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Inflammation can have social consequences, which may be relevant to inflammation's link with depression. The current study tests whether a typhoid vaccine increases feelings of social disconnection and avoidance behavior.In two full-day visits at least three weeks apart, 172 postmenopausal breast cancer survivors (Stage I-IIIA) each received a typhoid capsular polysaccharide vaccination and a saline placebo injection in a random sequence. Blood was drawn prior to the injection, as well as every 90 min thereafter for 8 h to assess the inflammatory response (interleukin-6, IL-6; interleukin-1 receptor antagonist, IL-1Ra). At both visits, women completed the Social Connection Scale at 0 and 8.5 h post-vaccination as well as implicit and explicit social avoidance tasks at 7 h post-vaccination.The typhoid vaccine triggered rises in both inflammatory markers (ps 0.01), but it did not impact feelings of social connection (p = .32), or performance on the implicit (p = .34) or explicit tasks (p = .37). Inflammatory rises did not predict feelings of social connection (ps 0.64) or performance on explicit (ps 0.73) or implicit (ps 0.88) social avoidance tasks.Milder inflammatory stimuli may not affect social processes. Higher levels of inflammation or, relatedly, more sickness symptoms may be necessary to recapitulate prior findings of social avoidance.

This study was conducted to compare the efficacy of using 0.5 mg/mL povidone-iodine solution as an irrigant and coolant in reducing postoperative sequelae like swelling, trismus, and pain with the conventional normal saline irrigation during the surgical removal of the impacted lower third molar.The research was conducted out toward the MES Dental College in Perinthalmanna, Kerala, in the Department of Oral and Maxillofacial Surgery. After mandibular third-molar surgical removal, researchers studied 60 individuals, 30 of whom had normal saline irrigation (group I), and 30 of whom received 0.05% povidone-iodine irrigation (group II). The postoperative discomforts were measured on the second and seventh days after surgery, respectively. After that, the data were analyzed using SPSS. The data analysis consideredAt the second postoperative visit, patients in the povidone-iodine group reported much less pain, swelling, and reduced mouth opening than those in the normal saline group. But on the seventh postoperative day, there was not much difference between either group.Following the surgical removal of teeth, it was revealed that povidone-iodine solution (0.5 mg/mL) was more effective as irrigation and cooling aid than regular saline solution.Low-concentrated povidone-iodine is a better option in dentistry as irrigant.

PURPOSE: To investigate breast cancer survivors’ inflammatory responses to typhoid vaccine as a window into their innate immune response to novel pathogens. METHODS: This double-blind crossover trial randomized 158 breast cancer survivors to either the vaccine/saline placebo or the placebo/vaccine sequence. The relative contributions of age, cardiorespiratory fitness (VO(2peak)), type of cancer treatment, central obesity, and depression to interleukin (IL)-6, IL-1 receptor antagonist (IL-1Ra), and WBC vaccine responses were assessed pre-injection and 1.5, 3, 4.5, 6, and 7.5 hours post-injection. RESULTS: The vaccine produced larger IL-6, IL-1Ra, and WBC responses than placebo, ps

Background: Approximately 10% of breast cancers (BC) are hormone receptor positive (HR+) and HER2 positive (HER2+). Despite treatment advances in the modern era of HER2 targeted therapies for early-stage disease, there remains a risk for late relapses. However, the role of adjuvant endocrine therapy (ET) to reduce recurrence in this BC subtype is unclear. Oncologists employ clinical judgment given lack of consensus, resulting in differences in treatment patterns. The ideal endocrine agent including the role of adding ovarian suppression (OS) in premenopausal women is unknown. These patients are largely underrepresented in clinical trials such as the phase III SOFT and TEXT studies. Additionally, these trials were initiated prior to the widespread use of trastuzumab with chemotherapy, which is now standard of care for HER2+ disease. We aimed to describe real world patterns surrounding choice of adjuvant ET and clinicopathologic features which predicted treatment with OS in premenopausal women with HR+/HER2+ BC. Methods: We performed a multi-institutional retrospective analysis of premenopausal women with non-metastatic HR+/HER2+ BC in the American Society of Clinical Oncology CancerlinQ® Discovery database from January 2010 to May 2020. Electronic health record data was obtained from 74 participating academic and community oncology sites. We collected clinical data on women less than 50 years who received chemotherapy, anti-HER2 therapy (trastuzumab with or without pertuzumab), and ET. Adjuvant OS was defined as receipt of at least 6 months of goserelin or leuprolide or surgical bilateral oophorectomy. Demographics, clinical characteristics, and treatment history was collected. Patients were categorized into 1 of 4 groups based on type of adjuvant ET prescribed at treatment initiation: aromatase inhibitor (AI) + OS, OS, tamoxifen + OS, or tamoxifen. Multivariable logistic regression was conducted to assess the association between clinicopathologic features and OS use. Results: Out of 360,540 patients with invasive breast cancer in the database, 937 met inclusion criteria. Mean age was 41.7 (SD 5.9) years; 83% had stage 1 or 2 BC and 78% had node positive disease. The majority (n=818, 87%) were prescribed tamoxifen whereas only 4 (0.4%), 50 (5.3%), and 65 (6.9%) received OS, tamoxifen + OS, and AI + OS, respectively. Table 1 includes demographic and clinical characteristics of the cohort. No clinicopathologic features predicted OS use apart from age; patients ≥35 years were less likely to receive OS compared with those < 35 (p< 0.001) (table 2). Conclusion: To our knowledge, this is the first real world study evaluating OS treatment in HR+/HER2+ BC. The use of OS was uncommon; this suggests a perception of its limited benefit when added to HER2-targeted therapy. Most patients received tamoxifen as the ET of choice. Age was the only factor to predict OS treatment; high risk features including node positivity and higher stage was not associated with its use. This highlights the wide variability in real world practice surrounding the clinical indications for OS. Further investigation is warranted to characterize the utility of ET including addition of OS to prevent recurrence in premenopausal HR+/HER2+ BC. This will better inform a personalized approach to tailor therapy for optimal outcomes in this distinct BC subtype. Table 1. Demographic and clinical characteristics of study participants by endocrine therapy treatment group. Table 2. Multivariable logistic regression model of clinicopathologic characteristics to predict use of ovarian suppression. Citation Format: Jasmine S. Sukumar, Sagar Sardesai, Andy Ni, Nicole Williams, Bhuvaneswari Ramaswamy, Robert Wesolowski, Mathew A. Cherian, Daniel Stover, Margaret Gatti-Mays, Ashley C. Pariser, Preeti K. Sudheendra, Mridula A. George, maryam lustberg. Real World Treatment Patterns of Adjuvant Endocrine Therapy and Ovarian Suppression in Premenopausal HR+/HER2+ Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-02-03.

Among women worldwide, breast cancer has the highest incidence and is the leading cause of cancer-related death. Patients with the triple-negative breast cancer (TNBC) subtype have an inferior prognosis in comparison to other breast cancers because the current therapies do not facilitate long-lasting responses. Thus, there is a critical need for novel therapeutic strategies that induce stronger responses. In our previous research, we discovered that augmenting the concentration of extracellular ATP (eATP) greatly enhances the chemotherapeutic response of TNBC cell lines by activating purinergic receptors (P2RXs), leading to cell death through the induction of non-selective membrane permeability. However, eATP levels are limited by several classes of extracellular ATPases. One endogenous molecule of interest that can inhibit multiple classes of extracellular ATPases is heparan sulfate. Heparan sulfate itself is degraded by heparanase, an enzyme that is known to be highly expressed in various cancers, including breast cancer. Heparan sulfate has previously been shown to regulate several cancer-related processes such as fibroblast growth factor signaling, neoangiogenesis by sequestering vascular endothelial growth factors in the extracellular matrix, hedgehog signaling and cell adhesion. In this project, we identified an additional mechanism for a tumor suppressor role of heparan sulfate: inhibition of extracellular ATPases, leading to augmented levels of eATP. Several heparanase inhibitors have been previously identified, including OGT 2115, suramin, PI-88, and PG 545. We hypothesized that heparanase inhibitors would augment eATP concentrations in TNBC by increasing heparan sulfate in the tumor microenvironment, resulting in increased cell death in response to chemotherapy. We treated TNBC cell lines MDA-MB 231, Hs 578t, and MDA-MB 468 and non-tumorigenic immortal mammary epithelial MCF-10A cells with increasing concentrations of the chemotherapeutic agent paclitaxel in the presence of heparan sulfate and/or OGT 2115 with eATP content and cell viability being assessed. Moreover, to confirm that the effects of OGT 2115 are mediated through eATP, we utilized specific antagonists to the purinergic receptors P2RX4 and P2RX7. In addition, the protein expression of heparanase was compared in all the examined cell lines via Western blot analysis. We also evaluated the effects of this combination on the breast cancer-initiating cell population in the treated cells using flow cytometry and tumorsphere formation efficiency assays. These results demonstrate that inhibiting the degradation of heparan sulfate in the tumor microenvironment enhances the susceptibility of TNBC cell lines to chemotherapy by augmenting extracellular ATP concentrations. This strategy could potentially be used to induce deeper and more durable responses in triple-negative breast cancer patients. Citation Format: Jasmine M. Manouchehri, Jharna Datta, Mathew A. Cherian. The role of heparan sulfate in enhancing the chemotherapeutic response in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 397.

The leading cause of cancer-related death among women worldwide is breast cancer. The triple-negative breast cancer (TNBC) subtype has limited therapeutic options that produce durable responses. As a result, it is associated with an especially poor prognosis compared to other breast cancer subtypes. Hence, the development of innovative therapeutic strategies that produce deeper and more durable responses is critically needed. We found that increasing extracellular ATP (eATP) can enhance the susceptibility of TNBC cell lines to chemotherapy through the activation of purinergic receptors (P2RXs) P2RX4 and P2RX7. However, eATP levels are limited by several different classes of eATPases, making the design of a single molecule that effectively inhibits all classes of eATPase complicated. Heparan sulfate, a carbohydrate moiety that is covalently linked to several cell surface and extracellular matrix proteins has previously been identified as an endogenous inhibitor of several classes of eATPases. Heparan sulfate is desulfated by sulfatases 1 and 2 at the 6-O-hydroxyl groups of glucosamine residues in heparan sulfate. Sulfatase 2 has been determined to be highly expressed in a variety of cancers including breast cancer, whereas sulfatase 1 is not. Several sulfatase inhibitors have been previously developed, such as OKN-007, which is a specific inhibitor of sulfatase 2. We hypothesized that OKN-007 would augment eATP levels in TNBC cell lines exposed to chemotherapy by increasing levels of heparan sulfate in the tumor microenvironment, leading to intensified cell death. TNBC cell lines MDA-MB 231, Hs 578t, and MDA-MB 468 and non-tumorigenic immortal mammary epithelial MCF-10A cells were treated with increasing concentrations of the chemotherapeutic agent paclitaxel in the presence of heparan sulfate and/or OKN-007, and eATP content and cell viability were evaluated. Inhibitors to the purinergic receptors P2RX4 and P2RX7 were used to further confirm that the mechanism of enhanced cell death induced by OKN-007 was through these receptors. In addition, basal protein and cell surface expression of sulfatases 1 and 2 were determined in all the examined cell lines via ELISA, Western blot, and flow cytometry analysis. To assess the effects on cancer-initiating cell properties, TNBC cell lines were treated with paclitaxel in the presence of heparan sulfate and/or OKN-007, and the tumorsphere formation efficiency assay used to assess for cancer-initiating cells. In parallel, we assessed for effects on cancer-initiating cells in treated cells using flow cytometry. Our results showed that inhibiting the 6-O desulfation of heparan sulfate increases eATP accumulation, thereby, enhancing TNBC cell lines’ response to chemotherapy. These findings may lead to therapies for TNBC based on sulfatase 2 inhibition that results in more effective responses with fewer side effects. Citation Format: Jasmine M. Manouchehri, Jharna Datta, Mathew A. Cherian. The inhibition of sulfation of heparan sulfate augments the chemotherapeutic response in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 398.

Background: Hormone receptor (HR) low (1-10%) HER2-negative breast cancer (BC) is emerging as a distinct subtype with similarities in clinical outcomes to triple-negative BC. However, there is a lack of consensus on treatment recommendations for chemo-immunotherapy and endocrine therapy in this subset. Here, we present results from a US National Cancer Database (NCDB) analyses of patients with HER2-negative BC evaluating response to neoadjuvant chemotherapy (NAC) and patterns of care by HR expression. Methods: Patients with stage I-III HER2-negative BC diagnosed in 2018 were identified in NCDB, a nationwide oncology outcomes database in the US. Quantitative HR expression was unavailable prior to 2018. Data were categorized into four groups by estrogen receptor (ER) and progesterone receptor (PR) expression: ER< 1% & PR< 1% (HR-Neg), ER 1-10% and/or PR 1-10% (HR-Low), ER >11-30% and/or PR>11-30% (HR-Int), ER> 30% and/or PR > 30% (HR-High). Those with undocumented HR status (3%) or without curative intent surgery (5%) were excluded. The primary outcome was pathologic complete response (pCR) by HR expression in those undergoing neoadjuvant chemotherapy. Key secondary objectives included assessment of clinicopathologic characteristics and practice patterns. The categorical variables were compared between the four groups using a Chi-square test. Age was compared using a Kruskal-Wallis test. Results: Out of 104,205 incident cases, 2541 (2.4%) were HR-Low and 1241 (1.2%) were HR-Int. Significant differences were found between HR groups with higher grade, clinical stage, and Ki-67 in HR-Low vs. HR-Int or HR-High groups (Table 1). Patients with HR-Low and HR-Int BC were more likely to receive chemotherapy than HR-High (74%, 70% vs. 20%; p < 0.001) and the use of adjuvant endocrine therapy correlated with HR expression. Only half of patients in the HR-Low group received any endocrine therapy compared to higher rates in the HR-Int and HR-High groups (52% vs. 74%, 92%; p< 0.001). pCR rates in those receiving neoadjuvant chemotherapy were significantly different by HR status, with higher pCR rates in HR-Low vs. HR-High groups (p< 0.001) (Table 2). NAC utilization significantly differed between groups. A higher proportion of patients with HR-Low BC received NAC than other HR-positive groups (p < 0.001). Additionally, there was an increased use of NAC in patients with HR-Low BC treated at academic vs. community cancer centers (p< 0.001). Conclusions: This is one of the largest real-world analyses comparing key differences in biology and practice patterns of HR-Low, HER2-negative BC. Consistent with prior studies, we report HR-Low BC to be a rare and distinct subtype with higher pCR rates compared to HR-High BC. Practice patterns show wide variability in utilization of neoadjuvant chemotherapy and endocrine therapy for these patients. Future studies should address this disparity and enhance representation of patients with HR-Low BC in clinical trials to improve long-term outcomes. Table 1: Patient demographics Table 2: Neoadjuvant chemotherapy response amongst differing HR expression levels Citation Format: Dionisia Quiroga, Michael Grimm, Julie Stephens, Kai Johnson, Nicole Williams, Preeti K. Sudheendra, Mathew A. Cherian, Daniel Stover, Ashley C. Pariser, Margaret Gatti-Mays, Robert Wesolowski, Jose G. Bazan, Sasha Beyer, Ko Un Park, Bridget Oppong, Bhuvaneswari Ramaswamy, Julia White, Sachin R. Jhawar, Sagar Sardesai. Impact of low hormone receptor expression on neoadjuvant chemotherapy response and patterns of care in early-stage HER2-negative breast cancer: a US National Cancer Database analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-17.

IntroductionBreast cancer affects two million patients worldwide every year and is the most common cause of cancer-related death among women. The triple-negative breast cancer (TNBC) sub-type is associated with an especially poor prognosis because currently available therapies fail to induce long-lasting responses. Therefore, there is an urgent need to develop novel therapies that result in durable responses. One universal characteristic of the tumor microenvironment is a markedly elevated concentration of extracellular adenosine triphosphate (eATP). Chemotherapy exposure results in further increases in eATP through its release into the extracellular space of cancer cells via P2RX channels. eATP is degraded by eATPases. Given that eATP is toxic to cancer cells, we hypothesized that augmenting the release of eATP through P2RX channels and inhibiting extracellular ATPases would sensitize TNBC cells to chemotherapy.MethodsTNBC cell lines MDA-MB 231, Hs 578t and MDA-MB 468 and non-tumorigenic immortal mammary epithelial MCF-10A cells were treated with increasing concentrations the chemotherapeutic agent paclitaxel in the presence of eATPases or specific antagonists of P2RXs with cell viability and eATP content being measured. Additionally, the mRNA, protein and cell surface expressions of the purinergic receptors P2RX4 and P2RX7 were evaluated in all examined cell lines via qRT-PCR, western blot, and flow cytometry analyses, respectively.ResultsIn the present study, we observed dose-dependent declines of cell viability and increases in eATP of paclitaxel-treated TNBC cell lines in the presence of inhibitors of eATPases, but not of the MCF-10A cell line. These effects were reversed by specific antagonists of P2RXs. Similar results, as those observed with eATPase inhibitors, were seen with P2RX activators. All examined cell lines expressed both P2RX4 and P2RX7 at the mRNA, protein and cell surface levels.ConclusionThese results reveal that eATP modulates the chemotherapeutic response in TNBC cell lines, which could be exploited to enhance the efficacy of chemotherapy regimens for TNBC.

International audience; Patients with hormone receptor (HR)-positive tumors breast cancer usually experience a relatively low pathological complete response (pCR) to neoadjuvant chemotherapy (NAC). Here, we derived a 10-microRNA risk score (10-miRNA RS)-based model with better performance in the prediction of pCR and validated its relation with the disease-free survival (DFS) in 755 HR-positive breast cancer patients (273, 265, and 217 in the training, internal, and external validation sets, respectively). This model, presented as a nomogram, included four parameters: the 10-miRNA RS found in our previous study, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status, and volume transfer constant (K-trans). Favorable calibration and discrimination of 10-miRNA RS-based model with areas under the curve (AUC) of 0.865, 0.811, and 0.804 were shown in the training, internal, and external validation sets, respectively. Patients who have higher nomogram score (>92.2) with NAC treatment would have longer DFS (hazard ratio=0.57; 95%CI: 0.39-0.83; P=0.004). In summary, our data showed the 10-miRNA RS-based model could precisely identify more patients who can attain pCR to NAC, which may help clinicians formulate the personalized initial treatment strategy and consequently achieves better clinical prognosis for patients with HR-positive breast cancer.

TPS12139 Background: Obesity at diagnosis is associated with an increase in breast cancer (BC) specific mortality. Behavioral interventions targeting obesity-related health choices offer a scalable approach to improve patient engagement in the community. Episodic Future Thinking (EFT) is a novel remotely delivered behavioral intervention which engages the science of prospection where participants mentally simulate positive, detailed, and personal events that can occur in the future. EFT targets a key behavioral economic measure – Delay Discounting (DD). As DD rate rises, an individual devalues future outcomes to a greater degree and has a higher bias for immediate gratification. EFT can decrease DD in obese patients, leading to improved diet quality and weight loss. However, valuation of the future may impact cancer survivors differently. Herein, we propose the first randomized Phase II trial evaluating adherence and changes in DD and body weight with 12-week remotely delivered EFT vs control in overweight or obese BC survivors. Methods: Eligible patients have a history of DCIS or stage 1 to 3 BC, BMI > 25 kg/m2, have completed surgery, radiation, and chemotherapy, and are motivated to lose weight. They are randomized 1:1 to a 12-week EFT intervention or control (Episodic Recent Thinking; ERT). ERT is a validated control in which patients imagine events in the recent past. Randomization will be stratified by baseline DD rate. There is an optional 12 week follow up period where patients can continue to receive EFT or ERT cues. DD will be measured at baseline and every 4 weeks for 24 weeks. The primary endpoint is adherence, measured by percentage of thrice daily smartphone prompts participants open and attend to during the 12-week trial. Secondary endpoints are changes in body weight and DD rate at 12 and 24 weeks and change in PROs (PROMIS scales), insulin resistance (HOMA-IR), hs-CRP, and diet quality (HEI 2015) at 12 weeks from baseline. With 20 subjects per arm, the study has 80% power to detect deviation of 14 points from a target adherence rate of 80% using a 1 sample t-test. The primary endpoint is evaluable for all subjects, regardless of drop-out. Secondary endpoints will be evaluated using a linear mixed effects model. Hypothesis tests and confidence intervals will be two-sided at 5% significance/95% confidence level. Since trial activation in November 2021, 9 of the planned 46 patients are enrolled. Accrual is closely integrated with the dedicated Ohio State University Comprehensive Cancer Center Survivorship Program. This work is supported by the Alliance Cancer Control Program Pilot Award (5UG1CA189823-08). Clinical trial information: NCT05012176.

1504 Background: Trial recruitment that requires specific actionable mutations based on next-generation sequencing (NGS) is challenging. Barriers can include competing studies, physician study awareness, site proximity, mutation incidence, among other concerns. Methods: This study (NCT04432454) opened clinical sites using two methods during the COVID-19 pandemic. The “Traditional” approach included site selection, IRB and contract approval, and trial activation prior to a patient being identified for enrollment. The second approach used the Tempus “TIME” Trials network that would only open a site after identifying a patient with a mutation of interest and eligible for the trial. Results: The first patient enrolled was on 10/12/20 and the last patient was on 6/24/21. A total of 16 sites (6 Traditional and 10 TIME) participated. All Traditional sites, and none of the TIME sites, were affiliated with major academic institutions. Duration for full CTA execution for Traditional sites averaged 200.5 days (range 142 to 257) and for TIME sites averaged 7.6 days (range 2 to 14). IRB approval time average for Traditional sites was 27.5 days (range 12 to 71) and TIME sites was 3.0 days (range 1 to 12 days). Days from site selection to activation letter for Traditional sites was on average 250.0 days (range 187 to 281) and for TIME sites was 131.6 days (range 22 to 248). Time from study activation to first consent was 33.3 days (range 18 to 58) for Traditional sites and 8.8 days (range 1 to 35) for TIME sites. The first patient on-study was at a TIME site 115 days prior to a Traditional site and the first 7 patients enrolled were at TIME sites. Traditional sites consented 23 and enrolled 16 patients while the TIME sites consented 16 and enrolled 13. The trial enrolled all 29 patients in 8 months with the anticipated enrollment duration being 12 to 18 months. Conclusions: Although the Traditional and TIME programs had different operational models, they both contributed a significant number of patients and reduced the projected enrollment timeline. TIME sites enrolled the initial patients. These results demonstrate that the “Just-in-Time model,” in conjunction with a Traditional model, can reduce projected overall time to enrollment in biomarker-driven studies. [Table: see text]

532 Background: Limited compelling prospective and retrospective data regarding the added benefit of anti-HER2 therapy in the management of small, node-negative HER2-positive breast cancer (HER2+BC) exists, in part due to differences in outcome reporting, unmatched analyses, and a lack of head-to-head comparisons. As a result, national guideline committees find themselves unable to confidently recommend anti-HER2 therapy and clinicians are left to exercise clinical judgement on whether the use of anti-HER2 therapy should be considered for such patients. Methods: Our team performed a multi-institutional retrospective analysis using the ASCO CancerLinQ database, with a focus on clinical data from small, node-negative HER2+BC patients diagnosed between 2010 to 2021. We compared clinical outcomes between those who received adjuvant trastuzumab therapy, with or without chemotherapy, to those who did not, with our primary outcomes being invasive disease-free survival (iDFS) and overall survival (OS). We performed both a univariate and multivariate analysis, using a Cox proportional hazard model to control for factors including age, ethnicity, body mass index, hormone status, tumor grade, histology type, BRCA status, region, and smoking history. Additionally, a three-arm univariate analysis was performed comparing untreated patients to trastuzumab alone versus combination therapy. Results: In total, 1206 patients met inclusion criteria, including 779 patients who received trastuzumab with or without chemotherapy. We found a statistically significant improvement in both iDFS (HR 0.73, p = 0.01) and OS (HR 0.63, p = 0.027) on univariate analysis for those receiving anti-HER2 therapy. Similarly on multivariate analysis, iDFS (HR 0.75, p = 0.030) and OS (HR 0.61, p = 0.029) were improved in those who received therapy, regardless of tumor size. Our three-arm univariate analysis involving no treatment (n = 427), trastuzumab monotherapy (n = 169), and combination therapy (n = 578) found that iDFS was significantly improved for both treatment arms compared to observation alone (p = 0.006), whereas OS trended towards significance in the treatment arms but did not reach this target (p = 0.061). No significant difference was noted between treatment arms. Conclusions: Our analysis found a statistically significant improvement in iDFS and OS when patients with small, node negative, HER2+BC received adjuvant anti-HER2 therapy with or without chemotherapy as compared to observation. From our univariate three-arm comparison, it appears that trastuzumab provides the majority of benefit to patients in terms of DFS, but this result is exploratory. Further investigation is warranted, including meta-analyses to better characterize the degree of benefit seen with anti-HER2 treatment. For now, this data adds to evidence suggesting added benefit with therapy over observation.

Purpose: To assess metastatic breast cancer (MBC) patient perceptions and comprehension of tumor genomic testing and to evaluate associations with psychological wellbeing. Methods: In a prospective, single institution, single-arm trial, patients with MBC underwent next-generation sequencing at study entry, with sequencing results released at progression. Patients who completed surveys before undergoing sequencing were included in the study (n=58). We administered four validated psychosocial measures: Center for Epidemiologic Studies Depression Scale, Beck Anxiety Inventory, Trust in Physician Scale, and Communication and Attitudinal Self-Efficacy scale for Cancer. Genetic comprehension was assessed using 7-question objective and 6-question subjective measures. Longitudinal data were assessed using paired Wilcoxon signed rank and McNemar’s test of agreement. Results: There were no significant differences between the beginning and end of study in depression, anxiety, physician trust, or self-efficacy (median time on study: 7.6 months). Depression and anxiety were positively associated with each other and both negatively associated with self-efficacy. Self-efficacy decreased from pre- to post-genomic testing (p=0.05). There was a wide range of objective genetics comprehension and comprehension was significantly lower in non-white patients (p=0.02) and patients with lower income (p=0.04). Patients expressed increased confidence in their ability to teach others about genetics at end of study. Conclusions: This is the only study, to our knowledge, to longitudinally evaluate multiple psychological metrics in MBC as patients undergo tumor genomic testing. Among patients with MBC, depression and anxiety metrics were negatively correlated with patient self-efficacy. Patients undergoing somatic genomic testing had limited genomic knowledge, which varied by demographic groups.

Methicillin-resistant Staphylococcus aureus (MRSA) has been now recognized as major pathogen in adults and children, causing a variety of infections including osteomyelitis. Deep venous thrombosis in children with S. aureus osteomyelitis occurs rarely. Two siblings of a Saudi family who acquired MRSA bacteremia and osteomyelitis concurrently are described in this report. The second patient had an invasive infection characterized by bacteremia, multifocal osteomyelitis and septic arthritis complicated by deep venous thrombosis of the left popliteal vein, necessitating anticoagulant treatment with heparin. To my best knowledge, such simultaneous occurrence of MRSA bacteremia and osteomyelitis affecting two family members has not been reported. Also, deep venous thrombosis complicating osteomyelitis is rare and has not been reported from this region of the world.

Recurrent estrogen receptor α (ERα)-positive breast and ovarian cancers are often therapy resistant. Using screening and functional validation, we identified BHPI, a potent noncompetitive small molecule ERα biomodulator that selectively blocks proliferation of drug-resistant ERα-positive breast and ovarian cancer cells. In a mouse xenograft model of breast cancer, BHPI induced rapid and substantial tumor regression. Whereas BHPI potently inhibits nuclear estrogen-ERα-regulated gene expression, BHPI is effective because it elicits sustained ERα-dependent activation of the endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR), and persistent inhibition of protein synthesis. BHPI distorts a newly described action of estrogen-ERα: mild and transient UPR activation. In contrast, BHPI elicits massive and sustained UPR activation, converting the UPR from protective to toxic. In ERα(+) cancer cells, BHPI rapidly hyperactivates plasma membrane PLCγ, generating inositol 1,4,5-triphosphate (IP3), which opens EnR IP3R calcium channels, rapidly depleting EnR Ca(2+) stores. This leads to activation of all three arms of the UPR. Activation of the PERK arm stimulates phosphorylation of eukaryotic initiation factor 2α (eIF2α), resulting in rapid inhibition of protein synthesis. The cell attempts to restore EnR Ca(2+) levels, but the open EnR IP3R calcium channel leads to an ATP-depleting futile cycle, resulting in activation of the energy sensor AMP-activated protein kinase and phosphorylation of eukaryotic elongation factor 2 (eEF2). eEF2 phosphorylation inhibits protein synthesis at a second site. BHPI's novel mode of action, high potency, and effectiveness in therapy-resistant tumor cells make it an exceptional candidate for further mechanistic and therapeutic exploration.

Background. We report a rare case of synchro- nous occurrence of thyroglossal duct cyst carcinoma and thy- roid carcinoma and discuss its management in detail. Methods. A 59-year-old woman was clinically diagnosed to have a thyroglossal duct cyst and a solitary nodule. Fine-nee- dle aspiration cytology revealed a papillary carcinoma in the thyroglossal duct cyst and a colloid in the thyroid nodule. Sis- trunk's procedure along with a total thyroidectomy was per- formed followed by postoperative radioiodine ablation. Results. Histopathologic examination revealed thyroglossal duct cyst carcinoma and bilateral foci of papillary carcinoma in the thyroid gland. She has remained free of disease on fol- low-up. Conclusion. Most cancers arising in thyroglossal duct cysts are of low risk, and Sistrunk's procedure is an adequate treat- ment for such cancers. However, for synchronously occurring cancers of the thyroglossal duct cyst and thyroid gland, or high-risk thyroglossal duct cyst cancers, more aggressive treatment comprising total thyroidectomy, Sistrunk's procedure, and radioiodine therapy is indicated. V C 2009 Wiley Periodicals, Inc. Head Neck 31: 1387-1391, 2009

Lung cancer is the most common cause of cancer mortality worldwide. Non-small-cell lung carcinomas (NSCLCs), which represent around 80% of lung tumors, exhibit poor prognosis and are usually refractory to conventional chemotherapy. Elucidating the molecular and cellular mechanisms that are dysregulated in NSCLCs may lead to new possibilities for targeted therapy or enhanced efficacy of current therapies. Here we demonstrate Wnt pathway activation in around 50% of human NSCLC cell lines and primary tumors, through different mechanisms, including autocrine Wnt pathway activation involving upregulation of specific Wnt ligands. Downregulation of activated Wnt signaling inhibited NSCLC proliferation and induced a more differentiated phenotype. Together, our findings establish importance of activated Wnt signaling in human NSCLCs and offer the possibility of targeting upregulated Wnt signaling as a new therapeutic modality for this disease.

The presence of hydrometrocolpos and postaxial polydactyly in a neonate can be caused by two genetic conditions; namely, McKusick-Kaufman syndrome and Bardet-Biedl syndrome. There are no distinct clinical features that allow discrimination between the two syndromes, as the cardinal features of rod-cone dystrophy, obesity, learning disability and renal dysfunction in Bardet-Biedl syndrome are age dependent. McKusick-Kaufman syndrome is characterized by vaginal atresia with hydrometrocolpos, postaxial polydactyly and congenital heart defect. Here we report an unusual presentation of Bardet-Biedl syndrome: a neonate born in a consanguineous family having an older sibling diagnosed with Bardet-Biedl syndrome presenting with postaxial polydactyly and vaginal atresia; the latter causing hydrometrocolpos, hydronephrosis and renal failure. Relief of urinary obstruction by exploratory laparotomy and aspiration of fluid, and vaginal reconstruction gradually reversed the hydronephrosis and renal failure. The patient developed end-stage renal failure towards the end of her first decade, possibly due to underlying renal pathology associated with Bardet-Biedl syndrome.

O(6)-methylguanine DNA methyltransferase (MGMT) deficiency is associated with an increased susceptibility to alkylating agent toxicity. To understand the contribution of MGMT in protecting against cyclophosphamide (CP)-induced toxicity, mutagenesis and tumorigenesis, we compared the biological effects of this agent in transgenic Mgmt knockout and wild-type mice. In addition, neurofibromin (Nf1)+/- background was used to increase the likelihood of CP-induced tumorigenesis. Cohorts of Mgmt-proficient or -deficient mice (either Nf1+/+ or Nf1+/-) were given 6 weekly injections of a maximally tolerated dose of CP (250 mg/kg) or vehicle and followed for 15 months. CP-treated mice had more deaths than control mice but there was no difference in the long-term survival between Mgmt+/+ and Mgmt-/- mice (12 of 83 Mgmt+/+ mice died compared to 12 of 80 Mgmt-/- mice, disregarding Nf1 status). Lymphomas and adrenal tumours were the most frequent malignancies. Interestingly, CP-treated, Mgmt-deficient mice developed fewer tumours than controls. Ten of 71 (14%) Mgmt-proficient mice developed tumours after CP treatment compared to only 2 of 68 (3%) Mgmt-deficient mice (P = 0.02). Mgmt-/-, Nf1+/- mice developed fewer tumours (1 of 35, 3%) following CP compared to Mgmt+/+, Nf1+/- mice (7 of 37, 19%) (P = 0.03). Hypoxanthine-guanine phosphoribosyltransferase mutation assays showed no significant increases in mutant frequencies in Mgmt-/- (18.1 x 10(6)) compared to Mgmt+/+ mice (12.9 x 10(6)). These data indicate that MGMT deficiency does not protect against long-term toxicity or mutagenicity from CP and appears to attenuate the occurrence of CP-induced tumours in an Nf1+/- background.

O 6-alkylguanine-DNA alkyltransferase (AGT) protects from the mutagenic and toxic lesions induced by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), and in many tumors, AGT overexpression provides a means of resistance. To circumvent this, O 6-benzylguanine, an inactivator of AGT, has been developed and is currently in clinical development with BCNU; however, the potential long-term toxicities associated with this treatment are unknown. With the inactivation of AGT by O 6-benzylguanine, a higher number of toxic and mutagenic O 6-alkylguanine lesions introduced by methylating or chloroethylating agents would be expected. In this study, cohorts of mice were treated with vehicle, O 6-benzylguanine (30 mg/kg), BCNU alone (low dose of 15 mg/kg or high dose of 50 mg/kg), or O 6-benzylguanine (30 mg/kg) plus BCNU (15 mg/kg) and followed for 12 months post-treatment. Mice treated with O 6-benzylguanine plus BCNU or high-dose BCNU died significantly earlier ( p < 0.0001) than mice in the other three cohorts with a median survival of 8.3 ( O 6-benzylguanine plus BCNU) and 7.9 months (high-dose BCNU). Histopathologic sections of tissues revealed that the most common morphological diagnosis in animals treated with O 6-benzylguanine plus BCNU (15 mg/kg) or BCNU (50 mg/kg) was cytomegaly in the lung with greater severity observed in mice receiving the combination O 6-benzylguanine plus BCNU. Four of five mice analyzed in this cohort had alveolar histiocytosis, with one also having alveolar edema. In contrast, liver and kidney toxicity was only observed in mice treated with BCNU (50 mg/kg). These results suggest that O 6-benzylguanine enhances long-term pulmonary toxicity associated with BCNU in mice.

This is an unusual case of isolated bilateral zygomatic complex and arch fracture, which is extremely rare. The literature has no such report of a case.

Estrogens, acting through estrogen receptor α (ERα), stimulate breast cancer proliferation, making ERα an attractive drug target. Since 384-well format screens for inhibitors of proliferation can be challenging for some cells, inhibition of luciferase-based reporters is often used as a surrogate end point. To identify novel small-molecule inhibitors of 17β-estradiol (E(2))-ERα-stimulated cell proliferation, we established a cell-based screen for inhibitors of E(2)-ERα induction of an estrogen response element (ERE)(3)-luciferase reporter. Seventy-five "hits" were evaluated in tiered follow-up assays to identify where hits failed to progress and evaluate their effectiveness as inhibitors of E(2)-ERα-induced proliferation of breast cancer cells. Only 8 of 75 hits from the luciferase screen inhibited estrogen-induced proliferation of ERα-positive MCF-7 and T47D cells but not control ERα-negative MDA-MB-231 cells. Although 12% of compounds inhibited E(2)-ERα-stimulated proliferation in only one of the ERα-positive cell lines, 40% of compounds were toxic and inhibited growth of all the cell lines, and ~37% exhibited little or no ability to inhibit E(2)-ERα-stimulated cell proliferation. Representative compounds were evaluated in more detail, and a lead ERα inhibitor was identified.

Type 1 diabetes is one of the most widely studied complex genetic disorders and the genes in human leukocyte antigen (HLA) locus are reported to account approximately 40%-50% of familial aggregation of type 1 diabetes. Genetic markers are helpful in assessing the risk of type 1 diabetes in the general population as well as in close relatives of a patient with type 1 diabetes. The major genetic determinants of this disease are polymorphisms of class II HLA genes encoding DQ and DR. The major susceptibility genes for type 1 diabetes are in the HLA region, and over 90% of patients carry genotypes DR4, DQ8 and/or DR3, DQ2. Absence of the above alleles makes type 1 diabetes very unlikely, especially if the subject carries protective genotypes such as DR2 and/or DQ6. In this brief report of a consanguineous Saudi family, four offsprings inherited one or both of balanced reciprocal translocations from their father. Two offsprings, one with a translocation and the other without, developed type 1 diabetes during early childhood. Both these diabetic children were found to have HLA genotype DQ 2/8, whereas the father and the youngest daughter, both carrying two sets of balanced translocations as well as the protective HLA genotype DQ6, were free of diabetes during several years of observation. This underscores the influence of HLA genotype DQ 2/8 in the susceptibility and DQ6 in the protective effect on type 1 diabetes even in individuals with gross chromosomal abnormalities.