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BACKGROUND: Radioactive tracer injections for breast cancer sentinel lymph node mapping can be painful. In this randomized trial, we compared four approaches to topical pain control for radiotracer injections. METHODS: Breast cancer patients were randomized (9 April 2021-8 May 2022) to receive the institutional standard of ice prior to injection (n = 44), or one of three treatments: ice plus a vibrating distraction device (Buzzy®; n = 39), 4% lidocaine patch (n = 44), or 4% lidocaine patch plus ice plus Buzzy® (n = 40). Patients completed the Wong-Baker FACES® pain score (primary outcome) and a satisfaction with pain control received scale (secondary). Nuclear medicine technologists (n = 8) rated perceived pain control and ease of administration for each patient. At study conclusion, technologists rank-ordered treatments. Data were analyzed as intention-to-treat. Wilcoxon rank-sum tests were used to compare pain scores of control versus pooled treatment arms (primary) and then control to each treatment arm individually (secondary). RESULTS: There were no differences in pain scores between the control and treatment groups, both pooled and individually. Eighty-five percent of patients were 'satisfied/very satisfied' with treatment received, with no differences between groups. No differences in providers' perceptions of pain were observed, although providers perceived treatments involving Buzzy© more difficult to administer (p < 0.001). Providers rated lidocaine patch as the easiest, with ice being second. CONCLUSION: In this randomized trial, no differences in patient-reported pain or satisfaction with treatment was observed between ice and other topical treatments. Providers found treatments using Buzzy® more difficult to administer. Given patient satisfaction and ease of administration, ice is a reasonable standard.

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Importance: Although longer times from breast cancer diagnosis to primary surgery have been associated with worse survival outcomes, the specific time point after which it is disadvantageous to have surgery is unknown. Identifying an acceptable time to surgery would help inform patients, clinicians, and the health care system. Objective: To examine the association between time from breast cancer diagnosis to surgery (in weeks) and overall survival and to describe factors associated with surgical delay. The hypothesis that there is an association between time to surgery and overall survival was tested. Design, Setting, and Participants: This was a case series study that used National Cancer Database (NCDB) data from female individuals diagnosed with breast cancer from 2010 to 2014 (with 5-year follow-up to 2019). The NCDB uses hospital registry data from greater than 1500 Commission on Cancer-accredited facilities, accounting for 70% of all cancers diagnosed in the US. Included participants were females 18 years or older with stage I to III ductal or lobular breast cancer who underwent surgery as the first course of treatment. Patients with prior breast cancer, missing receptor information, neoadjuvant or experimental therapy, or who were diagnosed with breast cancer on the date of their primary surgery were excluded. Multivariable Cox regression was used to evaluate factors associated with overall survival. Patients were censored at death or last follow-up. Covariates included age and tumor characteristics. Multinomial regression was performed to identify factors associated with longer time to surgery, using surgery 30 days or less from diagnosis as the reference group. Data were analyzed from March 15 to July 7, 2022. Exposures: Time to receipt of primary breast surgery. Measures: The primary outcome measure was overall survival. Results: The final cohort included 373 334 patients (median [IQR] age, 61 [51-70] years). On multivariable Cox regression analysis, time to surgery 9 weeks (57-63 days) or later after diagnosis was associated with worse overall survival (hazard ratio, 1.15; 95% CI, 1.08-1.23; P < .001) compared with surgery between 0 to 4 weeks (1-28 days). By multinomial regression, factors associated with longer times to surgery (using surgery 1-30 days from diagnosis as a reference) included the following: (1) younger age, eg, the adjusted odds ratio (OR) for patients 45 years or younger undergoing surgery 31 to 60 days from diagnosis was 1.32 (95% CI, 1.28-1.38); 61 to 74 days, 1.64 (95% CI, 1.52-1.78); and greater than 74 days, 1.58 (95% CI, 1.46-1.71); (2) uninsured or Medicaid status, eg, the adjusted OR for patients with Medicaid undergoing surgery 31 to 60 days from diagnosis was 1.35 (95% CI, 1.30-1.39); 61 to 74 days, 2.13 (95% CI, 2.01-2.26); and greater than 74 days, 3.42 (95% CI, 3.25-3.61); and (3) lower neighborhood household income, eg, the adjusted OR for patients with household income less than $38,000 undergoing surgery 31 to 60 days from diagnosis was 1.35 (95% CI, 1.02-1.07); 61 to 74 days, 1.21 (95% CI, 1.15-1.27); and greater than 74 days, 1.53 (95% CI, 1.46-1.61). Conclusions and Relevance: Findings of this case series study suggest the use of 8 weeks or less as a quality metric for time to surgery. Time to surgery of greater than 8 weeks may partly be associated with disadvantageous social determinants of health.

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BACKGROUND: Radiation-associated sarcoma (RAS) is a rare sequela of radiotherapy. Radiotherapy modalities for breast conservation and radiation treatment (BCT) have changed over time. We sought to determine if the incidence of RAS after BCT has changed over time. METHODS: We identified breast cancer survivors (diagnosed 1988-2012) treated with BCT within the SEER database. We excluded patients with prior cancer, <1-year follow-up/survival, and nonexternal beam radiation (n = 276 301). We identified patients with a subsequent chest sarcoma diagnosis. The primary predictor variable was a 5-year period of breast cancer diagnosis year (1988-1992, 1993-1997, etc.). The incidence of sarcoma was estimated by the Kaplan-Meier method, censoring at sarcoma diagnosis, death, or last follow-up (available through December 2017). Given the known latency of RAS, we used Joinpoint analysis to identify the time point at which RAS incidence significantly increased (start of the analytic window). A log-rank test assessed differences in RAS incidence by diagnosis year. RESULTS: The incidence of RAS was 0.03% at 5 years (95% confidence interval [CI]: 0.03-0.04) and 0.16% at 10 years (95% CI: 0.14-0.18). No statistical difference in RAS incidence by diagnosis year was observed (p = 0.2). CONCLUSIONS: RAS remains a rare but persistent sequela after BCT. As new radiation modalities become more common, ongoing surveillance is necessary to track these rare events.

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OBJECTIVE: We sought to evaluate local/regional recurrence rates after breast-conserving surgery in a cohort of patients enrolled in legacy trials of the Alliance for Clinical Trials in Oncology and to evaluate variation in recurrence rates by receptor subtype. BACKGROUND: Multiple randomized controlled trials have demonstrated equivalent survival between breast conservation and mastectomy, albeit with higher local/regional recurrence rates after breast conservation. However, absolute rates of local/regional recurrence have been declining with multi-modality treatment. METHODS: Data from 5 Alliance for Clinical Trials in Oncology legacy trials that enrolled women diagnosed with breast cancer between 1997 and 2010 were included. Women who underwent breast-conserving surgery and standard systemic therapies (n=4,404) were included. Five-year rates of local/regional recurrence were estimated from Kaplan-Meier curves. Patients were censored at the time of distant recurrence (if recorded as the first recurrence), death, or last follow-up. Multivariable Cox proportional hazards models were used to identify factors associated with time to local/regional recurrence, including patient age, tumor size, lymph node status, and receptor subtype. RESULTS: Overall 5-year recurrence was 4.6% (95% CI=4.0-5.4%). Five-year recurrence rates were lowest in those with ER+ or PR+ tumors (Her2+ 3.4% [95% CI 2.0-5.7%], Her2- 4.0% [95% CI 3.2-4.9%]) and highest in the triple-negative subtype (7.1% [95% CI 5.4-9.3%]). On multivariable analysis, increasing nodal involvement and triple-negative subtype were positively associated with recurrence ( P <0.0001). CONCLUSIONS: Rates of local/regional recurrence after breast conservation in women with breast cancer enrolled in legacy trials of the Alliance for Clinical Trials in Oncology are significantly lower than historic estimates. This data can better inform patient discussions and surgical decision-making.

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With the COVID19 pandemic, use of telehealth has expanded rapidly in subspecialties with limited prior telehealth experience. While telehealth offers many opportunities to improve patient convenience, access, and comfort, the virtual platform poses unique challenges for shared decision making. In this review article, we describe what occurs within a standard in-person breast surgery consult and propose a model for an ideal virtual breast surgery consult, including strategies to foster patient engagement and shared decision making. Our model incorporates pre-visit preparation, deliberate pauses, and targeted engagement as ways to encourage patients to integrate information and actively participate in treatment decisions. Intentional strategies such as these must be adopted to improve shared decision making on the virtual platform.

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BACKGROUND: Cutaneous melanoma survivors are at increased risk of a second primary melanoma. Valid estimates facilitate counseling on recommended surveillance after a melanoma diagnosis. However, most estimates of 5- and 10-year incidences of second melanomas are from older cohorts and/or single institutions. This study aimed to determine the 5- and 10-year incidences of second primary cutaneous melanomas in survivors of cutaneous melanoma. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify cases of non-metastatic, first cutaneous melanoma diagnosed between 1998 and 2012 (follow-up through December 2017). Eligible survivors were 18 years old or older who underwent surgery as a treatment component. Kaplan-Meier survival analysis was used to estimate 5- and 10-year incidences of a second melanoma, excluding new diagnoses within 3 months after the initial diagnosis. Patients were censored at second melanoma diagnosis, death, or 10-years, whichever was first. Multivariable Cox regression analysis was used to identify factors associated with a second cutaneous melanoma diagnosis. RESULTS: The study cohort comprised 152,811 patients. The incidence of second primary melanoma was 3.9% at 5 years (95% confidence interval [CI], 3.8-4.0%) and 6.7% at 10 years (95% CI, 6.6-6.9%). Older age, male sex, and regional disease were associated with increased risk of a second primary melanoma diagnosis. CONCLUSION: Melanoma survivors are at risk of a second primary melanoma, making routine skin surveillance part of recommended follow-up evaluation. A higher incidence of second melanoma with older age and regional disease at presentation is possibly explained by increased health care use providing more diagnostic opportunities, whereas male sex may represent an inherent risk factor.

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BACKGROUND: Some surgeons remain hesitant to perform immediate breast reconstruction (IBR) in patients with higher risk cancers owing to concerns about cancer recurrence and/or detection. Our objective was to determine the rate of ipsilateral local-regional recurrence for stage II/III patients who underwent IBR. METHODS: The National Cancer Database special study mechanism was used to create a stratified sample of women diagnosed with stage II/III breast cancer from 1217 facilities. Demographic, tumor, and recurrence data for women who underwent mastectomy with or without IBR were abstracted, including location of recurrence and method of detection. Estimates of 5-year local-regional recurrence rates were calculated and factors associated with recurrence were identified with multivariable Cox regression. RESULTS: Some 13% (692/5318) of stage II/III patients underwent IBR after mastectomy. Patients undergoing IBR were younger (P < .001), with fewer comorbid conditions (P < .001), and with lower tumor burden in the breast (P = .001) and the lymph nodes (P = 0.01). The 5-year rate of ipsilateral local-regional recurrence was 3.6% with no significant difference between patients with or without IBR (3.0% vs. 3.7%, P = .4). Most recurrences were detected by the patient (45%) or on physician examination (24%). Reconstruction was not associated with recurrence on multivariable analysis (hazard ratio = 0.83, P = .52). CONCLUSION: Women with stage II/III breast cancer selected for IBR had similar rates of ipsilateral local-regional recurrence compared with those undergoing mastectomy alone. Offering IBR after mastectomy in a patient-centered manner to select patients with stage II/III breast cancer is an acceptable consideration.

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ToxR-based transcriptional reporter assays allow the strength of transmembrane helix interactions in biological membranes to be measured. Previously, these assays have only been used to study single-pass transmembrane systems. To facilitate investigation of polytopic transmembrane domain (TMD) oligomerization, we applied the ToxR methodology to the study of multi-pass TMD oligomerization to give 'Multi-Tox'. Association propensities of the viral oncoprotein, latent membrane protein-1 (LMP-1), and the E. coli membrane-integral diacylglycerol kinase (DAGK) were studied by Multi-Tox, highlighting residues of particular mechanistic importance. Both homo- and hetero-oligomerizations were studied.

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The oversimplified view of protein transmembrane domains as merely anchors in phospholipid bilayers has long since been disproven. In many cases membrane-spanning proteins have evolved highly sophisticated mechanisms of action. One way in which membrane proteins can modulate their structures and functions is by direct and specific contact of hydrophobic helices, forming structured transmembrane oligomers. Much recent work has focused on the distribution of amino acids preferentially found in the membrane environment in comparison to aqueous solution and the different intermolecular forces that drive protein association. Nevertheless, studies of molecular recognition at the transmembrane domain of proteins still lags behind those of water-soluble regions. A major hurdle remains: despite the remarkable specificity and affinity that transmembrane oligomerization can achieve, direct measurement of their association is challenging. Traditional methodologies applied to the study of integral membrane protein function can be hampered by the inherent insolubility of the sequences under examination. Biophysical insights gained from studying synthetic peptides representing transmembrane domains can provide useful structural insight. However, the biological relevance of the detergent micellar or liposome systems used in these studies to mimic cellular membranes is often questioned; do peptides adopt a native-like structure under these conditions and does their functional behaviour truly reflect the mode of action within a native membrane? In order to study the interactions of transmembrane sequences in natural phospholipid bilayers, the Langosch lab developed ToxR transcriptional reporter assays. The transmembrane domain of interest is expressed as a chimeric protein with maltose binding protein for location to the periplasm and ToxR to provide a report of the level of oligomerization (Figure 1). In the last decade, several other groups (e.g. Engelman, DeGrado, Shai) further optimized and applied this ToxR reporter assay. The various ToxR assays have become a gold standard to test protein-protein interactions in cell membranes. We herein demonstrate a typical experimental operation conducted in our laboratory that primarily follows protocols developed by Langosch. This generally applicable method is useful for the analysis of transmembrane domain self-association in E. coli, where ß-galactosidase production is used to assess the TMD oligomerization propensity. Upon TMD-induced dimerization, ToxR binds to the ctx promoter causing up-regulation of the LacZ gene for ß-galactosidase. A colorimetric readout is obtained by addition of ONPG to lyzed cells. Hydrolytic cleavage of ONPG by ß-galactosidase results in the production of the light absorbing species o-nitrophenolate (ONP) (Figure 2).

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