂0.001). Univariate Cox proportional hazard analysis indicated that GBM thickness was associated with CR (HR per SD 0.617, 95% CI [0.471–0.809], p˂0.001). After adjusting for age, duration of PMN, estimated glomerular filtration rate (eGFR), urinary protein excretion, grade of C3 deposition, and titer of serum anti-phospholipase A2 receptor (PLA2R) antibody, GBM thickness remained an independent predictor of CR (HR per SD 0.580, 95% CI [0.436–0.772], p˂0.001). Further multivariable-adjusted restricted cubic spline analysis confirmed a significant reverse linear association between GBM thickness and CR (p for nonlinear = 0.1261). Conclusions GBM thickness is an independent risk factor of CR. PMN patients with an increased level of GBM thickening at diagnosis have a lower probability of achieving CR.

Abstract P4-02-18: Impact of clonal hematopoiesis on disease progression following CDK4/6 inhibitor therapy

Abstract Background Clonal Hematopoiesis (CH) is a well-established risk factor for adverse clinical outcomes including all-cause mortality, cardiovascular disease, and progression to hematologic malignancies. The presence of CH has been shown to adversely impact overall survival in non-hematologic cancers, however whether CH modulates response to specific therapies in breast cancer is not known. Here we investigate the impact of CH mutations on disease progression in patients with metastatic estrogen receptor (ER) positive breast cancer undergoing treatment with first line CDK4/6 inhibitors and endocrine therapy (CDK4/6i+ET). Methods We analyzed data from a well annotated cohort of patients with ER+ breast cancer who received endocrine therapy and CDK4/6 inhibitors. All patients underwent prospective tumor and matched WBC sequencing utilizing the MSK-IMPACT assay. CH variants were detected in blood samples utilizing the well-validated variant detection and filtration pipeline of MSK-IMPACT. CH mutations were defined as putative drivers (CH-PD) or non-putative drivers (CH) as previously described. To ensure the presence of CH at the time of therapy initiation, only patients who had CH sampling performed from 6 months before through 4 months after initiation of CDK4/6i+ET were included. We compared progression free survival (PFS) in patients with and without CH, as well as by CH-PD status and DNMT3A CH mutations. We investigated clinical covariates including type of endocrine therapy, receipt of prior neoadjuvant or adjuvant chemotherapy, and age at start of CDK4/6i+ET. Results The final cohort was comprised of 378 patients, of whom 135 (35.7%) had CH. The median time between sample collection and CDK4/6i+ET initiation was 0 (IQR -0.79 to 0.47 months). Patients with CH were older at time of therapy initiation (median 63.0 versus 54.7 years, p &amp;lt; 0.001). There were no significant differences between groups in terms of endocrine therapy (aromatase inhibitor or fulvestrant), prior chemotherapy, and time from CH sample collection to CDK4/6i+ET start. Univariate Cox-proportional hazard analysis did not reveal a difference between progression free survival and overall CH (HR 0.96, 95% CI 0.75 – 1.23, p = 0.76), CH-PD (HR 1.05, 0.77 – 1.43, p = 0.77), or DNMT3A mutations (HR 1.12, 0.80 – 1.60, p = 0.52) compared to patients without CH. Interestingly, age less than 60 years was found to be associated with PFS outcome (univariate HR 1.57, 1.22 – 2.01, p = 0.0004). Multivariate analysis adjusted for endocrine therapy partner and age at CDK4/6i+ET therapy did not reveal an association between outcome and overall CH (HR 1.07, 0.83 – 1.39, p = 0.59). In patients younger than age 60, presence of overall CH did not confer a significant PFS difference (HR 0.90, 0.63 – 1.29, p = 0.57). In the subset of patients older than 60 (n = 168) presence of CH conferred numerically, but not statistically, significant shorter PFS (HR 1.41 [0.96 – 2.09], p = 0.08). In this population, CH-PD conferred a shorter PFS (HR 1.75, 1.12 – 2.72, p = 0.02). Conclusion We found that CH, CH-PD and DNMT3A CH mutations did not affect PFS among metastatic ER+ breast cancer patients treated with first line CDK4/6 inhibitors. Younger age was associated with increased risk of progression, warranting further investigation. In the subset of patients with age older than 60, CH-PD conferred a shorter PFS. Further data, incorporating records of dose reductions, will be presented at the meeting. Citation Format: Jacqueline Tao, Pablo Sanchez Vela, Anton Safonov, Emanuela Ferraro, Sebastia Franch Exposito, Kamal Menghrajani, Ryan Ptashkin, Elizabeth Comen, Lior Z. Braunstein, Mark E. Robson, Sarat Chandarlapaty, Jorge Reis-Filho, Michael Berger, Ahmet Zehir, Larry Norton, Ross Levine, Pedram Razavi. Impact of clonal hematopoiesis on disease progression following CDK4/6 inhibitor therapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-18.

Abstract P1-04-06: Characterization of recurrence risk after lumpectomy and radiotherapy in HER2-positive ductal carcinoma in situ of the breast, using 7-gene predictive biosignature: Implications for the NSABP-B43 trial results

Abstract Background: HER2-positive versus HER2-negative ductal carcinoma in situ (DCIS) of the breast has been associated with an increased risk of local recurrence after breast-conserving surgery (BCS) and radiotherapy (RT). In recognition of this, the NASBP-B43 trial was designed to determine if two doses of trastuzumab would improve local control with BCS plus RT in HER2-positive DCIS. The trial demonstrated a non-statistically significant advantage with the addition of trastuzumab in reducing ipsilateral breast recurrence (IBR). The predictive 7-gene DCIS biosignature, DCISionRT with Residual Risk Subtype (PreludeDxTM, Laguna Hills, CA) has been shown to classify DCIS patients into two distinct groups of patients with substantially different rates of IBR following BCS plus RT. Based upon these differences in outcome, we assessed the IBR rate in patients with HER2(+) DCIS treated with BCS and RT who were or were not in the Residual Risk Subtype group defined using DCISionRT, while accounting for the varying clinicopathologic profile of the patients. Materials &amp; Methods: DCISionRT was evaluated in a subset of 178 women with HER2(+) DCIS treated with BCS and RT as part of a multinational cohort of 926 patients from the United States, Sweden, and Australia, who were used in the validation studies for DCISionRT. Central pathology review and biosignature testing were performed at a CLIA-certified lab (Laguna Hills, CA). HER2(+) DCIS was defined as patients with a HER2(3+) immunohistochemistry &amp;gt;10% per ASCO/CAP guidelines. The IBR rate was calculated for the overall group of HER2(+) patients and those in the Residual Risk group. Individual patient outcome and biosignature results were analyzed using Kaplan Meier and Cox Proportional Hazard analyses. Results: The biosignature classified 113 of the 178 (63%) HER2(+) women into the Residual Risk group (DS&amp;gt;2.8 with RRt). Patients in the Residual Risk group had a significantly greater IBR (HR=8.3; 95%CI: 1.1,50, p=.012) over 10-years, with a corresponding 10-year total IBR rate of 16.2% (95%CI: 9.7%, 26.5%) versus 1.6% (95%CI: 0.2%, 10.9%) for all other HER2(+) patients. In univariate analysis, younger patients tended to have higher IBR rate after BCS plus RT, but only Residual Risk was significantly associated with IBR rate after BCS plus RT. Moreover, multivariable analysis demonstrated that the Residual Risk group was eight times more likely to recur after BCS and RT, while clinicopathologic factors (age, grade, tumor size) were not associated with higher IBR rates. Conclusion: The DCISionRT Residual Risk group was predictive for 10-year IBR risk after BCS plus RT in women with HER2(+) DCIS. Approximately 40% of patients with HER2(+) DCIS would be expected to achieve low rates of recurrence with BCS and RT, while about 60% of these women (classified in the Residual Risk group) would have higher recurrence rates and may benefit from further therapy, such as HER2-directed therapies. These findings suggest that if the results of the B43 trial were re-analyzed using the predictive 7-gene biosignature (DCISionRT with Residual Risk Subtype), better clarity could be gained on the true impact of trastuzumab on IBR rates in patients with HER2(+) DCIS and the patients most likely to benefit from this additional therapy. Table 1. Univariate and Multivariable Cox Proportional Hazards Analyses. Citation Format: Frank Vicini, Chirag Shah, Rachel Rabinovitch, Pat Whitworth, Julie A. Margenthaler, Brian J. Czerniecki, DAVID J. DABBS, Sheila Weinmann, Michael Leo, G Bruce Mann, Fredrik Wärnberg, jess Savala, Steven C. Shivers, Karuna Mittal, Troy Bremer. Characterization of recurrence risk after lumpectomy and radiotherapy in HER2-positive ductal carcinoma in situ of the breast, using 7-gene predictive biosignature: Implications for the NSABP-B43 trial results [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-04-06.

Identification of Wnt/β-Catenin- and Autophagy-Related lncRNA Signature for Predicting Immune Efficacy in Pancreatic Adenocarcinoma

Pancreatic cancer is one of the tumors with a poor prognosis. Therefore, it is significant and urgent to explore effective biomarkers for risk stratification and prognosis prediction to promote individualized treatment and prolong the survival of patients with PAAD. In this study, we identified Wnt/β-catenin- and autophagy-related long non-coding RNAs (lncRNAs) and demonstrated their role in predicting immune efficacy for PAAD patients. The univariate and multivariate Cox proportional hazards analyses were used to construct a prognostic risk model based on six autophagy- and Wnt/β-catenin-related lncRNAs (warlncRNAs): LINC01347, CASC8, C8orf31, LINC00612, UCA1, and GUSBP11. The high-risk patients were significantly associated with poor overall survival (OS). The receiver operating characteristic (ROC) curve analysis was used to assess the predictive accuracy of the prognostic risk model. The prediction efficiency was supported by the results of an independent validation cohort. Subsequently, a prognostic nomogram combining warlncRNAs with clinical indicators was constructed and showed a good predictive efficiency for survival risk stratification. Furthermore, functional enrichment analysis demonstrated that the signature according to warlncRNAs is closely linked to malignancy-associated immunoregulatory pathways. Correlation analysis uncovered that warlncRNAs' signature was considerably associated with immunocyte infiltration, immune efficacy, tumor microenvironment score, and drug resistance.