Difference In Median Survival Research Articles

Radiotherapy protocol compliance in routine clinical practice for patients with stages I-III non-small-cell lung cancer.

Despite the availability of radiotherapy treatment protocols forlung cancer, considerable treatment variation occurs in clinical practice. This study assessed compliance with a radiotherapy protocol for the treatment of patients with stages I-III non-small-cell lung cancer (NSCLC) in routine clinical practice and to identify factors that were associated with compliance. The Cancer Institute New South Wales eviQ treatment protocol for external beam radiotherapy of stages I-III NSCLC was taken as the reference to measure compliance. All inoperable patients with stages I-III NSCLC and documented ECOG performance status treated with radiotherapy between 2007 and 2019 at two radiotherapy facilities were available for analysis. Protocol compliance rates were calculated. Univariate and multivariate logistic regression models with 23 input factors were used to determine factors significantly associated with compliance. Survival analysis was conducted for both compliant and non-compliant treatments. Overall, 656 patients met the inclusion criteria. Protocol compliance was 16%. Alternative dose/fractionation was responsible for 49% of non-compliant treatments with 30% receiving an alternative curative fractionation. Five of 23 factors (age at the start of radiotherapy, stage group, ECOG performance status, tumour location and alcoholism history) showed significant associations with protocol compliance on multivariate analysis. There was no significant difference in median survival between patients receiving protocol compliant treatment (15.1 months) and non-compliant treatment (15.6 months). Adherence to the eviQ curative radiotherapy protocol for stages I-III NSCLC was low. Alternative dose/fractionation schemes were the main reason for non-compliance. Protocol compliance was not associated with outcome.

Association of proteinuria at time of diagnosis with survival times in dogs with lymphoma.

Lymphoma has been implicated as a possible cause of proteinuria in dogs. However, information about the potential importance of proteinuria in dogs with lymphoma is limited. To determine if the presence of proteinuria at diagnosis was associated with median survival times in dogs with lymphoma and if lymphoma stage (I-V) or type (B vs T) were associated with the presence of proteinuria. Eighty-six client-owned dogs with a new diagnosis of lymphoma between 2008 and 2020. This was a retrospective cross-sectional study with dogs divided into proteinuric or nonproteinuric groups based on dipstick urine protein (protein ≥30 mg/dL classified as proteinuric) or a ratio of dipstick protein to urine specific gravity (ratio ≥1.5 classified as proteinuric). Dogs were excluded for: (1) treatment within 2 months with glucocorticoid, anti-neoplastic, or anti-proteinuric therapies, (2) diagnosed hypercortisolism or renal lymphoma, (3) active urine sediment, or (4) urine pH >8. Survival analysis utilized a Kaplan-Meier estimator and log-rank testing. There was a significant difference in median survival between proteinuric and nonproteinuric dogs classified by urine dipstick (245 days [91, 399] vs 335 days [214, 456]; P = .03) or UP : USG (237 days [158, 306] vs 304 days [173, 434]; P = .03). No difference in prevalence of proteinuria was identified between stages (I-V) or types (B and T). Proteinuria appears to be negatively associated with survival time in dogs newly diagnosed with lymphoma.

ENDOSCOPIC ULTRASOUND-GUIDED HEPATICOJEJUNOSTOMY IN PATIENTS WITH HISTORY OF TOTAL GASTRECTOMY: A MULTICENTER RETROSPECTIVE FEASIBILITY STUDY

Endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) is an effective biliary drainage technique for patients with altered anatomy or duodenal strictures. Endoscopic ultrasound-guided hepaticojejunostomy (EUS-HJS) can be used to create a fistula between the left hepatic duct and the jejunum in patients with a history of total gastrectomy. No specific data on this technique have been published. The aim of this study was to assess the feasibility and safety of EUS-HJS in patients with a history of total gastrectomy. This retrospective multicenter study included all adult patients who underwent EUS-HJS at three tertiary French centers and one tertiary Swiss center between May 2011 and February 2023. The primary outcome was clinical success, which was defined as the disappearance of pruritus, jaundice and/or cholangitis. An improvement in bilirubin greater than 30% within the first week and/or bilirubin normalization within 1 month after the procedure were also considered indicators of clinical success. Secondary outcomes included technical success, the rate of adverse events, the need for endoscopic revision, the possibility of resuming anticancer treatment, median survival, and technical differences compared to EUS-HGS. A total of 21 patients who underwent complete gastrectomy via EUS-HJS were included. Technical success was achieved in 100% of patients (95% CI 85%-100%). Clinical success was achieved in 80% of patients (95% CI 58%-92%). The incidence of recorded adverse events was 33% (95% CI 17%-55%), with cholangitis being the most frequent complication. Seven patients (39%) were able to benefit from anticancer treatment after the procedure. The median survival was 6 months (IQR 1.5-12). EUS-HJS is an effective and feasible procedure for patients whose anatomy has been altered by total gastrectomy.

Less is more: An analysis of venetoclax and hypomethylating agent post-induction treatment modifications in AML

Venetoclax (Ven) combined with a hypomethylating agent (HMA) enhances survival in elderly/unfit acute myeloid leukemia (AML) patients, yet often necessitates regimen modifications due to intolerance. However, it is unclear how these modifications affect patient outcome. This retrospective cohort study evaluates the impact of post-induction HMA/Ven regimen modifications on disease progression and survival. This study reviewed 142 AML patients treated with HMA/Ven within the Northwell Health System from January 2019 to December 2022. To assess the impact of post-induction regimen modifications, patients were grouped according to median days between cycles (≤34 or ≥35 days cycle intervals) and median Ven days per cycle (≤14 or ≥15 days/cycle) based on only cycle 3 and beyond. Kaplan-Meier and Cox proportional hazard regression analyses were employed for univariate and multivariate assessments, respectively. There was no significant difference in median progression-free survival (mPFS)(11.6 vs 11.8 months, p = 0.73) or median overall survival (mOS)(15.1 vs 21.8 months, p = 0.16) between cycle interval groups. However, there was a clinically and statistically significant advantage in mPFS (15.8 vs 8.7 months, p = 0.01) and mOS (24.7 vs 11.3 months, p = 0.006) for patients with a median of ≤14 Ven days/cycle compared to ≥15 Ven days/cycle. Multivariate analysis demonstrated that ≤14 days of Ven for cycle 3 and beyond was an independent predictor of decreased mortality (HR 0.18, CI 0.07–0.48, p = 0.0007). Extended cycle intervals did not adversely affect mortality while reduced Ven duration per cycle post-induction was associated with improved survival in elderly AML patients.

Prospective validation from a retrospective trial that validated an AI/ML-derived whole-genome biomarker as the most accurate and precise predictor of survival and response to treatment in glioblastoma.

e14028 Background: For 70 years, the best indicator of glioblastoma (GBM) survival has remained age at diagnosis. Factors across the entire genome affect every aspect of the disease. But typical artificial intelligence and machine learning (AI/ML) would require 3B-patient training sets to generate predictive models from the whole 3B-nucleotide genome. As a result, all other attempts to associate a tumor’s DNA copy-number alterations (CNAs) with the patient’s outcome failed. Methods: A genome-wide pattern of DNA CNAs in primary GBM tumors was recently validated in a retrospective clinical trial as the most accurate and precise predictor of survival and response to treatment [doi: 10.1063/1.5142559 ]. Applicable to the general population, this biomarker, the first to encompass the whole genome, and biomarkers in lung, nerve, ovarian, and uterine cancers, were repeatedly identified in open-source datasets from as few as 50–100 patients by using our data-agnostic unsupervised AI/ML, which extends the mathematics of quantum mechanics to overcome the limitations of typical AI/ML [doi: 10.1063/1.5099268 , 10.1073/pnas.0530258100 ]. Results: At 75–95% concordance, our biomarker is more accurate than and independent of age and all other indicators, including the one-gene tests for MGMT, IDH1, and TERT. Platform- and reference genome-agnostic, the biomarker’s >99% precision is greater than the community consensus of <70% reproducibility. It describes disease mechanisms and identifies drug targets and combinations of targets to sensitize tumors to treatment. Now, in follow-up results from the trial we, first, show correct prospective prediction of the outcome of the five of the 79 patients who were alive four years earlier, at the time of first results (log-rank P-value=3.9×10–2). Two patients, who were predicted to have shorter survival, lived less than five years from diagnosis, whereas of the three patients predicted to have longer survival, one lived more than five, and the remaining two are alive >11.5, years from diagnosis. Second, we demonstrate 100%-precise clinical prediction for the 59/79 patients with remaining tumor DNA, by using whole-genome sequencing in a Clinical Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP) laboratory. Third, we establish that the risk that a tumor’s whole genome confers upon outcome, as is reflected by the biomarker’s univariate Cox hazard ratio of 4.2 and Kaplan-Meier median survival difference of 2.25 years (log-rank P-value=6.0×10–4), is greater than that conferred by the patient’s Karnofsky performance score and access to chemotherapy, and the tumor’s percent resection, and is surpassed only by the patient’s access to radiotherapy. Conclusions: This is a proof of principle that our AI/ML is uniquely suited for personalized medicine.

The pluripotency factor NANOG contributes to mesenchymal plasticity and is predictive for outcome in esophageal adenocarcinoma

BackgroundDespite the advent of neoadjuvant chemoradiotherapy (CRT), overall survival rates of esophageal adenocarcinoma (EAC) remain low. A readily induced mesenchymal transition of EAC cells contributes to resistance to CRT.MethodsIn this study, we aimed to chart the heterogeneity in cell state transition after CRT and to identify its underpinnings. A panel of 12 esophageal cultures were treated with CRT and ranked by their relative epithelial-mesenchymal plasticity. RNA-sequencing was performed on 100 pre-treatment biopsies. After RNA-sequencing, Ridge regression analysis was applied to correlate gene expression to ranked plasticity, and models were developed to predict mesenchymal transitions in patients. Plasticity score predictions of the three highest significant predictive models were projected on the pre-treatment biopsies and related to clinical outcome data. Motif enrichment analysis of the genes associated with all three models was performed.ResultsThis study reveals NANOG as the key associated transcription factor predicting mesenchymal plasticity in EAC. Expression of NANOG in pre-treatment biopsies is highly associated with poor response to neoadjuvant chemoradiation, the occurrence of recurrences, and median overall survival difference in EAC patients (>48 months). Perturbation of NANOG reduces plasticity and resensitizes cell lines, organoid cultures, and patient-derived in vivo grafts.ConclusionsIn conclusion, NANOG is a key transcription factor in mesenchymal plasticity in EAC and a promising predictive marker for outcome.

Effect of FDG PET-CT for Staging and Radiotherapy Planning – A Comparison of Cohorts From Two Randomized Trials of Thoracic Radiotherapy in Limited-Stage SCLC

IntroductionFluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) is recommended for staging and defining target volume in limited-stage SCLC, though the impact on outcomes compared with CT staging and elective nodal irradiation (ENI) is not well documented. We analyzed patients receiving 45 Gy/30 fractions in two randomized trials of thoracic radiotherapy (TRT) in limited-stage SCLC (Higher Ability Selection Test [HAST] and THORA trials) to evaluate whether PET-CT for staging and radiotherapy planning reduces radiotoxicity and improves survival. MethodsPatients in HAST were staged with CT thorax/abdomen and magnetic resonance imaging of the brain. Patients in THORA were staged with PET-CT in addition. All patients were to receive four courses of platinum/etoposide chemotherapy and concurrent TRT starting three to four weeks after the first chemotherapy course. In HAST, target volumes included pathological lesions on CT plus ENI of lymph node stations 4–7 (bilateral). In THORA, target volumes were limited to PET-CT-positive lesions (selective nodal irradiation [SNI]). ResultsA total of 149 patients were included (PET-CT/SNI: n = 76, CT/ENI: n=73); the median age was 64 years, 56% were women, 85% had PS 0 to 1, and 81% had stage III disease. The PET-CT/SNI group experienced less grade III to IV esophagitis (18% versus 33%, p = 0.043), less grade III, one pneumonitis (5% versus 16%, p = 0.028), and less dysphagia after TRT (mean scores on European Organisation for Research and Treatment of Cancer 13-item lung cancer module: 45 versus 72). There was no difference in median overall survival (24 versus 25 mo, p = 0.59) or progression-free survival (11 versus 11 mo, p = 0.23). ConclusionsUsing PET-CT for staging and target volume definition of TRT reduces acute radiotoxicity but does not improve overall or progression-free survival in limited-stage SCLC.

Time from diagnosis to treatment has no impact on survival in newly diagnosed acute myeloid leukemia treated with venetoclax-based regimens.

In newly diagnosed acute myeloid leukemia (AML), immediate initiation of treatment is standard of care. However, deferral of antileukemic therapy may be indicated to assess comorbidities or pretherapeutic risk factors. We explored the impact of time from diagnosis to treatment on outcomes in newly diagnosed AML undergoing venetoclax-based therapy in two distinct cohorts. By querying the Study Alliance Leukemia database and the global health network TriNetX, we identified 138 and 717 patients respectively with an average age of 76 and 72 years who received venetoclax-based first-line therapy. When comparing patients who started treatment earlier or later than 10 days after initial diagnosis, no significant difference in median overall survival was observed - neither in the SAL cohort (7.7 vs. 9.6 months; P=0.42) nor in the TriNetX cohort (7.5 vs. 7.2 months; P=0.41). Similarly, severe infections, bleeding, and thromboembolic events were equally observed between early and later treatments, both in the overall patient groups and specific subgroups (age ≥75 years or leukocytes ≥20x109/L). This retrospective analysis indicates that delaying the start of venetoclax-based therapy in newly diagnosed AML might be a safe option for selected patients, provided that close clinical monitoring is performed.

Escalating Surgical Treatment for Left Ventricular Assist Device Infection and Expected Mortality: Clinical Risk Prediction Score.

Left ventricular assist devices (LVAD) improve survival for patients with cardiac failure, but LVAD specific infections (VSI) remain a challenge with poorly understood predictive risk factors. Furthermore, the indications and utility of escalating medical treatment to surgical debridement and potential flap reconstruction are not well-characterized. A retrospective review of consecutive patients undergoing primary LVAD implantation at a tertiary academic center was performed. The primary outcomes measures were 90-day and overall mortality after VSI. Cox proportional hazards regression was used to generate a risk-prediction score for mortality. Of the 760 patients undergoing primary LVAD implantation, 255 (34%) developed VSI; of these 91 (36%) were managed medically, 134 (52%) with surgical debridement, and 30 (12%) with surgical debridement and flap reconstruction. One-year survival after infection was 85% with median survival of 2.40 years. Factors independently associated with increased mortality were diabetes (hazard ratio (HR) 1.44, p=0.04), methicillin-resistant Staphylococcus aureus infection (HR 1.64, p=0.03), deep space (pump pocket/outflow cannula) involvement (HR 2.26, p<0.001) and extra-corporeal membrane oxygenation after LVAD (HR 2.52, p<0.01. Factors independently associated with decreased mortality were flap reconstruction (HR 0.49, p=0.02) and methicillin-sensitive Staphylococcus aureus infection (HR 0.63, p=0.03). A clinical risk prediction score was developed using these factors and showed significant differences in median survival, which was 5.67 years for low-risk (score 0-1), 3.62 years for intermediate-risk (score 2), and 1.48 years for high-risk (score >3) (p<0.001) patients. We developed a clinical risk prediction score to stratify VSI patients. In selected cases, escalating surgical treatment was associated with increased survival. Future work is needed to determine if early surgical debridement and flap reconstruction can alter outcomes in select cases of VSI.

The Real-Life Impact of Primary Tumor Resection of Synchronous Metastatic Colorectal Cancer-From a Clinical Oncologic Point of View.

The complex medical care of synchronous metastatic colorectal (smCRC) patients requires prudent multidisciplinary planning and treatments due to various challenges caused by the primary tumor and its metastases. The role of primary tumor resection (PTR) is currently uncertain; strong arguments exist for and against it. We aimed to define its effect and find its best place in our therapeutic methodology. We performed retrospective data analysis to investigate the clinical course of 449 smCRC patients, considering treatment modalities and the location of the primary tumor and comparing the clinical results of the patients with or without PTR between 1 January 2013 and 31 December 2018 at the Institute of Oncotherapy of the University of Pécs. A total of 63.5% of the 449 smCRC patients had PTR. Comparing their data to those whose primary tumor remained intact (IPT), we observed significant differences in median progression-free survival with first-line chemotherapy (mPFS1) (301 vs. 259 days; p < 0.0001; 1 y PFS 39.2% vs. 26.6%; OR 0.56 (95% CI 0.36-0.87)) and median overall survival (mOS) (760 vs. 495 days; p < 0.0001; 2 y OS 52.4 vs. 26.9%; OR 0.33 (95% CI 0.33-0.53)), respectively. However, in the PTR group, the average ECOG performance status was significantly better (0.98 vs. 1.1; p = 0.0456), and the use of molecularly targeted agents (MTA) (45.3 vs. 28.7%; p = 0.0005) and rate of metastasis ablation (MA) (21.8 vs. 1.2%; p < 0.0001) were also higher, which might explain the difference partially. Excluding the patients receiving MTA and MA from the comparison, the effect of PTR remained evident, as the mOS differences in the reduced PTR subgroup compared to the reduced IPT subgroup were still strongly significant (675 vs. 459 days; p = 0.0009; 2 y OS 45.9 vs. 24.1%; OR 0.37 (95% CI 0.18-0.79). Further subgroup analysis revealed that the site of the primary tumor also had a major impact on the outcome considering only the IPT patients; shorter mOS was observed in the extrapelvic IPT subgroup in contrast with the intrapelvic IPT group (422 vs. 584 days; p = 0.0026; 2 y OS 18.2 vs. 35.9%; OR 0.39 (95% CI 0.18-0.89)). Finally, as a remarkable finding, it should be emphasized that there were no differences in OS between the smCRC PTR subgroup and metachronous mCRC patients (mOS 760 vs. 710 days, p = 0.7504, 2 y OS OR 0.85 (95% CI 0.58-1.26)). The role of PTR in smCRC is still not professionally justified. Our survey found that most patients had benefited from PTR. Nevertheless, further prospective trials are needed to clarify the optimal treatment sequence of smCRC patients and understand this cancer disease's inherent biology.

Immediate Versus Deferred Systemic Therapy in Patients With Mesothelioma

BackgroundThe 2018 ASCO pleural mesothelioma (PM) treatment guideline states that “a trial of expectant observation may be offered” in patients with asymptomatic inoperable epithelioid mesothelioma with low disease burden. The aim of our analysis was to evaluate clinical characteristics and outcomes in PM-patients managed with initial observation and deferred treatment initiation. MethodsWe retrospectively collected clinicodemograhic and outcome data of patients with inoperable PM. Patients were assigned to 2 treatment decision groups: decision to start immediate systemic treatment (Immediate Treatment Group) versus observation and deferring treatment (Deferred Treatment group). ResultsOf 222 patients with advanced PM, systemic treatment was started immediately in the majority of patients (189, 85%; immediate group); treatment was deferred in 33 (15%) patients (deferred group); systemic therapy was chemotherapy-based in 91% and 79% respectively. Patients in the deferred group were older (70 vs 67 years, p = .05), less likely to have stage IV disease (28% vs. 51%, p = .08) and more often had epithelioid histology (90% vs. 70%, p = .03). Nineteen patients (58%) in the deferred group eventually received treatment.With a median follow-up time of 10.9 months median overall survival (OS) in the entire cohort was 12.4 months and was significantly longer in the deferred group (20.6 months vs. 11.5 months, p = .02). No difference in median progression-free survival (PFS) in first-line treatment between groups was seen (5.4 and 5.3 months). ConclusionThis real-world analysis suggests that deferral of systemic therapy and close observation may not impact OS or physician-assessed PFS in selected PM-patients.

Impact of race and social determinants of health on outcomes in patients with aggressive B-cell NHL treated with CAR-T therapy

AbstractChimeric antigen receptor (CAR) T-cell (CAR-T) immunotherapy is an effective therapy for relapsed/refractory B-cell non-Hodgkin lymphoma (r/r B-NHL). However, data are limited on the impact of the convergence of race and social determinants of health on outcomes for patients treated with CAR-T therapy. We examined the impact of interactions between race and insurance type on health care use and outcomes in patients treated with CAR-T therapy for aggressive B-NHL. Adult patients with r/r B-NHL treated with CD19 CAR-Ts were identified between 2015 and 2021 across 13 US academic centers. Insurance type, demographic, and clinical data were collected and analyzed. In total, 466 adult patients were included in our analysis. Median follow-up after CAR-T therapy was 12.7 months. Median progression-free survival (mPFS) was longer for Caucasians (11.5 months) than for African Americans (3.5 months; hazard ratio [HR], 1.56 [1.03-2.4]; P = .04) or Asians (2.7 months; HR, 1.7 [1.02-2.67]; P = .04). Differences in median overall survival (mOS) were not significant. For Medicare (n = 206) vs Medicaid (n = 33) vs private insurance (n = 219) vs self-pay (n = 7): mPFS was 15.9 vs 4.2 vs 6.0 vs 0.9 months (P < .001), respectively; and mOS was 31.2 vs 12.8 vs 21.5 vs 3.2 months (P < .001), respectively. Our multicenter retrospective analysis showed that race and insurance status can affect outcomes for patients treated with CAR-T therapy.

Therapy-related chronic myelomonocytic leukemia does not have the high-risk features of a therapy-related neoplasm

AbstractTherapy-related myeloid neoplasms (t-MNs) arise after exposure to cytotoxic therapies and are associated with high-risk genetic features and poor outcomes. We analyzed a cohort of patients with therapy-related chronic myelomonocytic leukemia (tCMML; n = 71) and compared its features to that of de novo CMML (dnCMML; n = 461). Median time from cytotoxic therapy to tCMML diagnosis was 6.5 years. Compared with dnCMML, chromosome-7 abnormalities (4% vs 13%; P = .005) but not complex karyotype (3% vs 7%; P = .15), were more frequent in tCMML. tCMML was characterized by higher TP53 mutation frequency (4% vs 12%; P = .04) and lower NRAS (6% vs 22%, P = .007) and CBL (4% vs 12%, P = .04) mutation frequency. Prior therapy with antimetabolites (odd ratio [OR], 1.22; 95% confidence interval [CI], 1.05-1.42; P = .01) and mitotic inhibitors (OR, 1.24; 95% CI, 1.06-1.44; P = .009) was associated with NF1 and SETBP1 mutations whereas prior mitotic inhibitor therapy was associated with lower TET2 mutation frequency (OR, 0.71; 95% CI, 0.55-0.92; P = .01). Although no differences in median overall survival (OS) were observed among tCMML and dnCMML (34.7 months vs 35.9 months, P = .26), multivariate analysis for OS revealed that prior chemotherapy was associated with increased risk of death (hazard ratio, 1.76; 95% CI, 1.07-2.89; P = .026). Compared with a cohort of therapy-related myelodysplastic syndrome, tCMML had lower TP53 mutation frequency (12% vs 44.4%, P < .001) and less unfavorable outcomes. In summary, tCMML does not exhibit the high-risk features and poor outcomes of t-MNs.

Assessing the clinical benefit of systemic anti-cancer treatments in the Netherlands: The impact of different thresholds for effectiveness

BackgroundIn the Netherlands, the clinical benefit of systemic anti-cancer treatments (SACTs) is assessed by the Committee for the Evaluation of Oncological Agents (cieBOM). For non-curative SACTs, the assessment is based on the hazard ratio (HR) for progression-free survival and/or overall survival (OS), and the difference in median survival. We evaluated the impact of different thresholds for effectiveness by reassessing the clinical benefit of SACTs. MethodsWe reassessed SACTs that were initially assessed by cieBOM between 2015 and 2017. Four scenarios were formulated: replacing an “OR” approach (initial assessment) by an “AND” approach (used in all scenarios), changing the HR threshold from < 0.70 (initial assessment) to < 0.60, changing the threshold for the difference in median survival from > 12 weeks (initial assessment) to > 16 weeks, and including thresholds for OS rates. The outcomes of these scenarios were compared to the outcomes of the initial assessment. ResultsReassessments were conducted for 41 treatments. Replacing the “OR” approach by an “AND” approach substantially decreased the number of positive assessments (from 33 to 22), predominantly affecting immunotherapies. This number further decreased (to 21 and 19, respectively) in case more restrictive thresholds for the HR and difference in median survival were used. Including thresholds for OS rates slightly mitigated the impact of applying an “AND” approach. ConclusionsThe scenario-specific thresholds had a substantial impact; the number of negative assessments more than doubled. Since this was not limited to treatments with marginal survival benefits, understanding the potential challenges that may arise from applying more restrictive thresholds is essential.

A292 IMPACT OF SIROLIMUS PROTEINURIA FOLLOWING LIVER TRANSPLANTATION

Abstract Background Sirolimus (Sr) is a potent immunosuppressant used in liver transplant recipients to prevent rejection in settings of calcineurin inhibitor toxicity and in transplanted hepatocellular carcinoma (HCC) patients. Sr can cause proteinuria, which can lead to poor renal function and survival. The significance of proteinuria is poorly understood, with a lack of studies assessing its risk factors and their impact on clinical outcomes. Aims We evaluated the incidence of proteinuria and its impact on clinical outcomes among liver transplant (LT) recipients who were Sr users compared with non-sirolimus (nonSr) users. Methods We analyzed patients with their first LT between 2001 and 2020. Data were gathered from Organ Transplant Tracking records and chart reviews. Sr users received Sr for at least 6 consecutive months in the first year post-LT. We studied demographics, pre-LT comorbidities, and immunosuppression use. We evaluated the development of proteinuria, renal dysfunction, and new comorbidities including features of metabolic syndrome and cardiovascular disease. Data on post-LT infections, graft rejection, and patient survival were collected. Results We analyzed 359 Sr and 762 non-Sr users (73.5% vs. 65% male). The average ages of Sr and non-Sr users were 54.9±9 and 51.7±11.6 years, respectively (pampersand:003C0.001). Of Sr users, 40.4% had HCC (pampersand:003C0.001). Among non-Sr users, 95% were on tacrolimus and 67.8% were on mycophenolate. Higher frequency of pre-LT hypertension (HTN) was observed in Sr users (27.2% vs. 18.2%; pampersand:003C0.001). There were no differences in pre-LT chronic kidney disease (CKD), cardiovascular disease (CVD), dyslipidemia (DLD), diabetes mellitus (DM) prevalence, creatinine levels, or proteinuria. Sr users had a higher incidence of proteinuria (13.1% vs. 7.9%, p=0.006). Protein-creatinine ratios and albumin-creatinine ratios 12 months post-LT were not significantly different in Sr and non-Sr users ([40.1±105.6 vs. 57.5±169.9 mg/g, p=0.39], and [56.2±101.4 vs. 54.6±166.8 mg/g, p=0.268], respectively). Pre-LT creatinine (OR1.5; pampersand:003C 0.001) and DM (OR2.7; pampersand:003C 0.001) were associated with an increased risk of proteinuria. Sr users had higher (pampersand:003C0.001) incidence of post-LT CVD (24% vs. 14.8%), DM (20.4% vs. 12.6%), HTN (41.5% vs. 30.3%), and DLD (41.3% vs. 20.3%). There was no difference in post-LT CKD between Sr vs non-Sr (41% vs. 47%; p =0.119). Sr users had a lower frequency of post-LT infection (43.1% vs. 53%, p=0.007). Higher incidence of graft rejection was seen in Sr users (43.5% vs 27.8%, pampersand:003C0.001). There was no difference in median graft (15.2 ± 0.40 vs. 14.4±0.30 years; p = 0.681) or patient survival (12.5±0.44 vs. 12.5±0.33 years; p = 0.536). Conclusions Although Sr users were less likely to develop CKD post-LT, they had significantly higher rates of proteinuria, CVD, HTN, and DLD. However, no significant difference was observed in graft or patient survival rates. Funding Agencies None

Machine learning based on blood test biomarkers predicts fast progression in advanced NSCLC patients treated with immunotherapy

ObjectiveFast progression (FP) represents a desperate situation for advanced non-small cell lung cancer (NSCLC) patients undergoing immune checkpoint inhibitor therapy. We aimed to develop a predictive framework based on machine...

Surgical site infections after glioblastoma surgery: boon or bane?

BackgroundSurgical site infections (SSIs) are among the most common postoperative complications. Glioblastoma multiforme is the most frequent malignant brain tumor with a dismal prognosis despite combined treatment. The effect of SSIs on the course of glioblastoma patients has not been fully clarified since available data are limited and partially contradictory. The aim of this study is to investigate the impact of SSIs on the course of patients with glioblastoma.MethodsThe medical records of all patients undergoing surgery for glioblastoma between 2010 and 2020 in our institution were scanned and those with surgical site infections after glioblastoma resection were identified and compared to an age-matched control group. Overall survival and progression-free survival were the primary endpoints followed by the number of hospitalizations and the length of stay in hospital.ResultsOut of 305 patients undergoing surgery for glioblastoma, 38 patients with postoperative surgical site infection after resection were identified and 15 (5 men and 10 women aged between 9 and 72) were included in this study. 23 patients were excluded. The control group consisted of 30 age-matched patients without SSI (18 men and 12 women). There were no significant differences in median overall survival. Progression-free survival was higher in the SSI group. The number of hospitalizations and the length of stay were significantly higher in the SSI group.ConclusionOur data suggest that SSIs might reduce early recurrences without affecting overall survival. Furthermore, they might decrease health-related quality of life by doubling the total length of hospital stay.

Non-responders to neoadjuvant chemotherapy in pancreatic adenocarcinoma: Characteristics and outcomes.

662 Background: For patients with localized pancreatic adenocarcinoma, resection and systemic therapy remain the mainstays of curative-intent treatment. Neoadjuvant chemotherapy has been frequently employed with the goals of addressing systemic disease early and improving patient selection for surgery. Those who do not respond to neoadjuvant therapy present a challenge with a lack of randomized data to aid in decision making. Here we sought to define the characteristics and outcomes of those patients to guide clinical practice. Methods: This was a single-institution retrospective cohort study using a prospectively maintained database of those diagnosed with pancreatic adenocarcinoma. Patients included in the study were those who received neoadjuvant chemotherapy. Non-responders were defined as those with both no radiographic and no biochemical response at the first re-assessment after initiation of therapy. Results: A total of 176 patients were identified who were treated with neoadjuvant chemotherapy with curative intent. Of those, 42 (23.8%) patients had no evidence of either radiographic or biochemical response. Of those patients, 14 were upfront resectable (33.3%) and 20 were borderline resectable (47.6%). An additional 8 (19%) were locally advanced. Most patients received FOLFIRINOX as a first line chemotherapy agent (n = 25, 59.5%). A total of 12 (28.6%) patients underwent neoadjuvant radiation therapy. A total of 19 (45.2%) proceeded to surgery and two of those were found to be unresectable at exploration, resulting in 17 (40.5%) who ultimately received curative-intent resection. Exactly half (n = 21) of the patients had their chemotherapy switched (CS). Of those who had CS, 11 (52.4%) had evidence of local tumor progression on their initial restaging scan compared to just 3 (14.3%) of those who did not (p = 0.02). Additionally, patients who had CS had higher incidence of vascular involvement on their initial scan (90.5% vs 52.3%, p = 0.051). A total of 6 (28.6%) who underwent CS had subsequent biochemical response compared 4 (19.0%) of those who did not. Ultimately, 6 (28.6%) of those who had CS ultimately proceeded to surgery compared to 13 (61.9%) of those who did not (p = 0.062). Interestingly, there was no significant difference in median overall survival between those who had CS (18.6 months) and those who did not (19.9 months, p = 0.525). Conclusions: Non-responders to frontline neoadjuvant systemic therapy present a clinical challenge and have poor rates of curative-intent resection. Chemotherapy switch was employed mostly in cases with worse prognostic factors and thus infrequently lead to resection. Despite this, patients who underwent CS had similar overall survival to those who did not. These data suggest there may be a role for chemotherapy switch in those who do not respond to front line chemotherapy.

Characterizing Immune Infiltration in Esthesioneuroblastoma Subtypes Through Gene Expression Deconvolution

BackgroundEsthesioneuroblastoma (ENB) is a rare cancer deriving from the olfactory mucosa. Among the basal or neural genomic subtypes, the basal subtype is associated with poorer survival, and poor differentiation, and higher levels of tumor-infiltrating immune cells (TIICs). The immune microenvironment of these ENB subtypes remains unclear. We used an established machine-learning algorithm on ENB transcriptomic profiles. MethodsThe authors characterized 22 immune cell populations using the CIBERSORTx deconvolutional machine-learning pipeline on RNAseq data from 18 ENB cases. The characterization aimed to elucidate differences in relative proportions and populations of TIICs between basal and neural ENB. ResultsNo differences in age, Hyams, Dulguerov, IDH2 mutation, or PD-L1 expression were seen between basal and neural subtypes of ENB (p>0.05). No difference in median overall survival was also appreciated (52.0±13.1 vs. 50.0±43.2 months, p=0.5). As a cohort, M2 macrophages were the most abundant subpopulation (14%) followed by naïve B-cells (13%) and CD4 memory resting T cells (12%). No gross differences on CD20, CD4, or CD8 cells/mm2 were apparent on gross histology (p>0.05). However, further analysis showed that activated CD4 memory T cells were significantly increased in the basal ENBs, whereas resting dendritic cells were increased in the neural ENB subtype. The TIIC profiles alone could not differentiate between basal and neural ENB but did suggest immunoprofile differences. ConclusionBasal and neural subtypes display distinct TIIC involvement, which may impact their difference in outcome. These findings provide the framework for further investigation in novel immunomodulation strategies for ENB.

The Impact of Proton Pump Inhibitors on the Efficacy of Immune Checkpoint Inhibitor Combinations in Patients with HBV-Associated Advanced Hepatocellular Carcinoma.

There is limited research on whether Proton Pump Inhibitors (PPIs) will affect the efficacy of immune checkpoint inhibitors (ICIs) in treating hepatocellular carcinoma (HCC).This study aimed to determine whether PPIs affect the survival outcomes of patients with HBV-associated advanced HCC receiving combination therapy based on ICIs. We retrospectively analyzed patients with hepatitis B virus (HBV)-associated advanced HCC who underwent ICIs combination therapy from January 1, 2020, to December 30, 2022. Patients were stratified into PPI and non-PPI groups based on whether they received PPI treatment within 30 days before or after ICIs therapy. Patients' survival and the risk of PPI-associated mortality was assessed. Adverse events were also evaluated. A total of 183 patients with HBV-associated HCC treated with ICI combination therapy were included. The median survival time (12.5 months vs 13.7 months, P = 0.285) and incidence of adverse events (P = 0.729) did not significantly differ between the PPI and non-PPI groups. Even after propensity score matching, the difference in median overall survival (OS) between the two groups was not significant (10.7 months vs 11.4 months; P = 0.596) and the patient's OS is not significantly related to the dosage of PPI application (P > 0.05).However, according to our subgroup analysis, among HCC patients with a serum HBV DNA concentration ≥ 200 IU/mL, the use of PPIs significantly increased the risk of mortality in patients receiving ICI combination therapy (P = 0.024). PPIs do not notably influence the survival prognosis of patients receiving ICI combination therapy for HBV-associated advanced HCC. However, among patients with high levels of HBV DNA, PPIs increase the risk of mortality. Therefore, antiviral therapy should be intensified in the patients with HBVDNA > 200 IU/mL. Additionally, PPIs do not impact the incidence of adverse reactions in these patients.