Impact of Systemic Therapy on Fertility in Women with Early-Stage Breast Cancer.

Purpose of Review: Fertility concerns are common among young women diagnosed with breast cancer, as systemic therapy increases the risk of premature ovarian insufficiency and delays family planning. Here, we review the impact of systemic therapies, including chemotherapy, endocrine therapy, HER-2 directed therapy, PARP inhibitors, and immunotherapy, on ovarian reserve. Recent Findings: With an improved understanding of disease biology, fewer women are treated with gonadotoxic chemotherapy. There are limited data on the fertility impact of novel targeted treatments and immunotherapy, though preclinical and preliminary studies suggest an impact on fertility is possible. Notably, a recent study investigated the outcomes in women who interrupted adjuvant endocrine therapy to attempt pregnancy. Summary: Further research is needed to characterize the fertility impact of novel therapies in breast cancer. Individualized fertility counseling should be offered to all women to discuss the possible impact of therapy on ovarian reserve and options for fertility preservation and timing of pregnancy.

Significance of the pee-value: relevance of 24-hour urine studies for patients with myeloma.

International Myeloma Working Group (IMWG) response criteria require refrigerated 24-hour urine specimens for most patients. However, given that serum free light chain testing has been shown to outperform 24-hour urine immunofixation as a prognostic marker, the importance of maintaining urine testing options or requirements within each level of IMWG response criteria has not been investigated. We analyzed responses to induction therapy for all transplant-eligible patients with multiple myeloma at our institution over a 3-year period using traditional versus 'urine-free' IMWG response criteria (where references to urine were removed from the descriptions for every depth of response). Of 281 evaluable patients, responses changed for only 4% of patients (95% confidence interval 2-7%) using urine-free criteria. Our results call into question the continued requirement for 24-hour urine measurements as part of IMWG response assessments for all patients. Research into the prognostic performance of urine-free IMWG criteria is ongoing.

Daratumumab Plus Bortezomib and Dexamethasone in Newly Diagnosed Systemic Light Chain Amyloidosis.

Light chain amyloidosis (AL) is a plasma cell dyscrasia characterized by organ dysfunction, morbidity, and early mortality. Daratumumab in combination with cyclophosphamide, bortezomib, and dexamethasone is now standard frontline AL therapy; however, not all patients are candidates for this intensive regimen. Given the potency of Daratumumab, we evaluated an alternative frontline regimen: daratumumab, bortezomib, and limited-duration dexamethasone (Dara-Vd). Over a 3 year period, we treated 21 patients with Dara-Vd. At baseline, all patients had cardiac and/or renal dysfunction, including 30% of patients with Mayo stage IIIB cardiac disease. Nineteen of 21 patients (90%) achieved a hematologic response with 38% achieving a complete response. The median time to response was 11 days. Ten of 15 (67%) evaluable patients achieved a cardiac response and 7 of 9 (78%) achieved a renal response. The 1-year overall survival was 76%. In untreated systemic AL amyloidosis, Dara-Vd produces rapid and deep hematologic and organ responses. Dara-Vd was well-tolerated and efficacious, even among patients with extensive cardiac dysfunction.

Infectious complications in patients with relapsed refractory multiple myeloma after BCMA CAR T-cell therapy.

B-cell maturation antigen-targeted chimeric antigen receptor T-cell therapy (BCMA CAR-T) is an effective treatment of relapsed refractory multiple myeloma (MM). However, the pattern of infectious complications is not well elucidated. We performed a single-center retrospective analysis of infection outcomes up to 1 year after BCMA CAR-T for MM from 2018 to 2020. Fifty-five patients with MM were treated with BCMA CAR-T. Before lymphodepletion (LD), 35% of patients had severe hypogammaglobulinemia and 18% had severe lymphopenia. Most patients (68%) received bridging chemotherapy (BC) before LD. In the first month after CAR-T, 98% patients had grade 3 to 4 neutropenia. At 1 year after infusion, 76% patients had hypogammaglobulinemia. With a median follow-up of 6.0 months (95% confidence interval, 4.7-7.4), there were a total of 47 infection events in 29 (53%) patients: 40% bacterial, 53% viral, and 6% fungal. Most (92%) were mild-moderate and of the lower/upper respiratory tract system (68%). Half of the infections (53%) occurred in the first 100 days after CAR-T infusion. Although no statistically significant risk factors for infection were identified, prior lines of therapy, use of BC, recent infections, and post-CAR-T lymphopenia were identified as possible risk factors that need to be further explored. This is the largest study to date to assess infectious complications after BCMA CAR-T. Despite multiple risk factors for severe immunosuppression in this cohort, relatively few life-threatening or severe infections occurred. Further larger studies are needed to better characterize the risk factors for and occurrence of infections after BCMA CAR-T.

The Distance Between Us: the COVID-19 Pandemic's Effects on Burnout Among Resident Physicians.

Entering the second year of the COVID-19 pandemic, we reflect on how this public health crisis has amplified burnout in the medical profession. In particular, the pandemic has had a significant impact on medical residents. Recognizing trainee burnout as a side effect of the pandemic is crucial and highlights the need for programmatic change to support medical trainees. We reviewed the literature and propose multiple interventions to improve trainee well-being, targeting individual, peer-to-peer, and system levels. The pandemic has highlighted the importance of institutional support for medical trainees to prevent burnout and protect the pipeline of future physicians.

Prognostic Significance of Residual Axillary Nodal Micrometastases and Isolated Tumor Cells After Neoadjuvant Chemotherapy for Breast Cancer.

BACKGROUND: The prognostic significance of low-volume residual nodal disease following neoadjuvant chemotherapy (NAC) is unknown. METHODS: Women with cT1-4N0-1 breast cancer treated with NAC were identified from Dana-Farber/Brigham and Women's Cancer Center (DFBWCC) and the National Cancer Database (NCDB). Disease-free survival (DFS) and overall survival (OS) estimates according to pathologic nodal status were calculated using the Kaplan-Meier method, with Cox proportional hazards regression used to assess the effect of clinical variables on survival outcomes. RESULTS: Among 967 DFBWCC patients, 27 (2.8%) had residual isolated tumor cells (ITCs) and 61 (6.3%) had micrometastases. Five-year DFS was significantly worse in those with residual ITCs (73.5%) and micrometastases (74.7%) relative to those who were ypN0 following NAC (88.4%, p < 0.001). On adjusted analysis, those with residual ITCs (hazard ratio [HR] 2.4, 95% confidence interval [CI] 1.20-3.81) and micrometastases (HR 2.14, 95% CI 1.20-3.81) had increased risk of recurrence relative to ypN0 patients. Among 35,536 NCDB patients, 543 (1.5%) had ITCs and 1132 (3.2%) had micrometastases. Five-year OS estimates were significantly worse with increasing residual nodal burden: ypN0, 88.9%; ypN0[i+], 82.8%; ypN1mi, 79.5%; ypN1, 77.6% (p < 0.001). Compared with patients with ypN0 disease, NCDB patients with ITCs and micrometastases had 1.9- and 2.2-fold risk of death (p < 0.001). On subgroup analysis, the effect of low-volume residual disease on mortality was most pronounced in patients with triple-negative and human epidermal growth factor receptor 2 (HER2)-positive disease. CONCLUSIONS: Low-volume residual nodal disease following NAC is associated with poorer DFS and OS relative to those who are node negative.

Impact of Genomic Assay Testing and Clinical Factors on Chemotherapy Use After Implementation of Standardized Testing Criteria.

BACKGROUND: For clinically appropriate early-stage breast cancer patients, reflex criteria for Oncotype DX ordering ("the intervention") were implemented at our comprehensive cancer center, which reduced time-to-adjuvant chemotherapy initiation. Our objective was to evaluate Oncotype DX ordering practices and chemotherapy use before and after implementation of the intervention. MATERIALS AND METHODS: We examined medical records for 498 patients who had definitive breast cancer surgery at our center. The post-intervention cohort consisted of 232 consecutive patients who had Oncotype DX testing after reflex criteria implementation. This group was compared to a retrospective cohort of 266 patients who were diagnosed and treated prior to reflex criteria implementation, including patients who did and did not have Oncotype DX ordered. Factors associated with Oncotype DX ordering pre- and post-intervention were examined. We used multivariate logistic regression to evaluate factors associated with chemotherapy receipt among patients with Oncotype DX testing. RESULTS: The distribution of Oncotype DX scores, the proportion of those having Oncotype DX testing (28.9% vs. 34.1%) and those receiving chemotherapy (14.3% vs. 19.4%), did not significantly change between pre- and post-intervention groups. Age ≤65 years, stage II, grade 2, 1-3+ nodes, and tumor size >2 cm were associated with higher odds of Oncotype DX testing. Among patients having Oncotype DX testing, node status and Oncotype DX scores were significantly associated with chemotherapy receipt. CONCLUSION: Our criteria for reflex Oncotype DX ordering appropriately targeted patients for whom Oncotype DX would typically be ordered by providers. No significant change in the rate of Oncotype DX ordering or chemotherapy use was observed after reflex testing implementation. IMPLICATIONS FOR PRACTICE: This study demonstrates that implementing multidisciplinary consensus reflex criteria for Oncotype DX ordering maintains a stable Oncotype DX ordering rate and chemotherapy rate, mirroring what was observed in a specific clinical practice, while decreasing treatment delays due to additional testing. These reflex criteria appropriately capture patients who would likely have had Oncotype DX ordered by their providers and for whom the test results are predicted to influence management. This intervention serves as a potential model for other large integrated, multidisciplinary oncology centers to institute processes targeting patient populations most likely to benefit from genomic assay testing, while mitigating treatment delays.

Nurse-midwives' ability to diagnose acute third- and fourth-degree obstetric lacerations in western Kenya.

BACKGROUND: Obstetric fistula devastates the lives of women and is found most commonly among the poor in resource-limited settings. Unrepaired third- and fourth-degree perineal lacerations have been shown to be the source of approximately one-third of the fistula burden in fistula camps in Kenya. In this study, we assessed potential barriers to accurate identification by Kenyan nurse-midwives of these complex perineal lacerations in postpartum women. METHODS: Nurse-midwife trainers from each of the seven sub-counties of Siaya County, Kenya were assessed in their ability to accurately identify obstetric lacerations and anatomical structures of the perineum, using a pictorial assessment tool. Referral pathways, follow-up mechanisms, and barriers to assessing obstetric lacerations were evaluated. RESULTS: Twenty-two nurse-midwife trainers were assessed. Four of the 22 (18.2%) reported ever receiving formal training on evaluating third- and fourth-degree obstetric lacerations, and 20 of 22 (91%) reported health-system challenges to adequately completing their examination of the perineum at delivery. Twenty-one percent of third- and fourth-degree obstetric lacerations in the pictorial assessment were incorrectly identified as first- or second-degree lacerations. CONCLUSION: County nurse-midwife trainers in Siaya, Kenya, experience inadequate training, equipment, staffing, time, and knowledge as barriers to adequate diagnosis and repair of third- and fourth-degree perineal tears.

Implementation of Surgeon-Initiated Gene Expression Profile Testing (Onco type DX) Among Patients With Early-Stage Breast Cancer to Reduce Delays in Chemotherapy Initiation.

PURPOSE: Delays to adjuvant chemotherapy initiation in breast cancer may adversely affect clinical outcomes and patient satisfaction. We previously identified an association between genomic testing (Onco type DX) and delayed chemotherapy initiation. We sought to reduce the interval between surgery and adjuvant chemotherapy initiation by developing standardized criteria and workflows for Onco type DX testing. METHODS: Criteria for surgeon-initiated reflex Onco type DX testing, workflows for communication between surgeons and medical oncologists, and a streamlined process for receiving and processing Onco type DX requests in pathology were established by multidisciplinary consensus. Criteria for surgeon-initiated testing included patients ≤ 65 years old with T1cN0 (grade 2 or 3), T2N0 (grade 1 or 2), or T1/T2N1 (grade 1 or 2) breast cancer on final surgical pathology. Medical oncologists could elect to initiate Onco type testing for cases falling outside the criteria. We then examined 720 consecutive patients with breast cancer who underwent Onco type DX testing postoperatively between January 1, 2014 and November 28, 2016 and measured intervals between date of surgery, Onco type DX order date, result received date, and chemotherapy initiation date (if applicable) before and after intervention implementation. RESULTS: The introduction of standardized criteria and workflows reduced time between surgery and Onco type DX ordering, and time from surgery to receipt of result, by 7.3 days ( P < .001) and 6.3 days ( P < .001), respectively. The mean number of days between surgery and initiation of chemotherapy was also reduced by 6.4 days ( P = .004). CONCLUSION: Developing consensus on Onco type DX testing criteria and implementing streamlined workflows has led to clinically significant reductions in wait times to chemotherapy decision making and initiation.

Distinct Roles for Matrix Metalloproteinases 2 and 9 in Embryonic Hematopoietic Stem Cell Emergence, Migration, and Niche Colonization.

Hematopoietic stem/progenitor cells (HSPCs) are formed during ontogeny from hemogenic endothelium in the ventral wall of the dorsal aorta (VDA). Critically, the cellular mechanism(s) allowing HSPC egress and migration to secondary niches are incompletely understood. Matrix metalloproteinases (MMPs) are inflammation-responsive proteins that regulate extracellular matrix (ECM) remodeling, cellular interactions, and signaling. Here, inhibition of vascular-associated Mmp2 function caused accumulation of fibronectin-rich ECM, retention of runx1/cmyb+ HSPCs in the VDA, and delayed caudal hematopoietic tissue (CHT) colonization; these defects were absent in fibronectin mutants, indicating that Mmp2 facilitates endothelial-to-hematopoietic transition via ECM remodeling. In contrast, Mmp9 was dispensable for HSPC budding, being instead required for proper colonization of secondary niches. Significantly, these migration defects were mimicked by overexpression and blocked by knockdown of C-X-C motif chemokine-12 (cxcl12), suggesting that Mmp9 controls CHT homeostasis through chemokine regulation. Our findings indicate Mmp2 and Mmp9 play distinct but complementary roles in developmental HSPC production and migration.