Comprehensive Analysis Identifies Variability in PI3K Pathway Alterations in Triple-Negative Breast Cancer Subtypes.

PURPOSE: The PI3K pathway is frequently altered in triple-negative breast cancer (TNBC). Limited cell line and human data suggest that TNBC tumors characterized as mesenchymal (M) and luminal androgen receptor (LAR) subtypes have increased incidence of alterations in the PI3K pathway. The impact of PI3K pathway alterations across TNBC subtypes is poorly understood. METHODS: Pretreatment tumor was evaluated from operable TNBC patients enrolled on a clinical trial of neoadjuvant therapy (NAT; A Robust TNBC Evaluation fraMework to Improve Survival [ClinicalTrials.gov identifier: NCT02276443]). Tumors were characterized into seven TNBC subtypes per Pietenpol criteria (basal-like 1, basal-like 2, immunomodulatory, M, mesenchymal stem-like, LAR, and unstable). Using whole-exome sequencing, RNA sequencing, and immunohistochemistry for PTEN, alterations were identified in 32 genes known to activate the PI3K pathway. Alterations in each subtype were associated with pathologic response to NAT. RESULTS: In evaluated patients (N = 177), there was a significant difference in the incidence of PI3K pathway alterations across TNBC subtypes (P < .01). The highest incidence of alterations was seen in LAR (81%), BL2 (79%), and M (62%) subtypes. The odds ratio for pathologic complete response (pCR) in the presence of PIK3CA mutation, PTEN mutation, and/or PTEN loss was highest in the LAR subtype and lowest in the M subtype, but these findings did not reach statistical significance. Presence of PIK3CA mutation was associated with pCR in the LAR subtype (P = .02). CONCLUSION: PI3K pathway alteration can affect response to NAT in TNBC, and targeted agents may improve outcomes, particularly in patients with M and LAR TNBC.

Pediatric Medullary Thyroid Carcinoma: Clinical Presentations and Long-term Outcomes in 144 Patients Over Six Decades.

CONTEXT: Sporadic medullary thyroid carcinoma (sMTC) rarely occurs in childhood and no studies have specifically focused on this entity. OBJECTIVE: To describe the clinical presentations and long-term outcomes of a large cohort of children and young adults with sMTC compared with hereditary MTC (hMTC). METHODS: Retrospective study of 144 patients diagnosed with MTC between 1961-2019 at an age ≤21 years and evaluated at a tertiary referral center. RESULTS: In contrast to hMTC (n=124/144, 86%), patients with sMTC (n=20/144, 14%) are older (p<0.0001), have larger tumors (p<0.0001), a higher initial stage grouping (p=0.001) and have more structural disease (p=0.0045) and distant metastases (DM) (p=0.00084) at last follow up, but are not more likely to die from MTC (p=0.42). Among 77 patients diagnosed clinically, not by family history (20/20 sMTC and 57/124 hMTC), there was no difference in the initial stage (p=0.27), presence of DM at diagnosis (p=1.0), disease status at last follow-up (p=0.13), overall survival (p=0.57), or disease specific survival (p=0.87). Of the twelve sMTC tumors that underwent somatic testing, eleven (91%) had an identifiable alteration: ten RET gene alterations and one ALK fusion. CONCLUSIONS: sMTC is primarily a RET-driven disease that represents 14% of childhood-onset MTC in this cohort. Pediatric sMTC patients are older, present with clinical disease at a more advanced TNM classification, and have more persistent disease at last follow up compared with hMTC, but these differences disappear when comparing those presenting clinically. Somatic molecular testing should be considered in sMTC patients who would benefit from systemic therapy.

Eltrombopag improves platelet engraftment after haploidentical bone marrow transplantation: Results of a Phase II study.

Slow platelet recovery frequently occurs after haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with bone marrow graft and post-transplant cyclophosphamide (PCy)-based graft-versus-host disease (GVHD) prophylaxis. Improved platelet recovery may reduce the need for transfusions and improve outcomes. We investigated the safety and efficacy of eltrombopag, a thrombopoietin receptor agonist, at enhancing platelet recovery post-haplo-HSCT. The prospective study included patients ≥18 years of age who received haplo-HSCT with bone marrow graft and PCy. Patients received eltrombopag 300 mg/day starting on Day +5. The primary objective was to estimate platelet engraftment (>50 000/µL by Day 60). In a post hoc analysis, they were compared to a contemporary matched control group who did not receive eltrombopag. One hundred ten patients were included in the analysis (30 eltrombopag and 80 control). Seventy-three percent and 50% of patients in the eltrombopag group and control group, respectively, attained >50 000/µL platelet count by Day 60 (p = .043). No eltrombopag-related grade ≥4 adverse events were observed. Median time to platelet recovery (>20 000/µL) was 29 days with eltrombopag and 31 days for controls (p = .022), while its cumulative incidence was 90% (95% confidence interval [CI]: 78%-100%) with eltrombopag versus 67.5% (95% CI: 57%-78%) for controls (p = .014). Number of platelet transfusions received, overall survival, progression-free survival, GVHD rate, relapse rate, and non-relapse mortality were similar between groups. Overall, eltrombopag is safe and improves platelet recovery in patients undergoing haplo-HSCT with bone marrow graft and PCy.

Impact of pretransplant minimal residual disease in patients with multiple myeloma and a very good partial response or better receiving autologous hematopoietic stem cell transplantation.

BACKGROUND: The prognostic significance of minimal residual disease (MRD) status before autologous hematopoietic stem cell transplantation (autoHCT) in patients with multiple myeloma (MM) has not been clearly elucidated. METHODS: Retrospective single-center study of adult MM patients who achieved ≥very good partial response (VGPR) after induction therapy from 2015 to 2021 received upfront autoHCT and had available pretransplant MRD status by next-generation flow cytometry. The cohort was divided into pretransplant MRD-negative (MRDneg) and MRD-positive (MRDpos) groups. RESULTS: A total of 733 patients were included in our analysis; 425 were MRDneg and 308 MRDpos at autoHCT. In the MRDpos group, more patients had high-risk cytogenetic abnormalities (48% vs. 38%, respectively; p = .025), whereas fewer patients achieved ≥CR before autoHCT (14% vs. 40%; p < .001). At day 100 after autoHCT, 37% of the MRDpos versus 71% of the MRDneg achieved ≥CR, and at best posttransplant response 65% versus 88% achieved ≥CR, respectively. After a median follow-up of 27.6 months (range, 0.7-82.3), the median PFS was significantly shorter for patients in the MRDpos group compared to the MRDneg group: 48.2 months (95% confidence interval [CI], 0.3-80.5) versus 80.1 months (95% CI, 0.5-80.1), respectively (p < .001). There was no significant difference in overall survival between the two groups (p = .41). Pretransplant MRDpos status was predictive of shorter PFS in multivariate analysis (hazard ratio, 1.80; 95% CI, 1.31-2.46; p < .001). The impact of pretransplant MRD status was retained in most of the examined subgroups. CONCLUSIONS: In patients achieving ≥VGPR to induction, pretransplant MRDpos status was associated with a lower CR rate after autoHCT and a shorter PFS.

Characteristics and outcomes of children, adolescents and young adults with relapsed/refractory non-hodgkin lymphoma undergoing autologous stem cell transplant.

BACKGROUND: There is paucity of data regarding outcomes of children, adolescents and young adults (CAYA) patients with non-Hodgkin lymphoma (NHL) undergoing autologous stem cell transplantation (ASCT). METHODS: Patients aged 0-39 years undergoing first ASCT for NHL at MD Anderson Cancer Center between 2000 and 2020 were analyzed. RESULTS: Two hundred twenty-one patients were included in the analysis, 129 (58%) were male and the median age was 32 (range 6-39) years. The most common histological subtypes were diffuse large B cell lymphoma (DLBCL) (44%), T-NHL (19%) and primary mediastinal B-Cell lymphoma (PMBCL) (19%). Younger patients (age ≤ 25) had lower incidence of DLBCL and higher incidence of PMBCL and T-NHL compared to older patients (age > 25) (P = 0.02). None of the younger patients had double hit (DH)/double expressor (DE) DLBCL, compared to 14 patients in the older age group (18%, P = 0.07). Considering the three main aggressive NHL subtypes (DLBCL, PMBCL and T-NHL), younger patients had numerically better 15-year post-transplant progression free survival (PFS) (67% vs. 54%) and overall survival (OS) (71% vs. 62%) compared to older patients, yet these differences did not reach statistical significance (P = 0.19 and P = 0.24, respectively). In multivariate analysis, not achieving a CR prior to ASCT was independently predictive of worse PFS [partial remission (PR) (HR, 3.9); stable disease (SD) (HR, 18.0), P = 0.03] and of worse OS [PR (HR, 4.2), SD (HR, 6.5) and progressive disease (HR, 4.7), P < 0.0001]. DH/DE status was an independent adverse predictor of PFS in multivariate analysis (HR 5.8, p = 0.03). Ten patients (4.5%) (all aged > 25 years) developed second primary malignancies (SPM), at a median of 34.4 (range, 1.0-196.6) months after ASCT, and SPM was the cause of death in five (50%) of them. CONCLUSIONS: CAYA NHL patients aged ≤ 25 years who received ASCT presented a distinct NHL histology as compared to older CAYA patients, and none in this younger age group had DH/DE DLBCL. We observed a trend towards improved PFS and OS in younger patients. Disease status at ASCT was predictive of both PFS and OS. DH/DE status was an adverse predictor of PFS.

Absence of lobular carcinoma in situ is a poor prognostic marker in invasive lobular carcinoma.

AIM: To determine if the outcomes of patients with ILC co-occurring with LCIS are similar to pure ILC and if the presence of LCIS is a prognostic factor for ILC. METHODS: In an observational, population-based investigation using data from the MD Anderson breast cancer prospectively collected electronic database, we analysed patients with a diagnosis of stage I-III ILC. Patients were divided into two groups: those with ILC with co-occurring ipsilateral LCIS (ILC + LCIS) and those with pure ILC without a histologically detected co-occurring ipsilateral LCIS (ILC alone). We obtained data on demographics, pathologic tumour size (pT), pathologic lymph node (pN) involvement, estrogen (ER), progesterone (PR) receptor status, HER2 status, Ki67, treatment received, distant recurrence-free and overall survival (DRFS, OS). RESULTS: We identified 4217 patients with stage I-III ILC treated at MD Anderson between 1966 and 2021. 45% of cases (n = 1881) had co-existing LCIS. Statistically and numerically, ILC alone tended to associate with pT4 and pN3 stage (P < 0.001), ER/PR negativity (P = 0.0002), HER2 positivity (P = 0.010), higher Ki67 (P = 0.005), non-classical ILC subtype (P = 0.04) and more exposure to neoadjuvant chemotherapy (P = 0.0002) compared to the ILC + LCIS group. The median follow-up time was 6.5 years. Patients with ILC + LCIS had better median DRFS (16.8 versus 10.1 years, Hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.50-0.60, P < 0.0001) and better median OS (18.9 versus 13.7 years, HR 0.62, 95% CI 0.56-0.69; P < 0.0001). Multivariate analysis showed the absence of LCIS to be an independent poor prognostic factor along with a higher pT stage and higher pN stage for DRFS and OS. CONCLUSION: The findings of this study suggests that the absence of ipsilateral LCIS with ILC is an independent poor prognostic factor and that further studies are warranted to understand this phenomenon.

PRAME and LEF1 in Combined Deep Penetrating Nevus and Combined Blue Nevus: Utility and Pitfalls.

ABSTRACT: Deep penetrating nevi (DPN), particularly those showing combined features, or combined deep penetrating nevi (CDPN), may show histopathological resemblance to blue nevus (BN) and melanoma. Preferentially Expressed Antigen in MElanoma (PRAME) is a marker that helps distinguish melanoma from benign melanocytic lesions. Lymphoid enhancer-binding factor 1 (LEF1) has been proposed to be used in conjunction with ß-catenin for diagnosis of DPN. The immunohistochemical expression of PRAME and LEF1 was evaluated in 10 DPN (including 6 CDPN and 2 DPN-like proliferations with atypical features), 16 BN (including combined and cellular BN), and 2 melanomas with features of DPN or BN. PRAME was negative in most DPN (n = 10/10, n = 9/10, one case with discrepancy between readers) and all BN (n = 16/16), while the 2 melanomas included were positive (n = 2/2). All DPN were positive for LEF1 (n = 9/9) while only a subset of BN were positive (n = 6/16, P = 0.0028; n = 5/16, P = 0.001, per both readers). LEF1 seemed to be easier to interpret than ß-catenin because of its nuclear pattern of expression. The expression of LEF1 in the regular nevus component of combined BN presents a potential pitfall in practice because it may lead to misinterpretation of LEF1 as positive in the BN component of the lesion. However, a subset (approximately one-third) of combined BN seemed to show true LEF1 expression. Taking into account pitfalls in interpretation, the combinatorial panel of PRAME and LEF1, in addition to conventional histopathological features, may be useful to distinguish CDPN from combined BN and other benign and malignant mimics.

Analysis of Technical Repeat Studies in Screening Mammography.

Objective: To identify causes of technical repeats, determine whether differences exist between mobile and fixed mammography units, and evaluate the rate of improvement on repeat imaging. Methods: IRB approval was obtained for retrospective review of Enhancing Quality Using the Inspection Program (EQUIP) logs of screening mammography technical repeats performed from March 2017 to December 2018 at a hospital breast imaging center and from April 2017 to December 2018 on mobile mammography units. Frequency tables and Fisher's exact tests were used for statistical analysis. Results: Technical deficiencies were reported in 483 cases and reviewed by two or three auditors. Auditors identified no technical deficiencies in 31 cases, which were excluded. The remaining 452 cases were assigned a technical recall category: motion, positioning/excluded tissue, skin folds, artifacts, undercompression, or contrast (under/overexposure). Motion was the most common technical recall category (253/452, 56.0%). Positioning/excluded tissue was the second most common reason (150/452, 33.2%). Statistically significant differences in technical deficiencies were identified between mammograms performed on mobile versus fixed mammography units for motion (94/143, 65.7% vs 159/309, 51.5%, respectively, P = 0.0058), skin folds (16/143, 11.2% vs 15/309, 4.8%, respectively, P = 0.02), and positioning/excluded tissue (30/143, 21% vs 120/309, 38.8%, respectively, P = 0.00016). Most recalls improved with repeat imaging (auditor 1: 451/483, 93% and auditor 2: 387/483, 80%). Conclusion: Motion and positioning/excluded tissue are the most common reasons for screening mammography technical recalls. The reasons for technical recall differ between patients imaged on mobile and fixed mammography units, likely because of differences in each location's patient population.

Survival Outcomes in Patients With Hormone Receptor-Positive Metastatic Breast Cancer With Low or No ERBB2 Expression Treated With Targeted Therapies Plus Endocrine Therapy.

Importance: Approximately 45% to 60% of hormone receptor (HR)-positive metastatic breast cancer (mBC) shows a low-level expression of ERBB2. Low ERBB2 expression is defined as ERBB2 immunohistochemical expression of 1+ or 2+ with a negative ERBB2 amplification by in situ hybridization. The efficacy of the antibody-drug conjugate trastuzumab deruxtecan in low-ERBB2, HR-positive mBC has been practice changing. However, there are conflicting data on the prognostic value of low ERBB2 expression in HR-positive mBC and whether low ERBB2 expression is a separate entity. Objective: To examine whether outcomes differ by immunohistochemical analysis for patients with HR-positive mBC with low ERBB2 expression vs those without ERBB2 expression when treated with targeted therapy (TT) plus endocrine therapy (ET). Design, Setting, and Participants: This single-institution cohort study used prospectively collected electronic data from the MD Anderson Cancer Center for patients with a diagnosis of HR-positive mBC treated with ET in combination with a TT (cyclin-dependent kinase 4/6 inhibitors [CDK4/6is], everolimus, or alpelisib) between January 1, 2010, and December 31, 2021. Exposure: HR-positive mBC with either low or no ERBB2 expression. Main Outcome and Measures: The main outcomes were median progression-free survival and overall survival. Data on demographic characteristics, estrogen and progesterone receptor status, ERBB2 status, histologic subtype, menopausal status, treatment duration, and survival status were collected. Results: A total of 1585 women (median [range] age, 51 [24-92] years) were included in the study. Of these women, 1013 (63.9%) had mBC with low ERBB2 expression and 572 (36.1%) had mBC with no ERBB2 expression. A total of 1084 (68.4%) were treated with a CDK4/6i (912 patients were treated in the first line and 172 were treated in the second line); 475 (30.0%) received everolimus and 26 (1.6%) received alpelisib. In the patients who received a first-line CDK4/6i, 618 (67.8%) received an aromatase inhibitor as their ET backbone and 265 (29.1%) received fulvestrant. With a median follow-up time of 17.9 months (range, 1-111 months), progression-free survival and overall survival were not statistically different between the patients with low and no ERBB2 expression treated with TT plus ET. Conclusions and Relevance: In this cohort study of patients with HR-positive mBC treated with TT plus ET, low ERBB2 expression did not have a significant association with prognosis.

Clinicopathologic Features of Therapy-Related Myeloid Neoplasms in Patients with Myeloma in the Era of Novel Therapies.

The development of therapy-related myeloid neoplasms (t-MN) is a rare complication that can occur in myeloma patients treated primarily with novel therapies. To better understand t-MNs in this context, we reviewed 66 such patients and compared them with a control group of patients who developed t-MN after cytotoxic therapies for other malignancies. The study group included 50 men and 16 women, with a median age of 68 years (range, 48-86 years). Therapies included proteasome inhibitors, immunomodulatory agents, and high-dose melphalan-based autologous stem cell transplantation (HDM-ASCT) in 64 (97%), 65 (98.5%), and 64 (97%) patients, respectively; 29 (43.9%) patients were exposed to other cytotoxic drugs besides HDM. The latency interval from therapy to t-MN was 4.9 years (range, 0.6-21.9 years). Patients who received HDM-ASCT in addition to other cytotoxic therapies had a longer latency period to t-MN compared with patients who only received HDM-ASCT (6.1 vs 4.7 years, P = .009). Notably, 11 patients developed t-MN within 2 years. Therapy-related myelodysplastic syndrome was the most common type of neoplasm (n = 60), followed by therapy-related acute myeloid leukemia (n = 4) and myelodysplastic syndrome/myeloproliferative neoplasm (n = 2). The most common cytogenetic aberrations included complex karyotypes (48.5%), del7q/-7 (43.9%), and/or del5q/-5 (40.9%). The most frequent molecular alteration was TP53 mutation, in 43 (67.2%) patients and the sole mutation in 20 patients. Other mutations included DNMT3A, 26.6%; TET2, 14.1%; RUNX1, 10.9%; ASXL1, 7.8%; and U2AF1, 7.8%. Other mutations in less than 5% of cases included SRSF2, EZH2, STAG2, NRAS, SETBP, SF3B1, SF3A1, and ASXL2. After a median follow-up of 15.3 months, 18 patients were alive and 48 died. The median overall survival after the diagnosis of t-MN in the study group was 18.4 months. Although the overall features are comparable to the control group, the short interval to t-MN (<2 years) underscores the unique vulnerable status of myeloma patients.

Physician Perspectives on Telemedicine in Radiation Oncology.

Purpose: Telemedicine enthusiasm and uptake in radiation oncology rapidly increased during the COVID-19 pandemic, but it is unclear if and how telemedicine should be used after the COVID-19 public health emergency ends is unclear. Herein, we report on our institution's provider experience after the mature adoption of telemedicine. Methods and Materials: We distributed a survey to all radiation oncology attending physicians at our institution in October 2021 to assess satisfaction, facilitators, and barriers to telemedicine implementation. We performed quantitative and qualitative analyses to characterize satisfaction and identify influencing factors whether telemedicine is employed. We calculated the average proportion of visits that providers expected to be appropriately performed with telemedicine for each disease site and visit type. Results: A total of 60 of the 82 eligible radiation oncologists (73%) responded to the survey, of whom 78% were satisfied with telemedicine in the radiation oncology department and 83% wished to continue offering video visits after the COVID-19 public health emergency ends. Common patient factors influencing whether physicians offer telemedicine include the patient's travel burden, patient preferences, and whether a physical examination is required. Approximately 20% of new consultations and 50% of weekly management visits were estimated to be appropriate for telemedicine. The central nervous system/pediatrics and thoracic faculty considered telemedicine appropriate for the greatest proportion of new consultations, and 93% of respondents felt comfortable determining whether telemedicine was appropriate. Conclusions: Surveyed radiation oncologists were satisfied with telemedicine in their practice, and wished to continue offering video visits in the future. Our data suggest that payers should continue to support this patient-centered technology.

Palliative Rehabilitation in Acute Inpatient Rehabilitation: Prognostic Factors and Functional Outcomes in Patients with Cancer.

BACKGROUND: Prognosis has a vital role for patients with cancer undergoing palliative rehabilitation in acute inpatient rehabilitation. This study aimed to identify the proportion of patients who survived <2 months after discharge and the associated prognostic factors. MATERIALS AND METHODS: This was a secondary analysis of a retrospective study of 163 consecutive patients admitted to acute inpatient rehabilitation from September 1, 2017, to February 28, 2018 at a cancer center. Baseline demographics, clinical characteristics, and putative prognostic factors, including Activity Measure for Post-Acute Care (AM-PAC) functional scores, were analyzed. RESULTS: Of 163 patients, 27 (17%; 95% CI, 11-23) died within 60 days of discharge. These patients were more likely to be male (OR = 2.83; 95% CI, 1.16-6.92; P = .017); have longer hospital stays (OR = 1.02; 95% CI, 1-1.04; P = .015); receive ≥ weekly packed red blood cell (OR = 5.31; 95% CI, 1.86-15.1; P = .003) or platelet (OR = 4.57; 95% CI, 1.44-14.5; P = .014) transfusions; have lower AM-PAC daily activity scores upon discharge (OR = 0.90; 95% CI, 0.83-0.97; P = .006); and have lower AM-PAC basic mobility scores upon admission (OR = 0.91; 95% CI, 0.85-0.98; P = .018) and discharge (OR = 0.88; 95% CI, 0.82-0.94; P = <.001). Multivariate analysis showed that the male sex (OR = 2.71; 95% CI, 1.03-7.15; P = .037) was independently associated with ≤2 months survival, whereas AM-PAC basic mobility score at admission of >33 (OR = 0.24, 95% CI, 0.07-0.79; P = .022) was less likely. CONCLUSION: Approximately 1 in 6 patients who completed acute inpatient rehabilitation died within 2 months of discharge, had poorer baseline functional status, and were less likely to regain function than those who lived longer.

Histology-based survival outcomes in hormone receptor-positive metastatic breast cancer treated with targeted therapies.

The addition of targeted therapies (TT) to endocrine therapy (ET) has improved the outcomes of patients with HR-positive, HER2-negative metastatic breast cancer (mBC). However, it is unknown whether patients with invasive lobular carcinoma (ILC) or mixed invasive ductal and lobular carcinoma (mixed) histologies experience the same magnitude of benefit from this therapy as those with invasive ductal carcinoma (IDC). We aim to determine whether patients with IDC, ILC, and mixed HR+/HER2- mBC derive similar benefit from the addition of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is), mammalian target of rapamycin inhibitor (mTORi), and phosphoinositide 3-kinase inhibitor (PI3Ki) to ET in HR+/HER2- mBC. We conducted an observational, population-based investigation using data from the MD Anderson prospectively collected database. We conducted a histology-based analysis of progression-free survival (PFS) and overall survival (OS) durations in 3784 patients with HR+/HER2- mBC who were treated with TT plus ET between January 1, 2010, and December 31, 2021. Out of the 3784 patients, 2975 were included in the final analysis. Of these, 2249 received CDK4/6is (81% IDC, 15% ILC, and 4% mixed), 1027 received everolimus (82% IDC, 14% ILC, and 4% mixed) and 49 received alpelisib (81% IDC and 19% ILC). The addition of targeted therapy to ET did not result in statistically significant differences in PFS or OS duration among patients with IDC, ILC, and mixed HR+/HER2- mBC. We concluded that for patients with HR+/HER2- mBC, the addition of TT to ET leads to a similar magnitude of benefit, irrespective of histology.

Hypofractionated, 3-week, preoperative radiotherapy for patients with soft tissue sarcomas (HYPORT-STS): a single-centre, open-label, single-arm, phase 2 trial.

BACKGROUND: The standard preoperative radiotherapy regimen of 50 Gy delivered in 25 fractions for 5 weeks for soft tissue sarcomas results in excellent local control, with major wound complications occurring in approximately 35% of patients. We aimed to investigate the safety of a moderately hypofractionated, shorter regimen of radiotherapy, which could be more convenient for patients. METHODS: This single-centre, open-label, single-arm, phase 2 trial (HYPORT-STS) was done at a single tertiary cancer care centre (MD Anderson Cancer Center, Houston, TX, USA). We administered preoperative radiotherapy to a dose of 42·75 Gy in 15 fractions of 2·85 Gy/day for 3 weeks (five fractions per week) to adults (aged ≥18 years) with non-metastatic soft tissue sarcomas of the extremities or superficial trunk and an Eastern Cooperative Oncology Group performance status of 0-3. The primary endpoint was a major wound complication occurring within 120 days of surgery. Major wound complications were defined as those requiring a secondary operation, or operations, under general or regional anaesthesia for wound treatment; readmission to the hospital for wound care; invasive procedures for wound care; deep wound packing to an area of wound measuring at least 2 cm in length; prolonged dressing changes; repeat surgery for revision of a split thickness skin graft; or wet dressings for longer than 4 weeks. We analysed our primary outcome and safety in all patients who enrolled. We monitored safety using a Bayesian, one-arm, time-to-event stopping rule simulator comparing the rate of major wound complications at 120 days post-surgery among study participants with the historical rate of 35%. This trial is registered with ClinicalTrials.gov, NCT03819985, recruitment is complete, and follow-up continues. FINDINGS: Between Dec 18, 2018, and Jan 6, 2021, we assessed 157 patients for eligibility, of whom 120 were enrolled and received hypofractionated preoperative radiotherapy. At no time did the stopping rule computation indicate that the trial should be stopped early for lack of safety. Median postoperative follow-up was 24 months (IQR 17-30). Of 120 patients, 37 (31%, 95% CI 24-40) developed a major wound complication at a median time of 37 days (IQR 25-59) after surgery. No patient had acute radiation toxicity (during radiotherapy or within 4 weeks of the radiotherapy end date) of grade 3 or worse (Common Terminology Criteria for Adverse Events [CTCAE] version 4.0) or an on-treatment serious adverse event. Four (3%) of 115 patients had late radiation toxicity (≥6 months post-surgery) of at least grade 3 (CTCAE or Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer Late Radiation Morbidity Scoring Scheme): femur fractures (n=2), lymphoedema (n=1), and skin ulceration (n=1). There were no treatment-related deaths. INTERPRETATION: Moderately hypofractionated preoperative radiotherapy delivered to patients with soft tissue sarcomas was safe and could therefore be a more convenient alternative to conventionally fractionated radiotherapy. Patients can be counselled about these results and potentially offered this regimen, particularly if it facilitates care at a sarcoma specialty centre. Results on long-term oncological, late toxicity, and functional outcomes are awaited. FUNDING: The National Cancer Institute.

Sensitivity and Specificity for Skin Cancer Diagnosis in Primary Care Providers: a Systematic Literature Review and Meta-analysis of Educational Interventions and Diagnostic Algorithms.

BACKGROUND: In areas without convenient access to dermatology care, primary care providers (PCPs) serve as an important patient resource for early skin cancer detection. To determine the most effective strategy for skin cancer detection training in PCPs, we conducted a systematic review of educational interventions and performed a meta-analysis on sensitivity and specificity outcomes in PCPs. OBJECTIVES: To summarize data on skin cancer sensitivity and specificity outcomes for PCP-targeted training programs and diagnostic algorithms. Our PCP cohort included practicing physicians, trainee physicians, and advanced practice practitioners. METHODS: A literature search was performed in MEDLINE, Embase, Web of Science, and the Cochrane Library for relevant English-language articles published worldwide from 2000 onward. Results were screened for eligibility, and overlapping datasets were reconciled. Data extracted included the educational intervention, diagnostic algorithm, and outcomes of interest (sensitivity and specificity). Outcomes were pooled across interventions that taught the same diagnostic algorithm. A bivariate model was fit to compare different interventions/algorithms. This review followed the PRISMA guidelines. RESULTS: In total, 21 articles were included in this review, encompassing over 58,610 assessments of skin lesions by about 1529 participants worldwide. Training programs that implemented the triage-amalgamated dermoscopic algorithm (TADA) demonstrated high pooled sensitivity (91.7%) and high pooled specificity (81.4%) among PCPs. CONCLUSIONS AND RELEVANCE: Overall, this systematic review and meta-analysis showed that dermoscopy training in PCPs was generally associated with gains in skin cancer sensitivity without loss of specificity. Clinically, this correlates with fewer skin cancers overlooked by PCPs and fewer excisions of benign lesions.

Clonal Hematopoiesis Is Associated with Increased Risk of Severe Neurotoxicity in Axicabtagene Ciloleucel Therapy of Large B-Cell Lymphoma.

To explore the role of clonal hematopoiesis (CH) in chimeric antigen receptor (CAR) T-cell therapy outcomes, we performed targeted deep sequencing on buffy coats collected during the 21 days before lymphodepleting chemotherapy from 114 large B-cell lymphoma patients treated with anti-CD19 CAR T cells. We detected CH in 42 (36.8%) pretreatment samples, most frequently in PPM1D (19/114) and TP53 (13/114) genes. Grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS) incidence was higher in CH-positive patients than CH-negative patients (45.2% vs. 25.0%, P = 0.038). Higher toxicities with CH were primarily associated with DNMT3A, TET2, and ASXL1 genes (DTA mutations). Grade ≥3 ICANS (58.9% vs. 25%, P = 0.02) and ≥3 cytokine release syndrome (17.7% vs. 4.2%, P = 0.08) incidences were higher in DTA-positive than in CH-negative patients. The estimated 24-month cumulative incidence of therapy-related myeloid neoplasms after CAR T-cell therapy was higher in CH-positive than CH-negative patients [19% (95% CI, 5.5-38.7) vs. 4.2% (95% CI, 0.3-18.4), P = 0.028]. SIGNIFICANCE: Our study reveals that CH mutations, especially those associated with inflammation (DNMT3A, TET2, and ASXL1), are associated with severe-grade neurotoxicities in lymphoma patients receiving anti-CD19 CAR T-cell therapy. Further studies to investigate the mechanisms and interventions to improve toxicities in the context of CH are warranted. See related content by Uslu and June, p. 382. This article is highlighted in the In This Issue feature, p. 369.

Landscape of NOTCH1 mutations and co-occurring biomarker alterations in chronic lymphocytic leukemia.

NOTCH1 is one of the most frequently mutated genes in chronic lymphocytic leukemia and has emerged as a marker of poor prognosis. In addition to coding NOTCH1 mutations involving exon 34, non-coding NOTCH1 mutations involving the 3' UTR have been described in a limited number of chronic lymphocytic leukemia (CLL) patients and were associated with adverse outcomes. In this study, 1574 CLL patients were assessed using targeted sequencing with a 29 gene panel and the results were correlated with prognostic characteristics. NOTCH1 mutations were detected in 252 (16%) patients, including both coding (220/252, 14%), non-coding (24/252, 1.5%) and a mixture of coding and non-coding (8/252, 0.5%) NOTCH1 mutations. NOTCH1 mutations were more commonly seen in patients with unmutated IGHV, ZAP70 positivity and CD38 positivity. Mixed NOTCH1 mutations were also more commonly seen in patients with unmutated IGHV and ZAP70. There was no association between mixed NOTCH1 mutations and CD38 expression in this cohort. The most common cytogenetic alteration detected in patients with coding and mixed NOTCH1 mutations was trisomy 12, whereas del13q was the most common cytogenetic alteration detected in patients with non-coding NOTCH1 mutation. The most common gene mutations co-occurring with coding NOTCH1 mutations were: TP53 (23.2%), SF3B1 (16.4%) and SPEN (10%). The most common gene mutations co-occurring with non-coding NOTCH1 mutations were: SF3B1 11(34.4%), ATM 4(12.5%) and TP53 4(12.5%). CLL patients with clonal coding and non-coding NOTCH1 mutations had a significantly shorter time-to-first treatment than patients with wild type NOTCH1 (4.3 vs 10.0 years and 0.9 vs 10.0 years respectively, p < 0.05). Similarly, CLL patients with subclonal coding NOTCH1 mutations had a significantly shorter time-to-first treatment than patients with wild type NOTCH1 (5.6 vs 10.0 years, p < 0.05). CLL patients with subclonal non-coding NOTCH1 mutations also had a shorter time-to-first treatment than patients with wild type NOTCH1 mutations, however, the difference was not significant (5.1 vs 10.0 years, p = 0.15). These data confirm that both coding and non-coding NOTCH1 mutations carry adverse prognostic impact and need to be included in sequencing assays performed for the prognostic workup of CLL patients.

Oncology Patients Who Develop Transfusion-Associated Circulatory Overload: An Observational Study.

BACKGROUND: Transfusion-associated circulatory overload (TACO) is a largely preventable transfusion complication that results in significant morbidity and mortality. Cancers, related treatments, and comorbidities are among the factors that can predispose patients to TACO, but currently there are limited data on this topic in the literature. METHODS: We collected data retrospectively from the electronic health records of 93 adult patients with cancer who met Centers for Disease Control and Prevention (CDC) criteria for TACO from July 1, 2019, through October 31, 2020. The parameters we studied included demographics, comorbidities, treatment modalities, transfusion practices, and outcomes. We summarized data by means and ranges for continuous variables, and proportions for categorical variables. RESULTS: During the study period, the incidence of TACO among oncology patients was 0.84 per 1000 transfusions (95% CI, 0.68-1.02), representing 6.6% of all reactions. This percentage is high, compared with 1%-6% among other populations. Unique characteristics such as hematology malignancy (75.3%), receipt of cardiotoxic chemotherapy (87.1%), pneumonia (57.0%), preexisting oxygen use (59.1%), dyspnea (62.4%), hypertension (55.9%), renal insufficiency (46.2%), daily use of corticosteroids (43.0%), daily use of diuretics (40.9%), daily use of beta-blockers (36.6%), and elevated NT-proBNP (33.3%) were frequently observed in these group of oncology patients. CONCLUSIONS: Our study indicates that oncology patients have unique factors that may lead to diagnosis of TACO. Developing appropriate guidelines that apply to oncology patients, in addition to those set forth by the CDC, should be considered. Implementation by ordering healthcare providers of a tools that can predict TACO can help in early recognition and mitigation of TACO.