The NUTRIENT Trial (NUTRitional Intervention among myEloproliferative Neoplasms): Results from a Randomized Phase I Pilot Study for Feasibility and Adherence.

PURPOSE: Chronic inflammation is integral to myeloproliferative neoplasm (MPN) pathogenesis. JAK inhibitors reduce cytokine levels, but not without significant side effects. Nutrition is a low-risk approach to reduce inflammation and ameliorate symptoms in MPN. We performed a randomized, parallel-arm study to determine the feasibility of an education-focused Mediterranean diet intervention among patients with MPN. EXPERIMENTAL DESIGN: We randomly assigned patients with MPN to either a Mediterranean diet or standard U.S. Dietary Guidelines for Americans (USDA). Groups received equal but separate education with registered dietician counseling and written dietary resources. Patients were prospectively followed for feasibility, adherence, and symptom burden assessments. Biological samples were collected at four timepoints during the 15-week study to explore changes in inflammatory biomarkers and gut microbiome. RESULTS: The Mediterranean diet was as easy to follow for patients with MPN as the standard USDA diet. Approximately 80% of the patients in the Mediterranean diet group achieved a Mediterranean Diet Adherence Score of ≥8 throughout the entire active intervention period, whereas less than 50% of the USDA group achieved a score of ≥8 at any timepoint. Improvement in symptom burden was observed in both diet groups. No significant changes were observed in inflammatory cytokines. The diversity and composition of the gut microbiome remained stable throughout the duration of the intervention. CONCLUSIONS: With dietician counseling and written education, patients with MPN can adhere to a Mediterranean eating pattern. Diet interventions may be further developed as a component of MPN care, and potentially incorporated into the management of other hematologic conditions. SIGNIFICANCE: Diet is a central tenant of management of chronic conditions characterized by subclinical inflammation, such as cardiovascular disease, but has not entered the treatment algorithm for clonal hematologic disorders. Here, we establish that a Mediterranean diet intervention is feasible in the MPN patient population and can improve symptom burden. These findings warrant large dietary interventions in patients with hematologic disorders to test the impact of diet on clinical outcomes.

Diabetes mellitus and blood glucose variability increases the 30-day readmission rate after kidney transplantation.

INTRODUCTION: Inpatient hyperglycemia is an established independent risk factor among several patient cohorts for hospital readmission. This has not been studied after kidney transplantation. Nearly one-third of patients who have undergone a kidney transplant reportedly experience 30-day readmission. METHODS: Data on first-time solitary kidney transplantations were retrieved between September 2015 and December 2018. Information was linked to the electronic health records to determine diagnosis of diabetes mellitus and extract glucometric and insulin therapy data. Univariate logistic regression analysis and the XGBoost algorithm were used to predict 30-day readmission. We report the average performance of the models on the testing set on bootstrapped partitions of the data to ensure statistical significance. RESULTS: The cohort included 1036 patients who received kidney transplantation; 224 (22%) experienced 30-day readmission. The machine learning algorithm was able to predict 30-day readmission with an average area under the receiver operator curve (AUC) of 78% with (76.1%, 79.9%) 95% confidence interval (CI). We observed statistically significant differences in the presence of pretransplant diabetes, inpatient-hyperglycemia, inpatient-hypoglycemia, minimum and maximum glucose values among those with higher 30-day readmission rates. The XGBoost model identified the index admission length of stay, presence of hyper- and hypoglycemia, the recipient and donor body mass index (BMI) values, presence of delayed graft function, and African American race as the most predictive risk factors of 30-day readmission. Additionally, significant variations in the therapeutic management of blood glucose by providers were observed. CONCLUSIONS: Suboptimal glucose metrics during hospitalization after kidney transplantation are associated with an increased risk for 30-day hospital readmission. Optimizing hospital blood glucose management, a modifiable factor, after kidney transplantation may reduce the risk of 30-day readmission.

Patient Perspectives and Quality of Life after Breast Reconstruction and the Impact of Subsequent Revisions.

There is limited research on the impact of revisional surgery after breast reconstruction on patient experience and postoperative quality of life (QoL). Methods: Patients undergoing mastectomy with immediate implant-based or autologous free-flap breast reconstruction from 2008 to 2020 were reviewed. These patients were categorized by revisions (0-1, 2-3, and 4+) and surveyed on QoL metrics using BREAST-Q and Was It Worth It? (WIWI) questionnaires. BREAST-Q QoL, satisfaction, and WIWI metrics between revision groups were evaluated. Results: Among 252 patients, a total of 150 patients (60%) underwent zero to one revisions, 72 patients (28%) underwent two to three revisions, and 30 patients (12%) underwent four or more revisions. Median follow-up was 6 years (range, 1-11 years). BREAST-Q satisfaction among patients with four or more revisions was significantly lower (P = 0.03), while core QoL domains (chest physical, psychosocial, and sexual well-being) did not significantly differ. Analysis of unplanned reoperations due to complications and breast satisfaction showed no significant difference in QoL scores between groups (P = 0.08). Regarding WIWI QoL metrics, four or more revisions were associated with a higher rate of worse QoL (P = 0.035) and worse overall experience (P = 0.001). Most patients in all revision groups felt it was worthwhile to undergo breast reconstruction (86%), would choose breast reconstruction again (83%), and would recommend breast reconstruction to others (79%). Conclusions: Overall, a majority of patients undergoing revisions after breast reconstruction still have a worthwhile experience. Although reoperations after breast reconstruction do not significantly impact long-term BREAST-Q QoL domains, patients undergoing four or more revisions have significantly lower breast satisfaction, worse QoL, and a postoperative experience worse than expected.

The NUTRIENT Trial (NUTRitional Intervention among myEloproliferative Neoplasms): Feasibility Phase.

Purpose: Chronic inflammation is integral to Myeloproliferative Neoplasm (MPN) pathogenesis. JAK inhibitors reduce cytokine levels, but not without significant side effects. Nutrition is a low-risk approach to reduce inflammation and ameliorate symptoms in MPN. We performed a randomized, parallel-arm study to determine the feasibility of an education-focused Mediterranean diet intervention among MPN patients. Experimental Design: We randomly assigned participants to either a Mediterranean diet or standard US Dietary Guidelines for Americans (USDA). Groups received equal but separate education with registered dietician counseling and written dietary resources. Patients were prospectively followed for feasibility, adherence, and symptom burden assessments. Biological samples were collected at four time points during the 15-week study to explore changes in inflammatory biomarkers and gut microbiome. Results: The Mediterranean diet was as easy to follow for MPN patients as the standard USDA diet. Over 80% of the patients in the Mediterranean diet group achieved a Mediterranean Diet Adherence Score of ≥8 throughout the entire active intervention period, whereas less than 50% of the USDA group achieved a score of ≥8 at any time point. Improvement in symptom burden was observed in both diet groups. No significant changes were observed in inflammatory cytokines. The diversity and composition of the gut microbiome remained stable throughout the duration of the intervention. Conclusions: With dietician counseling and written education MPN patients can adhere to a Mediterranean eating pattern. Diet interventions may be further developed as a component of MPN care, and potentially even be incorporated into the management of other chronic clonal hematologic conditions.

Phase 1/1b study of azacitidine and hedgehog pathway inhibitor sonidegib in patients with myeloid neoplasms.

BACKGROUND: Myeloid neoplasms (myelodysplastic syndrome [MDS], myelofibrosis, and chronic myelomonocytic [CMML]) are aggressive hematological malignancies for which, despite recent approvals, novel therapies are needed to improve clinical outcomes. The hedgehog (HH) pathway is one of the main pathways for cancer stem cells survival and several HH inhibitors (HHi) are approved in clinical practice. METHODS: Sonidegib (SON), an oral HHi, was tested in this phase 1/1b trial in combination with azacitidine (AZA, 75 mg/m2 days ×7) in patients with newly diagnosed and relapsed/refractory (r/r) chronic MN or acute myeloid leukemia (AML). RESULTS: Sixty-two patients (28 [45%] newly diagnosed) were treated in this study, including 10 patients in the dose-finding component and 52 patients in phase 1b. SON 200 mg oral daily on days 1-28 each cycle was deemed the recommended dose for phase 1b. Out of 21 rrAML patients, two achieved response (one complete response/one morphologic leukemia-free state) with no responses seen in seven r/r MDS/CMML patients. In newly diagnosed AML/MDS, response was seen in six (three had complete remission, two had morphological leukemia-free status) of 27 patients. Median overall survival was 26.4 and 4.7 months for newly diagnosed MDS and AML, respectively. Safety was satisfactory with common (>20%) side effects including fatigue, constipation, nausea, cough, insomnia, and diarrhea. Only 7% of patients died in the study, and none of the deaths were deemed related to treatment. CONCLUSIONS: Our study shows that AZA + SON are a safe combination in a patient with MN. Similar to other hedgehog inhibitors, this combination yielded limited response rate in patients with myeloid neoplasms.

Integrated analysis of next generation sequencing minimal residual disease (MRD) and PET scan in transplant eligible myeloma patients.

Minimal residual disease (MRD) assays allow response assessment in patients with multiple myeloma (MM), and negativity is associated with improved survival outcomes. The role of highly sensitive next generation sequencing (NGS) MRD in combination with functional imaging remains to be validated. We performed a retrospective analysis on MM patients who underwent frontline autologous stem cell transplant (ASCT). Patients were evaluated at day 100 post-ASCT with NGS-MRD and positron emission tomography (PET-CT). Patients with ≥ 2 MRD measurements were included in a secondary analysis for sequential measurements. 186 patients were included. At day 100, 45 (24.2%) patients achieved MRD negativity at a sensitivity threshold of 10-6. MRD negativity was the most predictive factor for longer time to next treatment (TTNT). Negativity rates did not differ according to MM subtype, R-ISS Stage nor cytogenetic risk. PET-CT and MRD had poor agreement, with high rates of PET-CT negativity in MRD-positive patients. Patients with sustained MRD negativity had longer TTNT, regardless of baseline risk characteristics. Our results show that the ability to measure deeper and sustainable responses distinguishes patients with better outcomes. Achieving MRD negativity was the strongest prognostic marker and could help guide therapy-related decisions and serve as a response marker for clinical trials.

The Impact of Same-Day Discharge and Enhanced Recovery on Patient Quality of Life After Mastectomy with Implant Reconstruction.

BACKGROUND: This study aimed to evaluate how enhanced recovery (ER) protocols and same-day discharge (SDD) influences patients' postoperative quality of life (QOL). METHODS: Patients who underwent mastectomy with implant-based breast reconstruction from 2008 to 2020 were identified in a prospective database. The study assessed QOL with BREAST-Q and Was It Worth It? (WIWI) questionnaires. Responses were compared between the ER and pre-ER groups and between the SDD and hospital stay (HS) groups using one-way analysis of variance (ANOVA) and chi-square tests. RESULTS: The inclusion criteria were met by 568 patients, with a 43% response rate, and 217 patients were included for analysis. Chest physical well-being was lower for the ER cohort, but postoperative breast satisfaction was higher. Psychosocial status, sexual well-being, and satisfaction with information given did not differ significantly between the ER group and the pre-ER or SDD group. In the compared groups, QOL did not differ significantly. CONCLUSIONS: Enhanced recovery with SDD after mastectomy using implant-based reconstruction did not have an adverse impact on patient postoperative QOL.

Proton therapy for isolated local regional recurrence of breast cancer after mastectomy alone.

Purpose/Objectives: To assess adverse events (AEs) and disease-specific outcomes after proton therapy for isolated local-regional recurrence (LRR) of breast cancer after mastectomy without prior radiotherapy (RT). Materials/Methods: Patients were identified from a multi-institutional prospective registry and included if diagnosed with invasive breast cancer, initially underwent mastectomy without adjuvant RT, experienced an LRR, and subsequently underwent salvage treatment, including proton therapy. Follow-up and cancer outcomes were measured from the date of RT completion. Results: Nineteen patients were included. Seventeen patients were treated with proton therapy to the chest wall and comprehensive regional lymphatics (17/19, 90%). Maximum grade AE was grade 2 in 13 (69%) patients and grade 3 in 4 (21%) patients. All patients with grade 3 AE received > 60 GyE (p=0.04, Spearman correlation coefficient=0.5). At the last follow-up, 90% of patients were alive with no LRR or distant recurrence. Conclusions: For breast cancer patients with isolated LRR after initial mastectomy without adjuvant RT, proton therapy is well-tolerated in the salvage setting with excellent loco-regional control. All grade 3 AEs occurred in patients receiving > 60 GyE.

Long-term breast and nipple sensation after nipple-sparing mastectomy with implant reconstruction: Relevance to physical, psychosocial, and sexual well-being.

BACKGROUND: The effect of postoperative sensation on quality-of-life (QoL) following nipple-sparing mastectomy (NSM) with implant-based reconstruction is not well described. We evaluated the impact of breast and nipple sensation on patient QoL by using BREAST-Q. METHODS: Patients undergoing NSM with implant reconstruction from 2008 to 2020 were mailed a survey to characterize their postoperative breast and nipple sensation. BREAST-Q metrics were compared between totally numb patients and those with sensation. RESULTS: A total of 349 patients were included. Overall, 131 (38%) responded; response rates regarding breast and nipple sensation were 36% (N = 124/349) and 34% (N = 117/349). Median time from surgery to survey completion was 6 years. The majority had bilateral procedures (101, 77%), including direct-to-implant (99, 76%) and tissue expander (32, 24%) reconstruction. Regarding breast sensation, the majority of patients reported their reconstructed breasts as totally numb (47, 38%) or much less sensation than before surgery (59, 48%). Regarding nipple sensation, the majority of patients reported their nipples were totally numb (67, 57%) or had much less sensation than before surgery (37, 32%). Total numbness of reconstructed breasts resulted in a significantly lower chest physical well-being (mean score: 73.5 vs. 81.2, respectively, P = 0.048). Total numbness of postoperative nipple(s) resulted in significantly lower chest physical (mean score: 74.8 vs. 85.2, respectively, P = 0.007), psychosocial (mean score 77.4 vs. 84.4, respectively, P = 0.041), and sexual well-being (mean score: 55.7 vs. 68.3, respectively, P = 0.002). CONCLUSIONS: Long-term breast and nipple sensation are significantly diminished after NSM with implant reconstruction. Patients with preserved sensation experience better physical, psychosocial, and sexual well-being.

Postoperative Hematomas in the Era of Outpatient Mastectomy: Is Ketorolac Really to Blame?

BACKGROUND: Enhanced recovery after surgery (ERAS) protocols following mastectomy with or without implant-based breast reconstruction (IBBR) include ketorolac for multimodal perioperative analgesia. There are concerns that ketorolac could be associated with increased risk of postoperative hematoma formation. METHODS: Retrospective review of patients undergoing mastectomy with or without IBBR between January 2013 and December 2019 at a single institution. Patients received 15 mg, 30 mg, or no ketorolac depending on ERAS protocol adherence, patient characteristics, and surgeon preference. Clinically significant hematoma was defined as requiring surgical intervention on day of surgery or postoperative day 1. Patients were compared by demographics, surgical characteristics, ketorolac dose, and hematoma prevalence. Univariable and multivariable logistic regression evaluated hematoma formation odds. RESULTS: Eight hundred patients met inclusion criteria: 477 received ketorolac. Those who received ketorolac were younger, had lower ASA scores, were more likely to have bilateral procedures and undergo concomitant IBBR, had longer operative times, were less likely to take antiplatelet or anticoagulation medications, had higher PACU pain scores, and had higher incidence of hematomas requiring surgical intervention. Of the cohort, 4.4% had clinically significant hematomas. The 15 mg and 30 mg ketorolac groups had similar prevalence (6.0% vs 5.8%, p = 0.95). On univariable regression, there were increased odds of hematoma formation in patients who were younger, had bilateral procedures, had longer OR times, and who received ketorolac. On multivariable regression, none of the prior variables remained significant. CONCLUSION: After accounting for associations with longer operative times, concomitant IBBR, and bilateral procedures, ketorolac administration did not remain an independent risk factor for hematoma formation.

Accuracy of Posttreatment Imaging for Evaluation of Residual in Breast Disease After Neoadjuvant Endocrine Therapy.

BACKGROUND: Neoadjuvant endocrine therapy (NET) can help downstage certain breast cancers prior to surgical resection. This study measured the accuracy of conventional mammography (MMG), ultrasound (US), magnetic resonance imaging (MRI), and contrast-enhanced mammography (CEM) for assessing breast tumor size in response to NET. PATIENTS AND METHODS: Patients who underwent surgery after NET from 2013 to 2021 were identified. The maximal dimension of residual tumor on imaging was compared with the maximal dimension on final pathology. Lin's concordance correlation coefficient (rc) and Spearman's rank correlation coefficient (r) were used to assess agreement. RESULTS: In total, 119 patients with invasive breast cancer underwent NET, posttreatment imaging, and surgery. Tumor size reported on posttreatment CEM correlated with size on final pathology to within 1 cm in n = 42 (58%) of patients, equivalent to the accuracy of MRI (n = 35, 58%). Size was accurately predicted by US in 54% and in 48% of MMG. Posttreatment imaging tumor size was moderately correlated with final tumor size on pathology CEM (r = 0.49; rc = 0.38), MRI (r = 0.52; rc = 0.45), and US (r = 0.41; rc = 0.28). MMG was weakly correlated (r = 0.21; rc = 0.16). Similar findings were shown in subgroup analysis; in those who received all four post-NET imaging, CEM and MRI again performed comparably, with r = 0.36 and 0.41, respectively, US (r = 0.43) and MMG (r = 0.28). CONCLUSIONS: Compared with mammography and US, CEM and MRI had higher accuracy in estimating final tumor size for breast cancers treated with NET. Contrast-enhanced imaging is a helpful adjunct when response to preoperative therapy will impact clinical management.

The impact of genetic aberrations on response to radium-223 treatment for castration-resistant prostate cancer with bone metastases.

BACKGROUND: Radium (Ra)-223 is an established treatment option for patients with metastatic castrate-resistant prostate cancer (mCRPC) who have symptomatic bone metastases without soft tissue disease. Studies have indicated genetic aberrations that regulate DNA damage response (DDR) in prostate cancer can increase susceptibility to treatments such as poly ADP-ribose polymerase inhibitors and platinum-based therapies. This study aims to evaluate mCRPC response to Ra-223 stratified by tumor genomics. METHODS: This is a retrospective study of mCRPC patients who received Ra-223 and genetic testing within the Mayo Clinic database (Arizona, Florida, and Minnesota) and Tulane Cancer Center. Patient demographics, genetic aberrations, treatment responses in terms of alkaline phosphatase (ALP) and prostate-specific antigen (PSA), and survival were assessed. Primary end points were ALP and PSA response. Secondary end points were progression-free survival (PFS) and overall survival (OS) from time of first radium treatment. RESULTS: One hundred and twenty-seven mCRPC patients treated with Ra-223 had germline and/or somatic genetic sequencing. The median age at time of diagnosis and Ra-223 treatment was 61.0 and 68.6 years, respectively. Seventy-nine (62.2%) had Gleason score ≥ 8 at time of diagnosis. 50.4% received prior docetaxel, and 12.6% received prior cabazitaxel. Notable alterations include TP53 (51.7%), BRCA 1/2 (15.0%), PTEN (13.4%), ATM (11.7%), TMPRSS2-ERG (8.2%), RB deletion (3.4%), and CDK12 (1.9%). There was no significant difference in ALP or PSA response among the different genetic aberrations. Patients with a TMPRSS2-ERG mutation exhibited a trend toward lower OS 15.4 months (95% confidence interval [CI] 10.0-NR) versus 26.8 months (95% CI 20.9-35.1). Patients with an RB deletion had a lower PFS 6.0 months (95% CI 1.28-NR) versus 9.0 months (95% CI 7.3-11.1) and a lower OS 13.9 months (95% CI 5.2-NR) versus 26.5 months (95% CI 19.8-33.8). CONCLUSIONS: Among mCRPC patients treated with Ra-223 at Mayo Clinic and Tulane Cancer Center, we did not find any clear negative predictors of biochemical response or survival to treatment. TMPRSS2-ERG and RB mutations were associated with a worse OS. Prospective studies and larger sample sizes are needed to determine the impact of genetic aberrations in response to Ra-223.

Does a Uterine Manipulator Increase the Distance of the Ureter to the Cervix and/or Vagina? An Anatomical Cadaver Study.

STUDY OBJECTIVE: To determine whether advancing a manipulator increased the distance of the ureter to the cervix and/or vagina. DESIGN: Prospective. SETTING: Academic institution. PATIENTS: A total of 22 intact fresh-frozen female pelvises. INTERVENTIONS: A total of 6 ureteral distances were measured per pelvis. Included were the following measurements on each side: (1) from the lateral cervical wall to the ureter at the intersection with the uterine artery; (2) from the lateral cervical wall to the parametrial ureter; and (3) from the vagina to the ureter at the intersection with the uterine artery. All measurements were obtained with and without advancement of a uterine manipulator. MEASUREMENTS AND MAIN RESULTS: The average distance from the ureter to the cervix and vagina without advancing the manipulator was 2.8 and 3.1 cm, respectively, and the distance from the parametrial ureter to the cervix was 3.3 cm. When the manipulator was advanced, all ureteral distances increased by 0.8, 0.6, and 0.6 cm, respectively, in 12 of the 22 pelvises (55%). Advancing the manipulator did not increase at least 1 of the distances in 10 of the 22 pelvises (45%). The advancement of the manipulator lengthened the 2 shortest ureteral distances of 1 cm noted in 1 pelvis (4.5%) by 0.9 and 0.4 cm. CONCLUSION: The uterine manipulator increased the distance of the ureter to the cervix and vagina for all measurements in 55.5% of the pelvises. The greatest increase was 0.9 cm. The manipulator did not increase at least 1 of the distances in 10 of the 22 pelvises (45.4%).

Seldom one and done: Characterizing rates of reoperation with direct-to-implant breast reconstruction after mastectomy.

BACKGROUND: Limited data exist outlining reoperations after direct-to-implant (DTI), tissue expander (TE) and autologous free-flap breast reconstruction. METHODS: Patients undergoing mastectomy with reconstruction from 2008 to 18 were reviewed. Patient factors, surgical techniques, planned, unplanned, and total reoperations were analyzed. RESULTS: Among 544 total patients, the majority underwent DTI (294, 54%) or TE (176, 32%); 74 (14%) received autologous free-flaps. Majority of DTI patients (55%) underwent subsequent reoperations. Compared to autologous tissue, DTI had less patients undergo additional surgery (76% vs. 55%, P = 0.001). Incidence of total unplanned reoperations did not significantly differ between reconstructive groups. The rate of unplanned reoperations due to complications was lowest for DTI (39%) when compared to TE (48%) and autologous (55%, P = 0.015). Compared to TE, DTI carried a lower risk for ≥2 total reoperations (OR = 0.21, 95% CI 0.13-0.33, P < 0.001). CONCLUSIONS: Seldom "one and done," additional surgery after DTI remains significant.

Is the presence of tumor-infiltrating lymphocytes predictive of outcomes in patients with melanoma?

BACKGROUND: The significance of tumor-infiltrating lymphocytes (TILs) in melanoma is debated. This article presents a multicenter, retrospective study assessing the predictive and prognostic value of TILs. METHODS: The Sentinel Lymph Node Working Group database was queried from 1993 to 2018 for cases with known TIL data. TILs were categorized as absent or present, which included nonbrisk (NB), brisk (B), and present but unspecified TIL levels. Clinicopathologic factors were correlated with TILs, sentinel lymph node (SLN) status, and melanoma-specific survival (MSS). RESULTS: Overall, 3203 patients were included. The median thickness was 1.5 mm, and 469 cases had SLN metastases. TILs were present in 2458 cases (76.7%), with NB, B, and unspecified TILs seen in 1691 (68.8%), 691 (28.1%), and 76 (3.1%), respectively. Multivariable analysis showed that the presence of TILs significantly predicted a negative SLN biopsy (P < .05). The median follow-up was 25.2 months. MSS was significantly better for cases with TILs than cases without TILs (P < .001). According to multivariable analysis, age, gender, thickness, mitotic rate, ulceration, lymphovascular invasion, and SLN status were significantly prognostic of MSS (all P values < .05). Although TILs were not prognostic of MSS, when multiple imputation was used and the SLN status was excluded, the presence of TILs was significantly prognostic of improved MSS (hazard ratio, 0.78; 95% confidence interval, 0.64-0.95; P = .0154). CONCLUSIONS: TILs are a favorable marker because their presence significantly predicts a negative SLN, and the absence of TILs may be a prognostic marker of worse survival in patients with a positive SLN but not a negative SLN. TILs may also serve as a prognostic marker of survival when the SLN status is not considered.