Glutamate decarboxylase-1 is essential for efficient acclimation of Arabidopsis thaliana to nutritional phosphorus deprivation.

Glutamate decarboxylase (GAD) is a Ca2+ -calmodulin-activated, cytosolic enzyme that produces γ-aminobutyrate (GABA) as the committed step of the GABA shunt. This pathway bypasses the 2-oxoglutarate to succinate reactions of the tricarboxylic acid (TCA) cycle. GABA also accumulates during many plant stresses. We tested the hypothesis that AtGAD1 (At5G17330) facilitates Arabidopsis acclimation to Pi deprivation. Quantitative RT-PCR and immunoblotting revealed that AtGAD1 transcript and protein expression is primarily root-specific, but inducible at lower levels in shoots of Pi-deprived (-Pi) plants. Pi deprivation reduced levels of the 2-oxoglutarate dehydrogenase (2-OGDH) cofactor thiamine diphosphate (ThDP) in shoots and roots by > 50%. Growth of -Pi atgad1 T-DNA mutants was significantly attenuated relative to wild-type plants. This was accompanied by: (i) an > 60% increase in shoot and root GABA levels of -Pi wild-type, but not atgad1 plants, and (ii) markedly elevated anthocyanin and reduced free and total Pi levels in leaves of -Pi atgad1 plants. Treatment with 10 mM GABA reversed the deleterious development of -Pi atgad1 plants. Our results indicate that AtGAD1 mediates GABA shunt upregulation during Pi deprivation. This bypass is hypothesized to circumvent ThDP-limited 2-OGDH activity to facilitate TCA cycle flux and respiration by -Pi Arabidopsis.

The Breast Cancer Screening and Timing of Breast MRI-Experience in a Genetic High-Risk Screening Clinic in a Comprehensive Cancer Center.

For women with genetic risk of breast cancer, the addition of screening breast MRI to mammography has become a standard. The order and interval of annual imaging can be variable among providers. To evaluate the clinical implications related to the timing, we conducted a chart review on a cohort of women (N = 276) with high-risk (BRCA1, BRCA2, CDH1, PTEN and TP53) and moderate high-risk (ATM and CHEK2) predisposition to breast cancer in a 48-month follow up. The estimated MRI detection rate in the entire group is 1.75% (18 per 1000 MRI tests). For the high-risk group, the estimated rate is 2.98% (30 per 1000 MRI tests). Many women discovered their genetic risk at an age much older (average age of the high-risk group was 48 years) than the age recommended to initiate enhanced screening (age 20 to 25 years). In total, 4 of the 11 primary breast cancers detected were identified by screening MRI within the first month after initial visit, which were not detected by previous mammography, suggesting the benefit of initiating MRI immediately after the discovery of genetic risk. Breast screening findings for women with Lynch syndrome and neurofibromatosis type 1 were also included in this report.

Effect of maternal dietary niacin intake on congenital anomalies: a systematic review and meta-analysis.

PURPOSE: The significance of niacin in embryonic development has clinical implications in the counseling of pregnant women and may be used to inform nutrition recommendations. This study, therefore, aims to review the associations between maternal periconceptional niacin intake and congenital anomalies. METHODS: A systematic search of Ovid MEDLINE, ClinicalTrials.gov, AMED, CENTRAL, Emcare, EMBASE, Maternity & Infant Care and Google Scholar was conducted between inception and 30 September 2020. Medical subject heading terms included "nicotinic acids" and related metabolites, "congenital anomalies" and specific types of congenital anomalies. Included studies reported the association between maternal niacin intake and congenital anomalies in their offspring and reported the measure of association. Studies involved solely the women with co-morbidities, animal, in vitro and qualitative studies were excluded. The risk of bias of included studies was assessed using the Newcastle-Ottawa Scale (NOS). A random effects-restricted maximum likelihood model was used to obtain summary estimates, and multivariable meta-regression model was used to adjust study-level covariates. RESULTS: Of 21,908 retrieved citations, 14 case-control studies including 35,743 women met the inclusion criteria. Ten studies were conducted in the U.S, three in Netherlands and one in South Africa. The meta-analysis showed that expectant mothers with an insufficient niacin intake were significantly more likely to have babies with congenital abnormalities (odds ratio 1.13, 95% confidence interval 1.02-1.24) compared to mothers with adequate niacin intake. A similar association between niacin deficiency and congenital anomalies was observed (OR 1.15, 95% CI 1.03-1.26) when sensitivity analysis was conducted by quality of the included studies. Meta-regression showed neither statistically significant impact of study size (p = 0.859) nor time of niacin assessment (p = 0.127). The overall quality of evidence used is high-thirteen studies achieved a rating of six or seven stars out of a possible nine based on the NOS. CONCLUSION: Inadequate maternal niacin intake is associated with an increased risk of congenital anomalies in the offspring. These findings may have implications in dietary counseling and use of niacin supplementation during pregnancy.

Evaluation of 2014 margin guidelines on re-excision and recurrence rates after breast conserving surgery: A multi-institution retrospective study.

INTRODUCTION: A 2014 consensus statement from the Society of Surgical Oncology and American Society for Radiation Oncology supported "no ink on tumor" as an adequate margin for breast conserving therapy (BCT). This study evaluates this statement in a multi-institution cohort. METHODS: A retrospective review of BCT cases at 3 comprehensive cancer centers was performed. Women age >18 receiving BCT for T1-2 breast cancer from 2008-2012 were included. Pre-2014, all sites considered 2 mm adequate. Estimated re-excision rates using the 2014 guidelines were calculated and factors predictive of re-excision were analyzed. RESULTS: 542 patients (545 lumpectomies) were eligible. Using a ≥2 mm margin standard, 32.8% of patients underwent re-excision compared to 14.1% after 2014 (p < 0.0001). Tumor size (p= 0.003), grade (p=0.015), and lymphovascular invasion (p=0.021) were predictive of re-excision. Patients with additional intraoperative margins excised were less likely to require reoperation (p=0.002). Local recurrence was unaffected by re-excision after mean followup of 66 months. CONCLUSIONS: The 2014 margin guidelines markedly reduce re-excision rates. There is no difference in local recurrence for patients after re-excision for a close margin versus without Powered.

Use of axillary lymph node dissection (ALND) in patients with micrometastatic breast cancer.

BACKGROUND: Sentinel lymph node (SLN) biopsy is the current prognostic tool for clinically node-negative breast cancer patients. If the SLN reveals macrometastasis, axillary lymph node dissection (ALND) is recommended. However, the use of ALND in patients with micrometastasis is debated. The objective of this study was to assess the utilization of ALND in the treatment of micrometastatic breast cancer. METHODS: An IRB approved, retrospective study of a pooled dataset of breast cancer patients with micrometastatic disease on SLN biopsy was performed. Patients diagnosed from 1999-2016 were identified via query of a single-institution National Comprehensive Cancer Network (NCCN) breast cancer database as well as a prospective tumor board. RESULTS: A total of 91 patients were diagnosed with micrometastatic nodal disease. The median age at diagnosis was 56 y (range: 31-85); median follow-up time was 47 mo (range: 0-203 mo). 42/91(46.2%) patients had ALND of which 37/42 (88.1%) were a second operation; 3/42(7.1%) patients had additional positive nodes found at ALND. 44/91 (48.4%) patients received radiation. 7/91 (7.7%) patients had a recurrence, 5/7 local, including one axillary (2.1%; patient declined ALND). CONCLUSIONS: Given that the risk of lymphedema after ALND ranges between 20%-53%, the morbidity of ALND may far exceed the likelihood of detecting further nodal involvement in women with micrometastatic disease: 7.1% in this series.

Menopausal status does not predict Oncotype DX recurrence score.

BACKGROUND: Adjuvant treatment for early stage, estrogen receptor (ER) positive invasive breast cancer has been based on prognosticators such as menopausal status. The recurrence score (RS) from the 21-gene assay Oncotype DX (ODX) is predictive of a 10-y distant recurrence in this population but is rarely applied to premenopausal patients. The relationship between menopausal status and RS was evaluated. MATERIALS AND METHODS: An institutional review board-approved retrospective review was conducted of invasive breast cancer patients with known RS. ODX eligibility was based on National Comprehensive Cancer Network guidelines or physician discretion. Perimenopausal women were classified as premenopausal for statistical analyses. Comparisons of menopausal status and RS were made using general linear regression model and the exact Wilcoxon rank-sum test. RESULTS: Menopausal status was available for 575 patients (142 premenopausal, 433 postmenopausal). Median age was 46 y for premenopausal and 62 y for postmenopausal. Median invasive tumor size was 1.5 cm for both cohorts. Mastectomy rate was higher in the premenopausal group (54.8%) than postmenopausal (42%; P = 0.0001). Premenopausal women had a higher local-regional recurrence rate (2.8% versus 0%; P = 0.0384) but distant recurrence and overall survival were not statistically different (P = 0.6808). Median ER H-score was lower in premenopausal (H-score = 270) than postmenopausal women (H-score = 280; P < 0.0001). Median RS was 16 for both premenopausal (range, 0-54) and postmenopausal (range, 0-63) women. Menopausal status as a categorical variable was not predictive of RS (P-value = 0.6780). CONCLUSIONS: Menopausal status has limited predictive power for distant recurrence. Therefore, menopausal status alone should not preclude performance of ODX in ER-positive, early stage breast cancer.

Ipsilateral nodal recurrence after axillary dissection for breast cancer.

INTRODUCTION: Level I/II axillary lymph node dissection (ALND) is the standard operation for patients with node-positive breast cancer. The objective of this study was to assess the incidence of regional nodal recurrence (RNR) after ALND performed for definitive operative treatment for primary breast cancer. MATERIALS AND METHODS: A retrospective, Institutional Review Board-approved query of our single-institution National Comprehensive Cancer Network database was performed for patients undergoing ALND who developed subsequent RNR. All patients were treated from 1999 to 2009. A detailed chart review was performed and clinical, pathologic, treatment, and outcome data were collected. RESULTS: A total of 1614 patients had an ALND for initial staging; 14/1614 (0.9%) patients had RNR. Two other patients had contralateral breast/axillary recurrences and were excluded. The mean age at diagnosis for the sample group was 52.7 y (range 34-77); mean follow-up time was 47.1 mo (range 12.6-114.6). The median number of nodes for ALND was 16 (range 8-27). The median number of positive nodes was 2.5 (range 0-7). Nine (64.3%) cases were estrogen receptor/progesterone receptor negative. Twelve (85.7%) patients had axillary recurrences, and six of 12 (50.0%) had concurrent chest wall lesions. Twelve patients (85.7%) had distant metastases; nine of 12 (75.0%) died; two were lost to follow-up. Mean time from RNR to distant recurrence was 6.0 mo (range 0-29.3 mo). CONCLUSIONS: RNR after ALND is rare but a harbinger of poor outcome. This is apparent regardless of treatment used for initial disease or recurrence. Specifically, RNR after primary ALND is related to increased risk of mortality and distant metastatic disease.

Factors affecting lymph node yield in patients undergoing axillary node dissection for primary breast cancer: a single-institution review.

BACKGROUND: A minimum of 10 level I/II axillary nodes is recommended for accurate breast cancer staging. The goal of this study was to assess the effect of neoadjuvant chemotherapy on lymph node yield at axillary lymph node dissection. METHODS: A single-institution National Comprehensive Cancer Network (NCCN) breast cancer database was queried for cases with axillary node dissection from 2000 to 2008. All dissections were performed at the same institution. Demographic, chemotherapy, and clinicopathologic data were collected. Age and body mass index at diagnosis were calculated for subset analyses. Statistical analyses used Student's t-test or analysis of variance with Tukey multiple comparison and Fisher's exact test. RESULTS: Two hundred forty patients had axillary node dissection after neoadjuvant chemotherapy; an additional 903 women with primary lymph node dissection were identified as contemporaneous control subjects. There was a far lower nodal yield in patients undergoing axillary dissection after neoadjuvant chemotherapy than those undergoing primary surgery. Patients with pathologic stage II or III disease undergoing primary surgery had more lymph nodes at axillary dissection than stage I disease. CONCLUSIONS: Age, type of breast surgery, body mass index, and clinical stage have no effect on yield of lymph nodes at axillary lymph node dissection. Neoadjuvant chemotherapy, however, is associated with a far fewer nodes at axillary dissection, and alteration of the guidelines should be considered for this population of patients.

Male breast cancer: management and follow-up recommendations.

National Comprehensive Cancer Network (NCCN) guidelines for female breast cancer treatment and surveillance are well established, but similar guidelines on male breast cancers are less recognized. As an NCCN institution, our objective was to examine practice patterns and follow-up for male breast cancer compared to established guidelines for female patients. After Institutional Review Board approval, a prospective breast database from 1990 to 2009 was queried for male patients. Medical records were examined for clinico-pathological factors and follow-up. The 5-year survival rates with 95% confidence intervals were estimated using Kaplan-Meier method and Greenwood formula. Of the 19,084 patients in the database, 73 (0.4%) were male patients; 62 had complete data. One patient had bilateral synchronous breast cancer. The median age was 68.8 years (range 29-85 years). The mean/median invasive tumor size was 2.2/1.6 cm (range 0.0-10.0 cm). All cases had mastectomy (29 with axillary node dissection, 23 with sentinel lymph node biopsy only, 11 with sentinel node biopsy followed by completion axillary dissection). Lymph node involvement occurred in 25/63 (39.7%). Based on NCCN guidelines, chemotherapy, hormonal therapy, and radiation are indicated in 34 cases, 62 cases, and 14 cases, respectively. Only 20/34 (59%) received chemotherapy, 51/62 (82%) received hormonal therapy, and 10/14 (71%) received post-mastectomy radiation. Median follow-up was 26.2 months (range: 1.6-230.9 months). The 5-year survival estimates for node positive and negative diseases were 68.5% and 87.5%, respectively (p = 0.3). Despite the rarity of male breast cancer, treatment options based on current female breast tumors produce comparable results to female breast cancer. Increased awareness and a national registry for patients could help improve outcomes and tailor treatment recommendations to the male variant.