Development of the Binocular Circuit.

Seeing in three dimensions is a major property of the visual system in mammals. The circuit underlying this property begins in the retina, from which retinal ganglion cells (RGCs) extend to the same or opposite side of the brain. RGC axons decussate to form the optic chiasm, then grow to targets in the thalamus and midbrain, where they synapse with neurons that project to the visual cortex. Here we review the cellular and molecular mechanisms of RGC axonal growth cone guidance across or away from the midline via receptors to cues in the midline environment. We present new views on the specification of ipsi- and contralateral RGC subpopulations and factors implementing their organization in the optic tract and termination in subregions of their targets. Lastly, we describe the functional and behavioral aspects of binocular vision, focusing on the mouse, and discuss recent discoveries in the evolution of the binocular circuit.

The Role of the Medial Prefrontal Cortex in Spatial Margin of Safety Calculations.

Naturalistic observations show that animals pre-empt danger by moving to locations that increase their success in avoiding future threats. To test this in humans, we created a spatial margin of safety (MOS) decision task that quantifies pre-emptive avoidance by measuring the distance subjects place themselves to safety when facing different threats whose attack locations vary in predictability. Behavioral results show that human participants place themselves closer to safe locations when facing threats that attack in spatial locations with more outliers. Using both univariate and multivariate pattern analysis (MVPA) on fMRI data collected during a 2 h session on participants of both sexes, we demonstrate a dissociable role for the vmPFC in MOS-related decision-making. MVPA results revealed that the posterior vmPFC encoded for more unpredictable threats with univariate analyses showing a functional coupling with the amygdala and hippocampus. Conversely, the anterior vmPFC was more active for the more predictable attacks and showed coupling with the striatum. Our findings converge in showing that during pre-emptive danger, the anterior vmPFC may provide a safety signal, possibly via foreseeable outcomes, while the posterior vmPFC drives unpredictable danger signals.

Suppressing a ß-1,3-glucanase gene expression increases the seed and fibre yield in cotton.

Seeds are initiated from the carpel margin meristem (CMM) and high seed yield is top one of breeding objectives for many crops. ß-1,3-glucanases play various roles in plant growth and developmental processes; however, whether it participates in CMM development and seed formation remains largely unknown. Here, we identified a ß-1,3-glucanase gene (GLU19) as a determinant of CMM callose deposition and seed yield in cotton. GLU19 was differentially expressed in carpel tissues between Gossypium barbadense (Gb) and Gossypium hirsutum (Gh). Based on resequencing data, one interspecies-specific InDel in the promoter of GLU19 was further detected. The InDel was involved in the binding site of the CRABS CLAW (CRC) transcription factor, a regulator of carpel development. We found that the CRC binding affinity to the GLU19 promoter of G. barbadense was higher than that of G. hirsutum. Since G. barbadense yields fewer seeds than G. hirsutum, we speculated that stronger CRC binding to the GLU19 promoter activated higher expression of GLU19 which in turn suppressed seed production. Consistent with this hypothesis was that the overexpression of GhGLU19 caused reduced seed number, boll weight and less callose formation in CMM. Conversely, GhGLU19-knockdown (GhGLU19-KD) cotton led to the opposite phenotypes. By crossing GhGLU19-KD lines with several G. hirsutum and G. barbadense cotton accessions, all F1 and F2 plants carrying GhGLU19-KD transgenic loci exhibited higher seed yield than control plants without the locus. The increased seed effect was also found in the down-regulation of Arabidopsis orthologs lines, indicating that this engineering strategy may improve the seed yield in other crops.

An enhancer trap system to track developmental dynamics in Marchantia polymorpha.

A combination of streamlined genetics, experimental tractability and relative morphological simplicity compared to vascular plants makes the liverwort Marchantia polymorpha an ideal model system for studying many aspects of plant biology. Here we describe a transformation vector combining a constitutive fluorescent membrane marker with a nuclear marker that is regulated by nearby enhancer elements and use this to produce a library of enhancer trap lines for Marchantia. Screening gemmae from these lines allowed the identification and characterization of novel marker lines, including markers for rhizoids and oil cells. The library allowed the identification of a margin tissue running around the thallus edge, highlighted during thallus development. The expression of this marker is correlated with auxin levels. We generated multiple markers for the meristematic apical notch region, which have different spatial expression patterns, reappear at different times during meristem regeneration following apical notch excision and have varying responses to auxin supplementation or inhibition. This reveals that there are proximodistal substructures within the apical notch that could not be observed otherwise. We employed our markers to study Marchantia sporeling development, observing meristem emergence as defining the protonema-to-prothallus stage transition, and subsequent production of margin tissue during the prothallus stage. Exogenous auxin treatment stalls meristem emergence at the protonema stage but does not inhibit cell division, resulting in callus-like sporelings with many rhizoids, whereas pharmacologically inhibiting auxin synthesis and transport does not prevent meristem emergence. This enhancer trap system presents a useful resource for the community and will contribute to future Marchantia research.

Impact of visual rotations on heading direction and center of mass control during steady-state gait.

Visual information is essential to navigate the environment and maintain postural stability during gait. Visual field rotations alter the perceived heading direction, resulting in gait trajectory deviations, known as visual coupling. It is unclear how center of mass (CoM) control relative to a continuously changing base of support (BoS) is adapted to facilitate visual coupling. This study aimed to characterize mediolateral (ML) balance control during visual coupling in steady-state gait. Sixteen healthy participants walked on an instrumented treadmill, naive to sinusoidal low-frequency (0.1 Hz) rotations of the virtual environment around the vertical axis. Rotations were continuous with 1) high or 2) low amplitude or were 3) periodic with 10-s intervals. Visual coupling was characterized with cross-correlations between CoM trajectory and visual rotations. Balance control was characterized with the ML margin of stability (MoSML) and by quantifying foot placement control as the relation between CoM dynamics and lateral foot placement. Visual coupling was strong on a group level (continuous low: 0.88, continuous high: 0.91, periodic: 0.95) and moderate to strong on an individual level. Higher rotation amplitudes induced stronger gait trajectory deviations. The MoSML decreased toward the deviation direction and increased at the opposite side. Foot placement control was similar compared with regular gait. Furthermore, pelvis and foot reorientation toward the rotation direction was observed. We concluded that visual coupling was facilitated by reorientating the body and shifting the extrapolated CoMML closer to the lateral BoS boundary toward the adjusted heading direction while preserving CoM excursion and foot placement control.NEW & NOTEWORTHY Healthy, naive participants were unaware of subtle, low-frequency rotations of the visual field but still coupled their gait trajectory to a rotating virtual environment. In response, participants decreased their margin of stability toward the new heading direction, without changing the center of mass excursion magnitude and foot placement strategy.

Prelude to malignancy: A gene expression signature in normal mammary gland from breast cancer patients suggests pre-tumorous alterations and is associated with adverse outcomes.

Despite advances in early detection and treatment strategies, breast cancer recurrence and mortality remain a significant health issue. Recent insights suggest the prognostic potential of microscopically healthy mammary gland, in the vicinity of the breast lesion. Nonetheless, a comprehensive understanding of the gene expression profiles in these tissues and their relationship to patient outcomes remain missing. Furthermore, the increasing trend towards breast-conserving surgery may inadvertently lead to the retention of existing cancer-predisposing mutations within the normal mammary gland. This study assessed the transcriptomic profiles of 242 samples from 83 breast cancer patients with unfavorable outcomes, including paired uninvolved mammary gland samples collected at varying distances from primary lesions. As a reference, control samples from 53 mammoplasty individuals without cancer history were studied. A custom panel of 634 genes linked to breast cancer progression and metastasis was employed for expression profiling, followed by whole-transcriptome verification experiments and statistical analyses to discern molecular signatures and their clinical relevance. A distinct gene expression signature was identified in uninvolved mammary gland samples, featuring key cellular components encoding keratins, CDH1, CDH3, EPCAM cell adhesion proteins, matrix metallopeptidases, oncogenes, tumor suppressors, along with crucial genes (FOXA1, RAB25, NRG1, SPDEF, TRIM29, and GABRP) having dual roles in cancer. Enrichment analyses revealed disruptions in epithelial integrity, cell adhesion, and estrogen signaling. This signature, named KAOS for Keratin-Adhesion-Oncogenes-Suppressors, was significantly associated with reduced tumor size but increased mortality rates. Integrating molecular assessment of non-malignant mammary tissue into disease management could enhance survival prediction and facilitate personalized patient care.

Association of clinicopathologic and molecular factors with the occurrence of positive margins in breast cancer.

PURPOSE: To explore the association of clinicopathologic and molecular factors with the occurrence of positive margins after first surgery in breast cancer. METHODS: The clinical and RNA-Seq data for 951 (75 positive and 876 negative margins) primary breast cancer patients from The Cancer Genome Atlas (TCGA) were used. The role of each clinicopathologic factor for margin prediction and also their impact on survival were evaluated using logistic regression, Fisher's exact test, and Cox proportional hazards regression models. In addition, differential expression analysis on a matched dataset (71 positive and 71 negative margins) was performed using Deseq2 and LASSO regression. RESULTS: Association studies showed that higher stage, larger tumor size (T), positive lymph nodes (N), and presence of distant metastasis (M) significantly contributed (p ≤ 0.05) to positive surgical margins. In case of surgery, lumpectomy was significantly associated with positive margin compared to mastectomy. Moreover, PAM50 Luminal A subtype had higher chance of positive margin resection compared to Basal-like subtype. Survival models demonstrated that positive margin status along with higher stage, higher TNM, and negative hormone receptor status was significant for disease progression. We also found that margin status might be a surrogate of tumor stage. In addition, 29 genes that could be potential positive margin predictors and 8 pathways were identified from molecular data analysis. CONCLUSION: The occurrence of positive margins after surgery was associated with various clinical factors, similar to the findings reported in earlier studies. In addition, we found that the PAM50 intrinsic subtype Luminal A has more chance of obtaining positive margins compared to Basal type. As the first effort to pursue molecular understanding of the margin status, a gene panel of 29 genes including 17 protein-coding genes was also identified for potential prediction of the margin status which needs to be validated using a larger sample set.

CMOS-Integrated Ternary Content Addressable Memory using Nanocavity CBRAMs for High Sensing Margin.

The development of data-intensive computing methods imposes a significant load on the hardware, requiring progress toward a memory-centric paradigm. Within this context, ternary content-addressable memory (TCAM) can become an essential platform for high-speed in-memory matching applications of large data vectors. Compared to traditional static random-access memory (SRAM) designs, TCAM technology using non-volatile resistive memories (RRAMs) in two-transistor-two-resistor (2T2R) configurations presents a cost-efficient alternative. However, the limited sensing margin between the match and mismatch states in RRAM structures hinders the potential of using memory-based TCAMs for large-scale architectures. Therefore, this study proposes a practical device engineering method to improve the switching response of conductive-bridge memories (CBRAMs) integrated with existing complementary metal-oxide-semiconductor (CMOS) transistor technology. Importantly, this work demonstrates a significant improvement in memory window reaching 1.87 × 107 by incorporating nanocavity arrays and modifying electrode geometry. Consequently, TCAM cells using nanocavity-enhanced CBRAM devices can exhibit a considerable increase in resistance ratio up to 6.17 × 105, thereby closely approximating the sensing metrics observed in SRAM-based TCAMs. The improved sensing capability facilitates the parallel querying of extensive data sets. TCAM array simulations using experimentally verified device models indicate a substantial sensing margin of 65× enabling a parallel search of 2048 bits.

The role of D3-type cyclins is related to cytokinin and the bHLH transcription factor SPATULA in Arabidopsis gynoecium development.

MAIN CONCLUSION: We studied the D3-type cyclin function during gynoecium development in Arabidopsis and how they are related to the hormone cytokinin and the transcription factor SPATULA. Growth throughout the life of plants is sustained by cell division and differentiation processes in meristematic tissues. In Arabidopsis, gynoecium development implies a multiphasic process where the tissues required for pollination, fertilization, and seed development form. The Carpel Margin Meristem (CMM) is a mass of undifferentiated cells that gives rise to the gynoecium internal tissues, such as septum, ovules, placenta, funiculus, transmitting tract, style, and stigma. Different genetic and hormonal factors, including cytokinin, control the CMM function. Cytokinin regulates the cell cycle transitions through the activation of cell cycle regulators as cyclin genes. D3-type cyclins are expressed in proliferative tissues, favoring the mitotic cell cycle over the endoreduplication. Though the role of cytokinin in CMM and gynoecium development is highly studied, its specific role in regulating the cell cycle in this tissue remains unclear. Additionally, despite extensive research on the relationship between CYCD3 genes and cytokinin, the regulatory mechanism that connects them remains elusive. Here, we found that D3-type cyclins are expressed in proliferative medial and lateral tissues. Conversely, the depletion of the three CYCD3 genes showed that they are not essential for gynoecium development. However, the addition of exogenous cytokinin showed that they could control the division/differentiation balance in gynoecium internal tissues and outgrowths. Finally, we found that SPATULA can be a mechanistic link between cytokinin and the D3-type cyclins. The data suggest that the role of D3-type cyclins in gynoecium development is related to the cytokinin response, and they might be activated by the transcription factor SPATULA.

The spatial distribution of intermediate fibroblasts and myeloid-derived cells dictate lymph node metastasis dynamics in oral cancer.

BACKGROUND: Oral cancer poses a significant health challenge due to limited treatment protocols and therapeutic targets. We aimed to investigate the invasive margins of gingivo-buccal oral squamous cell carcinoma (GB-OSCC) tumors in terms of the localization of genes and cell types within the margins at various distances that could lead to nodal metastasis. METHODS: We collected tumor tissues from 23 resected GB-OSCC samples for gene expression profiling using digital spatial transcriptomics. We monitored differential gene expression at varying distances between the tumor and its microenvironvent (TME), and performed a deconvulation study and immunohistochemistry to identify the cells and genes regulating the TME. RESULTS: We found that the tumor-stromal interface (a distance up to 200 µm between tumor and immune cells) is the most active region for disease progression in GB-OSCC. The most differentially expressed apex genes, such as FN1 and COL5A1, were located at the stromal ends of the margins, and together with enrichment of the extracellular matrix (ECM) and an immune-suppressed microenvironment, were associated with lymph node metastasis. Intermediate fibroblasts, myocytes, and neutrophils were enriched at the tumor ends, while cancer-associated fibroblasts (CAFs) were enriched at the stromal ends. The intermediate fibroblasts transformed into CAFs and relocated to the adjacent stromal ends where they participated in FN1-mediated ECM modulation. CONCLUSION: We have generated a functional organization of the tumor-stromal interface in GB-OSCC and identified spatially located genes that contribute to nodal metastasis and disease progression. Our dataset might now be mined to discover suitable molecular targets in oral cancer.

Canopy temperatures strongly overestimate leaf thermal safety margins of tropical trees.

Current estimates of temperature effects on plants mostly rely on air temperature, although it can significantly deviate from leaf temperature (Tleaf). To address this, some studies have used canopy temperature (Tcan). However, Tcan fails to capture the fine-scale variation in Tleaf among leaves and species in diverse canopies. We used infrared radiometers to study Tleaf and Tcan and how they deviate from air temperature (ΔTleaf and ΔTcan) in multispecies tropical tree plantations at three sites along an elevation and temperature gradient in Rwanda. Our results showed high Tleaf (up to c. 50°C) and ΔTleaf (on average 8-10°C and up to c. 20°C) of sun-exposed leaves during 10:00 h-15:00 h, being close to or exceeding photosynthetic heat tolerance thresholds. These values greatly exceeded simultaneously measured values of Tcan and ΔTcan, respectively, leading to strongly overestimated leaf thermal safety margins if basing those on Tcan data. Stomatal conductance and leaf size affected Tleaf and Tcan in line with their expected influences on leaf energy balance. Our findings highlight the importance of leaf traits for leaf thermoregulation and show that monitoring Tcan is not enough to capture the peak temperatures and heat stress experienced by individual leaves of different species in tropical forest canopies.

Clinicopathological Predictors of Positive Resection Margins in Breast-Conserving Surgery.

BACKGROUND: Ductal carcinoma in situ (DCIS) is associated with risk of positive resection margins following breast-conserving surgery (BCS) and subsequent reoperation. Prior reports grossly underestimate the risk of margin positivity with IBC containing a DCIS component (IBC + DCIS) due to patient-level rather than margin-level analysis. OBJECTIVE: The aim of this study was to delineate the relative risk of IBC + DCIS compared with pure IBC (without a DCIS component) on margin positivity through detailed margin-level interrogation. METHODS: A single institution, retrospective, observational cohort study was conducted in which pathology databases were evaluated to identify patients who underwent BCS over 5 years (2014-2019). Margin-level interrogation included granular detail into the extent, pathological subtype and grade of disease at each resection margin. Predictors of a positive margin were computed using multivariate regression analysis. RESULTS: Clinicopathological details were examined from 5454 margins from 909 women. The relative risk of a positive margin with IBC + DCIS versus pure IBC was 8.76 (95% confidence interval [CI] 6.64-11.56) applying UK Association of Breast Surgery guidelines, and 8.44 (95% CI 6.57-10.84) applying the Society of Surgical Oncology/American Society for Radiation Oncology guidelines. Independent predictors of margin positivity included younger patient age (0.033, 95% CI 0.006-0.060), lower specimen weight (0.045, 95% CI 0.020-0.069), multifocality (0.256, 95% CI 0.137-0.376), lymphovascular invasion (0.138, 95% CI 0.068-0.208) and comedonecrosis (0.113, 95% CI 0.040-0.185). CONCLUSIONS: Compared with pure IBC, the relative risk of a positive margin with IBC + DCIS is approximately ninefold, significantly higher than prior estimates. This margin-level methodology is believed to represent the impact of DCIS more accurately on margin positivity in IBC.

To Revise or Not Revise? Isolated Margin Positivity in Localized Pancreatic Ductal Adenocarcinoma.

BACKGROUND: The study determined the proportion of patients with pancreatic adenocarcinoma (PDAC) who had margin-positive disease and no other adverse pathologic findings (APF) using institutional and administrative datasets. METHODS: Patients with clinical stage I or II PDAC in the National Cancer Database (NCDB 2010-2020) and those who underwent pancreatectomy at the authors' institution (2010-2021) were identified. Isolated margin positivity (IMP) was defined as a positive surgical margin with no APF (negative nodes, no lymphovascular/perineural invasion). RESULTS: The study included 225 patients from the authors' institution and 23,598 patients from the NCDB. The margin-positive rates were 21.8% and 20.3%, and the IMP rates were 0.4% and 0.5%, respectively. In the institutional cohort, 68.4% of the patients had recurrence, and most of the patients (65.6%) had distant recurrences. The median recurrence-free survival (RFS) was 63.3 months for no APF, not reached for IMP, 14.8 months for negative margins & 1 APF, 20.3 months for positive margins & 2 APFs, and 12.9 months with all APF positive. The patients in the NCDB with IMP had a lower median OS than the patients with no APF (20.5 vs 390 months), but a higher median OS than those with margin positivity plus 1 APF (20.5 vs 18.0 months) or all those with APF positivity (20.5 vs 15.4 months). Based on institutional rates of IMP, any margin positivity, neck margin positivity (NMP), and no APF, the fraction of patients who might benefit from neck margin revision was 1 in 100,000, and those likely to benefit from any margin revision was 1 in 18,500. In the NCDB, those estimated to derive potential benefit from margin revision was 1 in 25,000. CONCLUSIONS: Isolated margin positivity in resected PDAC is rare, and most patients experience distant recurrence. Revision of IMP appears unlikely to confer benefit to most patients.

Prognostic Relevance of the Proximal Resection Margin Distance in Distal Gastrectomy for Gastric Adenocarcinoma.

BACKGROUND: The risk for recurrence in patients with distal gastric cancer can be reduced by surgical radicality. However, dispute exists about the value of the proposed minimum proximal margin distance (PMD). Here, we assess the prognostic value of the safety distance between the proximal resection margin and the tumor. PATIENTS AND METHODS: This is a single-center cohort study of patients undergoing distal gastrectomy for gastric adenocarcinoma (2001-2021). Cohorts were defined by adequacy of the PMD according to the European Society for Medical Oncology (ESMO) guidelines (≥ 5 cm for intestinal and ≥ 8 cm for diffuse Laurén's subtypes). Overall survival (OS) and time to progression (TTP) were assessed by log-rank and multivariable Cox-regression analyses. RESULTS: Of 176 patients, 70 (39.8%) had a sufficient PMD. An adequate PMD was associated with cancer of the intestinal subtype (67% vs. 45%, p = 0.010). Estimated 5-year survival was 63% [95% confidence interval (CI) 51-78] and 62% (95% CI 53-73) for adequate and inadequate PMD, respectively. Overall, an adequate PMD was not prognostic for OS (HR 0.81, 95% CI 0.48-1.38) in the multivariable analysis. However, in patients with diffuse subtype, an adequate PMD was associated with improved oncological outcomes (median OS not reached versus 131 months, p = 0.038, median TTP not reached versus 88.0 months, p = 0.003). CONCLUSION: Patients with diffuse gastric cancer are at greater risk to undergo resection with an inadequate PMD, which in those patients is associated with worse oncological outcomes. For the intestinal subtype, there was no prognostic association with PMD, indicating that a distal gastrectomy with partial preservation of the gastric function may also be feasible in the setting where an extensive PMD is not achievable.

Irreversible Electroporation Margin Accentuation in Pancreaticoduodenectomy: A Propensity Score Matching Analysis.

BACKGROUND: Margin accentuation using irreversible electroporation (MA-IRE) improves recurrence and overall survival (OS) in pancreatic cancer patients; however, there have been limited outcome comparisons to similarly risked patients who did not receive MA-IRE. METHODS: Patients with borderline resectable or locally advanced pancreatic adenocarcinoma who underwent a pancreaticoduodenectomy (PD) between 2017 and 2022 were included. Those who did not receive neoadjuvant chemotherapy for major vessel involvement were excluded. One-to-one propensity score matching (PSM) was used to match the MA-IRE group with the corresponding non-MA-IRE control group with similar risk factors. RESULTS: A total of 36 patients were included in this study. Seventeen (47.2%) patients who underwent MA-IRE matched with 19 control patients (52.8%) with similar risk factors who did not have MA-IRE. Before matching, OS and disease-free survival (DFS) were comparable between the MA-IRE and non-MA-IRE groups. After matching, the MA-IRE group showed improved OS (746 vs. 509 days, hazard ratio 0.313; p = 0.034) compared with the non-MA-IRE group. DFS (p = 0.768), negative margin status (p = 0.317), and 30-day complication rates (p = 1.000) remained statistically different between the groups. CONCLUSIONS: MA-IRE in PD results in longer OS but does not impact margin status, DFS, or postoperative complication rates in our cohort. These findings suggest that MA-IRE is safe and potentially promotes immune cell activation rather than upfront margin mitigation.

Impact of Surgical Margin Status on Survival and Recurrence After Pancreaticoduodenectomy for Distal Cholangiocarcinoma: Is Microscopic Residual Tumor (R1) Associated with Higher Rates of Local Recurrence?

BACKGROUND: Patients undergoing macroscopically curative resection for distal cholangiocarcinoma (DCC) have high recurrence rates and poor prognoses. This study aimed to investigate the impact of surgical margin status on survival and recurrence after resection of DCC, specifically focusing on microscopic residual tumor (R1) and its relationship to local recurrence. PATIENTS AND METHODS: This was a retrospective analysis of patients who had undergone pancreaticoduodenectomy (PD) for DCC between 2005 and 2021. Surgical margin was classified as R0, R1cis (positive bile duct margin with carcinoma in situ), and R1inv (positive bile duct margin with an invasive subepithelial component and/or positive radial margin). RESULTS: In total, 29 of 133 patients (21.8%) had R1cis and 23 (17.3%) R1inv. The 5-year overall survival (OS) for R0 (55.7%) did not differ significantly from that for R1cis/R1inv (47.4%/33.6%, respectively). The 5-year recurrence-free survival (RFS) for R0 was significantly longer than that for R1inv (50.1% vs. 17.4%, p = 0.003), whereas RFS did not differ significantly between those with R0 and R1cis. R1cis/R1inv status was not an independent predictor of OS and RFS in multivariate analysis. Cumulative incidence of isolated distant recurrence was significantly higher for R1cis/R1inv than for R0 (p = 0.0343/p = 0.0226, respectively), whereas surgical margin status was not significantly associated with rates of local or local plus distant recurrence. CONCLUSIONS: Surgical margin status does not significantly impact OS and RFS in patients undergoing PD for DCC following precise preoperative imaging evaluation. Additionally, R1 status is significantly linked to higher isolated distant recurrence rather than local recurrence, highlighting the importance of multidisciplinary therapy.

Margin Width and Local Recurrence in Patients with Phyllodes Tumors of the Breast.

BACKGROUND: Optimal surgical margin width for patients with phyllodes tumors (PTs) of the breast remains debated. The aim of this study was to assess the influence of margin width on long-term local recurrence risk. PATIENTS AND METHODS: This was a single-institution retrospective review of patients with confirmed PT treated from 2008-2015. Margins were defined as positive (ink on tumor), narrow (no tumor at inked margin but < 10mm), or widely free (>/= 10mm). LR rates were estimated by the Kaplan-Meier method. RESULTS: Among 117 female patients, histology included 55 (47%) benign, 29 (25%) borderline, and 33 (28%) malignant PT. Final margins were positive in 16 (14%), narrow in 32 (27%), widely free in 64 (55%), and unknown in 5 (4%) patients. Compared with margins > 10 mm, patients with positive and narrow margins had a higher LR risk [HR 10.57 (95% CI 2.48-45.02) and HR 5.66 (95% CI 1.19-26.99), respectively]. Among benign PTs, the 10-year LR-free rates were 100%, 94%, and 66% for widely negative, narrow, and positive margins, respectively (p = 0.056). For borderline/malignant PT, the 10-year LR-free rates were 93% and 57% for widely negative and narrow margins, respectively (p = 0.02), with no difference in LR between narrow and positive margin groups (p = 1.00). CONCLUSIONS: For benign PTs, a margin of no ink on tumor appears sufficient to optimize local control. In patients with borderline or malignant PTs, achieving a wide surgical margin may remain important as narrower margins were associated with LR rates comparable to those with positive margins.

Adjuvant Therapy for Patients with a Tumor-Positive Resection Margin After Neoadjuvant Chemoradiotherapy and Esophagectomy.

BACKGROUND: Approximately 4-9% of patients have a tumor-positive resection margin after neoadjuvant chemoradiotherapy (nCRT) and esophagectomy. Although it is associated with decreased survival, Western guidelines do not recommend adjuvant treatment. OBJECTIVE: The aim of this study was to assess the proportion of patients who received adjuvant therapy, and to evaluate overall survival (OS) after esophagectomy in patients with a tumor-positive resection margin. METHODS: Patients diagnosed with resectable (cT2-4a/cTxN0-3/NxM0) esophageal cancer between 2015 and 2022, and treated with nCRT followed by irradical esophagectomy, were selected from the Netherlands Cancer Registry. The primary outcome was the proportion of patients with a tumor-positive resection margin who started adjuvant treatment ≤16 weeks after esophagectomy, including chemotherapy/radiotherapy, immunotherapy, or targeted therapy. OS was calculated from the date of surgery until the date of death or last day of follow-up. RESULTS: Overall, 376 patients were included in our study, of whom 357 were treated with nCRT. Of these 357 patients, 98.3% had a microscopically irradical resection and 1.7% had a macroscopically irradical resection. Approximately 72.3% of tumors showed a partial response (Mandard 2-3) and 11.8% showed little/no pathological response (Mandard 4-5) to nCRT. One of 357 patients underwent adjuvant chemoradiotherapy and 39 patients (61%) underwent adjuvant immunotherapy (nivolumab). The median and 5-year OS rate of all patients was 16.4 months (95% confidence interval 13.1-19.8) and 21%, respectively. CONCLUSION: Real-world population-level data showed that no patients with a tumor-positive resection margin underwent adjuvant therapy following nCRT and esophagectomy prior to 2021. Interestingly, 61% of patients were treated with adjuvant nivolumab in 2021-2022. OS after irradical esophagectomy is poor and long-term data will explore the added value of nivolumab.

Is the Number or Proximity of Margins Less than 2 mm Associated with an Increased Mastectomy Rate in Patients Attempting Breast Conservation Therapy for Ductal Carcinoma In Situ?

BACKGROUND: Consensus guidelines recommend ≥ 2 mm margins in patients undergoing partial mastectomy (PM) for ductal carcinoma in situ (DCIS). It is unknown whether the number or proximity of margins less than 2 mm is associated with an increased mastectomy rate in patients attempting breast conservation therapy (BCT) for DCIS. The aim of this study is to examine this relationship. PATIENTS AND METHODS: An institutional database review identified 208 patients with DCIS who underwent PM at a tertiary referral center and community hospitals from July 2020 to June 2023. Patients with a history of breast cancer, previous surgery for breast cancer, ipsilateral invasive carcinoma, papillary carcinoma, Paget's disease, more lobular carcinoma in situ (LCIS) than DCIS present, initial mastectomy, no DCIS present, routine shave margins (of all vectors), and ≥ 2 mm margins of all six vectors were excluded. Selective intraoperative margin re-excisions were included. RESULTS: A total of 208 patients who met inclusion criteria were retrospectively reviewed. 122 (25%) had one close/positive (< 2 mm) margin and 86 (18%) had two or more close/positive margins. Of the patients with one close/positive margin, 7% (9/122) eventually underwent mastectomy. Of the patients with two or more close/positive margins, 20% (17/86) eventually underwent mastectomy. Overall, no patients with opposing margins underwent mastectomy. CONCLUSIONS: Patients undergoing PM for DCIS have a mastectomy rate that is increased threefold, with two or more close/positive margins at initial PM, when compared with those with only one close/positive margin. The presence of opposing close/positive margins at initial PM did not increase the mastectomy rate and most were cleared with re-excision.

Positive Nipple Margins in Nipple-Sparing Mastectomy: Management of Nipples Containing Cancer or Atypia.

BACKGROUND: Nipple-sparing mastectomy (NSM) is an oncologically safe approach for breast cancer treatment and prevention; however, there are little long-term data to guide management for patients whose nipple margins contain tumor or atypia. METHODS: NSM patients with tumor or atypia in their nipple margin were identified from a prospectively maintained, single-institution database of consecutive NSMs. Patient and tumor characteristics, treatment, recurrence, and survival data were assessed. RESULTS: A total of 3158 NSMs were performed from June 2007 to August 2019. Nipple margins contained tumor in 117 (3.7%) NSMs and atypia only in 164 (5.2%) NSMs. Among 117 nipple margins that contained tumor, 34 (29%) margins contained invasive cancer, 80 (68%) contained ductal carcinoma in situ only, and 3 (3%) contained lymphatic vessel invasion only. Management included nipple-only excision in 67 (57%) breasts, nipple-areola complex excision in 35 (30%) breasts, and no excision in 15 (13%) breasts. Only 23 (24%) excised nipples contained residual tumor. At 67 months median follow-up, there were 2 (1.8%) recurrences in areolar or peri-areolar skin, both in patients with nipple-only excision. Among 164 nipple margins containing only atypia, 154 (94%) nipples were retained. At 60 months median follow-up, no patient with atypia alone had a nipple or areola recurrence. CONCLUSIONS: Nipple excision is effective management for nipple margins containing tumor. No intervention is required for nipple margins containing only atypia. Our results support broad eligibility for NSM with careful nipple margin assessment.