Shah, Sahrish

Abstract BACKGROUND Leptomeningeal disease (LMD) carries poor prognosis with an average survival of 3-6 months after diagnosis. Ommaya reservoirs (OR) are an accessible alternative to serial lumbar punctures for delivery of intrathecal chemotherapy (IC) and disease monitoring but are not widely used. Intraventricular administration of chemotherapy may be associated with superior efficacy and improved patient comfort. The purpose of this study was to assess safety and efficacy of IC and disease monitoring via OR in routine clinical practice. MATERIAL AND METHODS Patients who received at least one administration of IC via OR for LMD between 2017 and 2022 were included. Demographics, treatment type, complications and outcomes were recorded. RESULTS We identified 22 patients (17 females, 5 males) with mean age 50.9 ± 14.8 years. The primary tumors were: breast (12), leukemia (3), ovarian carcinoma (3), CNS lymphoma (1), urothelial carcinoma (1), spinal melanocytoma (1), and high-grade glioma (1). A total of 208 OR injections were performed [median was 9 OR injections per patient, interquartile range (IQR) (5, 13)]. Five patients (23%) experienced mild adverse events of grade 2 or lower by Common Terminology Criteria for Adverse Events. Overall risk of adverse event from injection was 3.4% (7/208). Eight patients (36.3%) converted into negative CSF cytology (median 1 month following first injection), and 18 patients (82%) had clinical or radiological progression of their LMD (median 2 months following first injection). Eleven patients (50%) died of their LMD during follow-up. Median OS and PFS from the first injection were 5.3 months [95% CI 4.8-NE (not estimable)] and 4.3 months [95% CI 1.8-16.0], respectively. CONCLUSION Use of OR in routine clinical practice is a safe and feasible option and should be strongly considered for treatment and frequent disease monitoring of patients with LMD, especially in the era of circulating tumor cells analysis. The median OS in our cohort is comparable to prior published series.

Abstract Background Early-stage breast cancer is among the most common cancer diagnoses. Adjuvant radiotherapy is an essential component of breast-conserving therapy, and several options exist for tailoring its extent and duration. This study assesses the comparative effectiveness of partial-breast irradiation (PBI) compared with whole-breast irradiation (WBI). Methods A systematic review was completed to identify relevant randomized clinical trials and comparative observational studies. Independent reviewers working in pairs selected studies and extracted data. Randomized trial results were pooled using a random effects model. Prespecified main outcomes were ipsilateral breast recurrence (IBR), cosmesis, and adverse events (AEs). Results Fourteen randomized clinical trials and 6 comparative observational studies with 17 234 patients evaluated the comparative effectiveness of PBI. PBI was not statistically significantly different from WBI for IBR at 5 years (RR = 1.34, 95% CI = 0.83 to 2.18; high strength of evidence [SOE]) and 10 years (RR = 1.29, 95% CI = 0.87 to 1.91; high SOE). Evidence for cosmetic outcomes was insufficient. Statistically significantly fewer acute AEs were reported with PBI compared with WBI, with no statistically significant difference in late AEs. Data from subgroups according to patient, tumor, and treatment characteristics were insufficient. Intraoperative radiotherapy was associated with higher IBR at 5, 10, and over than 10 years (high SOE) compared with WBI. Conclusions Ipsilateral breast recurrence was not statistically significantly different between PBI and WBI. Acute AEs were less frequent with PBI. This evidence supports the effectiveness of PBI among selected patients with early-stage, favorable-risk breast cancer who are similar to those represented in the included studies.

Abstract Funding Acknowledgements Type of funding sources: None. Background/Introduction Immune checkpoint inhibitor (ICI) myocarditis is a life-threatening condition characterized by lymphocytic myocardial infiltration[1]. Complete heart block (CHB) occurs in 15% of cases and is often fatal[2-4]. The nature and optimal management of this often-malignant condition is poorly understood[5]. Purpose This case series assesses prognostic factors associated with survival at 90 days among people with ICI myocarditis and CHB. Methods The electronic patient record system was used to identify patients admitted with ICI myocarditis. A two-physician review was used to assess the presence of ICI-associated CHB. Wilcoxon rank sum and Spearman’s rank correlation were used for categorical and quantitative variables respectively. Data was analysed using STATA/IC 16.1. The primary outcome was person-day survival 90 days after presenting symptom onset. Results Six patients were included in the final analysis. Mean survival was 47 person days. All had metastatic disease and presented 15 to 32 days after the first ICI infusion. All had muscle weakness. Other common self-symptoms were shortness of breath (4), blurred vision (4), double vision (3), collapse (3), and leg swelling (1). Proximal myopathy (2), fatigable myopathy (1), ptosis (3), and peripheral oedema (1) were present on examination. Raised troponin T and white blood cell count (WBC) were associated with 90-day survival (see Table 1). Nt-pro BNP, AST, and CK levels were raised in all patients. Two patients were tested for anti-striated muscle antibody titres, and both were strongly positive. Increase in QRS duration compared to baseline ECG was associated with lower survival at 90 days. Only one patient had CHB on admission. Steroid dose, IVIG, and plasmapheresis weren’t associated with survival. One patient declined device therapy. One declined permanent pacemaker (PPM) after insertion of transvenous pacemaker (TVP). Both died within 2 weeks. Three people underwent insertion of a transvenous pacemaker (TVP) followed by PPM insertion (table 2). All three eventually died within 100 days. One person received isoproterenol and immunosuppression as a bridge to PPM and survived. One patient was managed initially with TVP but subsequently declined PPM insertion. TVP removal resulted in CHB recurrence, and they died shortly after discharge. One person declined device therapy and died while receiving comfort care. Lead malfunction was frequent. One patient experienced bradycardia arrest with failure of a TVP lead to capture, while another experienced lead dislodgement. Conclusion CHB secondary to ICI is often fatal. It should be considered in patients presenting with symptoms of myositis, raised troponin and increased QRS duration. Despite a small sample size, this study identifies several prognostic factors which can guide both patients and physicians with decision-making. Larger studies are needed to better understand the role of device therapy in this population.

AbstractContextHypercalcemia is a common complication of malignancy that is associated with high morbidity and mortality.ObjectiveTo support development of the Endocrine Society Clinical Practice Guideline for the treatment of hypercalcemia of malignancy in adults.MethodsWe searched multiple databases for studies that addressed 8 clinical questions prioritized by a guideline panel from the Endocrine Society. Quantitative and qualitative synthesis was performed. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess certainty of evidence.ResultsWe reviewed 1949 citations, from which we included 21 studies. The risk of bias for most of the included studies was moderate. A higher proportion of patients who received bisphosphonate achieved resolution of hypercalcemia when compared to placebo. The incidence rate of adverse events was significantly higher in the bisphosphonate group. Comparing denosumab to bisphosphonate, there was no significant difference in the rate of patients who achieved resolution of hypercalcemia. Two-thirds of patients with refractory/recurrent hypercalcemia of malignancy who received denosumab following bisphosphonate therapy achieved resolution of hypercalcemia. Addition of calcitonin to bisphosphonate therapy did not affect the resolution of hypercalcemia, time to normocalcemia, or hypocalcemia. Only indirect evidence was available to address questions on the management of hypercalcemia in tumors associated with high calcitriol levels, refractory/recurrent hypercalcemia of malignancy following the use of bisphosphonates, and the use of calcimimetics in the treatment of hypercalcemia associated with parathyroid carcinoma. The certainty of the evidence to address all 8 clinical questions was low to very low.ConclusionThe evidence summarized in this systematic review addresses the benefits and harms of treatments of hypercalcemia of malignancy. Additional information about patients’ values and preferences, and other important decisional and contextual factors is needed to facilitate the development of clinical recommendations.

AbstractContextIndividuals with diabetes or newly recognized hyperglycemia account for over 30% of noncritically ill hospitalized patients. Management of hyperglycemia in these patients is challenging.ObjectiveTo support development of the Endocrine Society Clinical Practice Guideline for management of hyperglycemia in adults hospitalized for noncritical illness or undergoing elective surgical procedures.MethodsWe searched several databases for studies addressing 10 questions provided by a guideline panel from the Endocrine Society. Meta-analysis was conducted when feasible. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess certainty of evidence.ResultsWe included 94 studies reporting on 135 553 patients. Compared with capillary blood glucose, continuous glucose monitoring increased the number of patients identified with hypoglycemia and decreased mean daily blood glucose (BG) (very low certainty). Data on continuation of insulin pump therapy in hospitalized adults were sparse. In hospitalized patients receiving glucocorticoids, combination neutral protamine hagedorn (NPH) and basal-bolus insulin was associated with lower mean BG compared to basal-bolus insulin alone (very low certainty). Data on NPH insulin vs basal-bolus insulin in hospitalized adults receiving enteral nutrition were inconclusive. Inpatient diabetes education was associated with lower HbA1c at 3 and 6 months after discharge (moderate certainty) and reduced hospital readmissions (very low certainty). Preoperative HbA1c level < 7% was associated with shorter length of stay, lower postoperative BG and a lower number of neurological complications and infections, but a higher number of reoperations (very low certainty). Treatment with glucagon-like peptide-1 agonists or dipeptidyl peptidase-4 inhibitors in hospitalized patients with type 2 diabetes and mild hyperglycemia was associated with lower frequency of hypoglycemic events than insulin therapy (low certainty). Caloric oral fluids before surgery in adults with diabetes undergoing surgical procedures did not affect outcomes (very low certainty). Counting carbohydrates for prandial insulin dosing did not affect outcomes (very low certainty). Compared with scheduled insulin (basal-bolus or basal insulin + correctional insulin), correctional insulin was associated with higher mean daily BG and fewer hypoglycemic events (low certainty).ConclusionThe certainty of evidence supporting many hyperglycemia management decisions is low, emphasizing importance of shared decision-making and consideration of other decisional factors.

BACKGROUND As the use of injectable skin fillers increase in popularity, an increase in the reported adverse events is expected. OBJECTIVE This systematic review supports the development of American Society for Dermatologic Surgery practice guideline on the management of adverse events of skin fillers. METHODS AND MATERIALS Several databases for studies on risk factors or treatments of injection-related visual compromise (IRVC), skin necrosis, inflammatory events, and nodules were searched. Meta-analysis was conducted when feasible. RESULTS The review included 182 studies. However, IRVC was very rare (1–2/1,000,000 patients) but had poor prognosis with improvement in 19% of cases. Skin necrosis was more common (approximately 5/1,000) with better prognosis (up to 77% of cases showing improvement). Treatments of IRVC and skin necrosis primarily depend on hyaluronidase injections. Risk of skin necrosis, inflammatory events, and nodules may be lower with certain fillers, brands, injection techniques, and volume. Treatment of inflammatory events and nodules with antibiotics, corticosteroids, 5-FU, and hyaluronidase was associated with high response rate (75%–80%). Most of the studies were small and noncomparative, making the evidence certainty very low. CONCLUSION Practitioners must have adequate knowledge of anatomy, elicit history of skin filler use, and establish preemptive protocols that prepare the clinical practice to manage complications.

Abstract Background: The World Health Organization (WHO) system lists five morphological categories of systemic mastocytosis (SM): indolent (ISM), smouldering (SSM), SM with an associated hematological neoplasm (SM-AHN), aggressive (ASM) and mast cell leukemia (MCL) (Blood. 2016;127:2391). Recent studies have highlighted the prognostic importance of mutations in SM, including ASXL1, RUNX1 and SRSF2 (AJH 2016;91:888;Leukemia 2016;30:2342). In the current study, we reviewed the cytogenetic findings in 348 cases of SM, in order to clarify incidence and prognostic impact of cytogenetic abnormalities, stratified by WHO morphologic subcategories. Methods : Study patients were selected, based on availability of cytogenetic information. Diagnoses of SM and its morphological subcategories were confirmed by both clinical and bone marrow examinations, in line with WHO criteria (Blood. 2016;127:2391). Next-generation sequencing was performed in a subset of the study population. Abnormal karyotype was further distinguished into favorable and unfavorable class based on previously published criteria for myelodysplastic syndromes (MDS) (Blood 2012;120:2454) and myeloproliferative neoplasms (MPN) (Leukemia 208;32:1189). Statistical analyses considered clinical and laboratory data collected at the time of initial diagnosis at the Mayo Clinic, which coincided with collection of bone marrow for cytogenetic studies. Conventional statistics was used for calculation of overall survival and determination of risk factors. JMP® Pro 13.0.0 software from SAS Institute, Cary, NC, USA, was used for all calculations. Results: 348 SM patients were included in the current study (median age 59 years; range 18-88 years; 53% males); 142 (41%) constituted ISM and 206 (59%) advanced SM; the latter included 155 (45%) SM-AHN, 49 (14%) ASM and 2 MCL cases. The SM-AHN cases included 39 (11%) SM-MPN, 36 (10%) SM-CMML, 22 (6%) SM-MDS, 22 (6%) SM-myeloid unclassified, 14 (4%) SM-MDS/MPN, 12 (3%) SM-lymphoid malignancy and 10 (3%) SM-acute leukemia. Adverse mutations, including ASXL1 (19% mutated), RUNX1 (3% mutated) and NRAS (3% mutated) were detected in 30 (23%) of 129 cases screened. After a median follow-up of 21 months, 139 (40%) deaths and 6 (5%) leukemic transformations were documented. Karyotype was abnormal in 53 (15%) cases and included unfavorable (n=29; 8%) and favorable (n=24; 7%) abnormalities. Abnormal karyotype incidences were 6% for ISM and 22% for advanced SM (p<0.001). Among advanced SM cases, abnormal karyotype incidences were 26% for SM-AHN and 8% for ASM (p<0.001); one of 2 MCL cases displayed abnormal karyotype. Among SM-AHN cases, abnormal karyotype incidences were 0% for SM-AHN-lymphoid, 28% for SM-AHN-myeloid (p<0.001); the latter included 19% for SM-CMML, 21% for SM-MDS/MPN, 23% for SM-MPN, 36% for SM-MDS and 41% of SM-myeloid-unclassified (p<0.001). Clinical correlative studies disclosed significant associations between abnormal karyotype and male sex (p=0.002), age >60 years (p=0.04), thrombocytopenia (p<0.001; 27% vs 10%) and anemia (p<0.001; 25% vs 6%), but not with the presence of adverse mutations (p=0.19). In univariate analysis, abnormal karyotype was associated with inferior survival (HR 3.0, 95% CI 2.0-4.3) and significance was sustained when analysis was adjusted for two-tiered (advanced vs indolent SM; p<0.01) or multi-tiered (ISM vs ASM vs SM-AHN; p<0.01) WHO subcategories. WHO category-specific analysis clarified prognostic relevance of abnormal karyotype in ASM (HR 4.4, 95% CI 1.0-14.4; p=0.05; figure 1a) and SM-AHN-myeloid (HR 1.9, 95% CI 1.2-2.9; p=0.005; figure 1b); however, the near-significance in ASM was fully accounted for by thrombocytopenia (p value corrected to 0.35) and for SM-AHN-myeloid by thrombocytopenia and anemia (p value corrected to 0.06); further stratification of abnormal karyotype into favorable vs unfavorable categories did not affect the results in ASM but revealed an independent prognostic effect for unfavorable karyotype in SM=AHN-myeloid (p=0.009). Conclusions: Abnormal karyotype in SM clusters with SM-AHN-myeloid. We found no correlation between abnormal karyotype and adverse mutations. Anemia and thrombocytopenia were significantly associated with abnormal karyotype and accounted for the apparent prognostic relevance of the latter in ASM. Unfavorable karyotype carries independent prognostic effect in SM-AHN-myeloid. Disclosures No relevant conflicts of interest to declare.

Abstract Background: The 2016 World Health Organization (WHO) system lists five morphological categories of systemic mastocytosis (SM): indolent (ISM), smoldering (SSM), SM with an associated hematological neoplasm (SM-AHN), aggressive (ASM) and mast cell leukemia (MCL) (Blood. 2016;127:2391). In the current study, we capitalized on the large number of accumulated cases of SM seen at the Mayo Clinic, between 1968 and 2015 (n=580), in order to devise two separate but complementary prognostic models that are based on either clinically-derived variables, or a combination of both clinical and molecular information. Methods : Study patients (n=580) were recruited from the Mayo Clinic, Rochester, MN, USA. Diagnoses of SM and its morphological subcategories were confirmed by both clinical and bone marrow examinations, in line with the 2016 WHO criteria (Blood. 2016;127:2391). Next-generation sequencing (NGS) was performed in a subset of the study population (n=150). Statistical analyses considered clinical and laboratory data collected at the time of initial diagnosis at the Mayo Clinic. Conventional statistics was used for calculation and of overall survival and determination of inter-independent risk factors. Receiver operating characteristic (ROC) curves were used to determine the prognostically most discriminative platelet threshold. The JMP® Pro 13.0.0 software from SAS Institute, Cary, NC, USA, was used for all calculations. Results: 580 patients with SM (median age 55 years; range 18-88 years; 52% males) were included in the current study; 291 (50%) constituted indolent and 289 (50%) advanced variants; the latter included 85 (15%) ASM, 199 (34%) SM-AHN and 5 MCL cases. At presentation, anemia defined by hemoglobin level below the lower limit of the sex-adjusted reference range, was present in 41% of the patients, hemoglobin <10 g/dl in 16%, red cell transfusion-dependency in 9%, platelet count below the ROC-determined limit of 150 x 109/l in 26%, serum albumin below the lower normal limit (LNL) of the reference range in 22%, serum alkaline phosphatase (ALP) above the upper normal limit (UNL) of the reference range in 54%, urticaria pigmentosa in 41%, mast cell mediator symptoms in 46%, palpable hepatomegaly in 21%, palpable splenomegaly in 31%, "C" findings in 23% and "B" findings in 42%. Median follow-up was 34 months with 239 (41%) deaths and 9 (1.5%) leukemic transformations documented. Cytogenetic information was available in 342 cases, including 51 (15%) with abnormal karyotype and 27 (8%) with unfavorable karyotype. NGS-derived mutation information was available in 150 cases and most frequent mutations were KIT (75%), TET2 (29%), ASXL1 (17%) and CBL (11%). Age-adjusted multivariable analysis of clinical variables, which did not include mutation or cytogenetic information, identified age >60 years (HR 2.5, 95% CI 1.8-3.4), advanced vs ISM (HR 2.3, 95% CI 1.5-3.7), thrombocytopenia <150 x 109/l (HR 2.4, 95% CI 1.8-3.4), anemia (HR 2.1, 95% CI 1.5-3.0), ALP above UNL (HR 2.1, 95% CI 1.5-3.1) and albumin below LNL (HR 1.4, 95% CI 1.0-1.9). A similar age-adjusted multivariable analysis for mutations identified ASXL1 (HR 3.3, 95% CI 1.9-5.5), RUNX1 (HR 4.1, 95% CI 1.2-10.2) and NRAS (HR 5.7, 95% CI 1.7-14.9) as independent molecular risk factors; these mutations were henceforth labelled as "adverse". The addition of "adverse" mutations (HR 2.7, 95% CI 1.6-4.7) to the list of the aforementioned clinical risk factors resulted in loss of significance for age and anemia while platelets below 150 x 109/l (HR 2.9, 95% CI 1.8-4.8), ALP above UNL (HR 3.2, 95% CI 1.8-6.1), albumin below LNL (HR 2.5, 95% CI 1.6-4.0) and advanced vs ISM (HR4.2, 95% CI 1.9-10.7) remained significant. Subsequently, based on the number of risk factors present, a "clinical" (figure 1a; n=380 informative cases) and "clinical-molecular" (figure 1b; n=129 informative cases) risk models were prepared; both risk models performed effectively for advanced and indolent SM, when analyzed separately (data not shown). Conclusions: The current study advances two separate but complimentary risk models for SM and illustrates the additional prognostic contribution of mutations and underlines the importance of thrombocytopenia and serum ALP and albumin levels in both risk models. Furthermore, we show effective application of both risk models in advanced and indolent SM. Disclosures No relevant conflicts of interest to declare.