Objective-To characterize the results of surgery for GIST in the pre-and post-imatinib eras at a single-institution and identify current prognostic clinicopathologic factors.Summary Background Data-Imatinib has radically changed the management of GIST, yet the magnitude of impact on outcome across the spectrum of GIST presentation and relevance of historical prognostic factors are not well defined.Methods-We retrospectively analyzed 1,000 patients who underwent surgery for GIST at our institution from 1982-2016. Patients were stratified by presentation status as primary tumor only (PRIM), primary with synchronous metastasis (PRIM+MET), or metachronous recurrence/ metastases (MET), as well as imatinib era (before and after it became available). Cox proportional hazard models and Kaplan Meier methods were used to model and estimate overall and recurrence-free survival (OS, RFS).Results-OS was longer in the imatinib era compared to the pre-imatinib era in each presentation group, including in Miettinen high risk primary tumors. Among PRIM patients from the pre-imatinib era, tumor site, size, and mitotic rate were independently associated with OS and RFS on multivariate analysis. PRIM patients in the imatinib era who received imatinib (neoadjuvant and/or adjuvant) had higher risk tumors, but after adjusting for treatment, only size >10cm remained independently prognostic of RFS (HR 3.85, p<0.0001) and OS (HR 3.37, p=0.001).
Summary Intra‐operative hypotension is a known predictor of adverse events and poor outcomes following major surgery. Hypotension often occurs on induction of anaesthesia, typically attributed to hypovolaemia and the haemodynamic effects of anaesthetic agents. We assessed the efficacy of fluid optimisation for reducing the incidence of hypotension on induction of anaesthesia. This prospective trial enrolled 283 patients undergoing radical cystectomy and randomly allocated them to goal‐directed fluid therapy (n = 142) or standard fluid therapy (n = 141). Goal‐directed fluid therapy patients received fluid optimisation based on stroke volume response to passive leg raise before induction; those with positive passive leg raise received intravenous crystalloid fluid boluses until stroke volume was optimised. Baseline mean arterial pressure was measured on the morning of surgery and on arriving in the operating theatre. This post‐hoc analysis defined haemodynamic instability as either a > 30% relative drop in mean arterial pressure compared with baseline or absolute mean arterial pressure < 55 mmHg, within 15 min of induction. Forty‐two (30%) goal‐directed fluid therapy patients underwent fluid optimisation after finding an intravascular fluid deficit via passive leg raise testing; 106 (75%) goal‐directed fluid therapy and 112 (79%) standard fluid therapy patients met criteria for haemodynamic instability. There was no significant difference in the incidence of haemodynamic instability between the goal‐directed fluid therapy and standard fluid therapy groups using absolute mean arterial pressure drop below 55 mmHg (p = 0.58) or using pre‐surgical testing or pre‐surgical mean arterial pressure values as baseline (p = 0.21, p = 0.89, respectively); however, the difference in the incidence of haemodynamic instability was significant using the operating theatre baseline mean arterial pressure (p = 0.004). We conclude that fluid optimisation before induction of general anaesthesia did not significantly impact haemodynamic instability.
PURPOSE To detect alterations in DNA damage repair (DDR) genes, measure homologous recombination deficiency (HRD), and correlate these findings with clinical outcome in patients with leiomyosarcoma (LMS). PATIENTS AND METHODS Patients with LMS treated at Memorial Sloan Kettering (MSK) Cancer Center who consented to prospective targeted next-generation sequencing with MSK-IMPACT were screened for oncogenic somatic variants in one of 33 DDR genes; where feasible, an experimental HRD score was calculated from IMPACT data. Progression-free survival (PFS) and overall survival (OS) were estimated after stratifying patients by DDR gene alteration status and HRD score. RESULTS Of 211 patients with LMS, 20% had an oncogenic DDR gene alteration. Univariable analysis of PFS in 117 patients who received standard frontline chemotherapy in the metastatic setting found that an altered homologous recombination pathway gene was significantly associated with shorter PFS (hazard ratio [HR], 1.79; 95% CI, 1.04 to 3.07; P = .035). Non- BRCA homologous recombination gene alteration was associated with shorter PFS (HR, 2.61; 95% CI, 1.35 to 5.04; P = .004) compared with BRCA-altered and wild-type homologous recombination genes. Univariable analysis of OS from diagnosis in the entire cohort of 211 patients found that age, tumor size, number of metastatic sites, localized disease, and non- BRCA homologous recombination gene alteration were significantly associated with OS. On multivariable analysis, non- BRCA homologous recombination pathway gene alteration remained significant (HR, 4.91; 95% CI, 2.47 to 9.76; P < .001). High HRD score was not associated with a different PFS or OS. CONCLUSION Patients with LMS with homologous recombination pathway gene alterations have poor clinical outcomes, particularly those with non- BRCA gene alterations. HRD score calculated from a targeted exome panel did not discern disparate clinical outcomes.
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