The survival benefit of adjuvant trastuzumab with or without chemotherapy in the management of small (T1mic, T1a, T1b, T1c), node negative HER2+ breast cancer.

There is limited data regarding the added benefit of adjuvant systemic therapy in the management of small, node-negative, HER2+ breast cancer. In a multi-institutional retrospective analysis using the American Society of Clinical Oncology CancerLinQ database, we compared survival outcomes among T1a-c N0 HER2+ patients diagnosed between 2010 to 2021 who received locoregional therapy alone or in combination with adjuvant trastuzumab (+/- chemotherapy). Primary outcomes were invasive disease-free survival (iDFS) and overall survival (OS). Of the 1,184 patients, 436 received locoregional therapy alone. We found a statistically significant improvement in iDFS (HR 0.73, P = 0.003) and OS (HR 0.63, P = 0.023) on univariate analysis with adjuvant trastuzumab with or without chemotherapy which remained statistically significant on multivariate analysis. Three-arm univariate analysis found that iDFS was significantly improved with trastuzumab monotherapy (P = 0.003) and combination therapy (P = 0.027) compared to observation. Subgroup data suggests that T1b/c tumors derive the greatest benefit.

Real-world treatment patterns of adjuvant endocrine therapy and ovarian suppression in premenopausal HR+/HER2+ breast cancer.

BACKGROUND: The optimal adjuvant endocrine therapy (ET) in hormone receptor positive (HR+) and human epidermal growth factor receptor 2 positive (HER2+) premenopausal breast cancer (BC) remains unclear. Moreover, the benefit and clinical indications of ovarian suppression (OS) is poorly elucidated. We described real-world patterns surrounding choice of ET and clinicopathologic features which predicted treatment with OS in a contemporary cohort of premenopausal women with HR+/HER2+ BC. METHODS: This retrospective analysis included premenopausal patients with nonmetastatic HR+/HER2+ BC from the CancerLinQ Discovery database from January 2010 to May 2020. Women were less than 50 years and received chemotherapy, anti-HER2 therapy, and ET. They were categorized into 1 of 4 groups based on type of ET prescribed at initiation: aromatase inhibitor (AI) + OS, OS, tamoxifen + OS, or tamoxifen. Multivariable logistic regression assessed associations between clinicopathologic features and OS use. RESULTS: Out of 360,540 patients with BC, 937 were included. The majority (n = 818, 87%) were prescribed tamoxifen, whereas 4 (0.4%), 50 (5.3%), and 65 (6.9%) received OS, tamoxifen + OS and AI + OS, respectively. No clinicopathologic features predicted OS use apart from age; patients <35 years were more likely to receive OS compared with those ≥35 years (odds ratio 2.33, p < 0.001). CONCLUSIONS: This is the first real-world study evaluating ET treatment patterns in HR+/HER2+ premenopausal BC. OS use was uncommon and the majority received tamoxifen as the preferred ET regardless of most clinicopathologic risk factors. Additional research is needed to optimize ET decisions in young women with this distinct BC subtype.

Potent Estrogen Receptor ß Agonists with Inhibitory Activity In Vitro , Fail to Suppress Xenografts of Endocrine-Resistant Cyclin-dependent Kinase 4/6 inhibitor-Resistant Breast Cancer Cells.

Objective: Seventy percent of newly diagnosed breast cancers are estrogen receptor-α positive and HER2/neu negative [1]. First-line treatments incorporate endocrine therapy and cyclin-dependent kinase 4/6 inhibitors [2]. However, therapy resistance occurs in most patients [3-5]. Hence, there is an urgent need for effective second-line treatments. We previously showed that the potent estrogen receptor-ß agonists, OSU-ERb-12 and LY500307, synergized with the selective estrogen receptor modulator, tamoxifen, in vitro. Furthermore, we showed that these compounds inhibited endocrine-resistant and cyclin-dependent kinase 4/6-inhibitor-resistant estrogen receptor α-positive cell lines in vitro [6]. Here, we used fulvestrant- and abemaciclib-resistant T47D-derived cell line xenografts to determine the efficacy of the combination of OSU-ERb-12 and LY500307 with tamoxifen in vivo. Results: Despite efficacy in vitro, treatments failed to reduce xenograft tumor volumes. Hence, we conclude that this treatment strategy lacks direct cancer cell-intrinsic cytotoxic efficacy in vivo.

Comparison of Contrast-Enhanced 3D Imaging with 2D Imaging in the Evaluation of Perianal Fistula at 3T: A Prospective Observational Study.

Introduction Perianal fistula and its recurrence is a challenging entity for surgeons. It is a well-establi1shed fact that magnetic resonance imaging (MRI) findings influence surgical procedures and reduce the rate of recurrence. In this study, we assessed the contrast-enhanced (CE) three dimensional T1 sequences [sampling perfection with application optimized contrast using different flip angle evolution (SPACE) and volumetric interpolated breath-hold examination (VIBE)] in a 3T MRI system to evaluate perianal fistulas and compared them with two-dimensional (2D) sequences. Materials and Methods Forty-four patients (mean age, 38.8 ± 15.3 [standard deviation]; 32 males, 12 females) with perianal fistula were included in this prospective study. The patients underwent conventional noncontrast, 2D sequences, diffusion-weighted imaging, followed by postcontrast, 2D T1 images in both axial and coronal planes, and 3D sequences at 3T. Acquisition times were recorded for each sequence. Each postcontrast sequence was evaluated in terms of image quality, presence of artifacts, fistula type, presence of an abscess, visibility, and number of internal orifices. The surgical findings were considered the gold standard. The imaging findings were compared with the surgical findings. Results In all three sequences, the fistula type and abscess were identified correctly in all patients. The sensitivity value for identification of ramifications utilizing CE 3D T1 VIBE sequence, CE 3D T1 SPACE, and CE 2D T1 images was 100, 86, and 36%, respectively. The number of internal orifices was identified by the CE 3D T1 VIBE and CE 3D T1 SPACE sequences in 100 and 92% of patients, respectively. CE 2D T1 images correctly identified internal orifices in 80% of patients. The overall scan time for each 3D sequence was shorter than for the combined postcontrast 2D sequences. Conclusion CE 3D T1 SPACE and CE 3D T1 VIBE sequences outperformed conventional CE 2D sequences in the evaluation of perianal fistulas in terms of visibility and the number of internal orifices with a shorter scanning time. Among the 3D sequences, CE 3D T1 VIBE is slightly superior to CE 3D T1 SPACE sequence.

Phase Ib study of HSP90 inhibitor, onalespib (AT13387), in combination with paclitaxel in patients with advanced triple-negative breast cancer.

Background: Heat shock protein 90 (HSP90) is a molecular chaperone required for stabilization of client proteins over-activated in triple-negative breast cancer (TNBC). Over-expression of HSP90 client proteins has been implicated in paclitaxel resistance. Onalespib (AT13387) is a potent inhibitor of HSP90 that could improve paclitaxel efficacy when administered in combination. Design: This phase Ib trial administered onalespib with paclitaxel in patients with advanced TNBC to assess safety and establish a recommended phase II dose (RP2D). Objectives: The primary objectives were determining the dose-limiting toxicities and maximum tolerated dose of combination therapy. Secondary objectives included pharmacokinetic (PK) analysis and determination of overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Methods: Patients with advanced TNBC were treated with standard dose intravenous paclitaxel in combination with intravenous onalespib at doses ranging from 120 to 260 mg/m2 administered on days 1, 8, and 15 of a 28-day cycle using a standard 3 + 3 design. A total of 15 patients were enrolled to dose expansion cohort at RP2D to confirm safety profile. Results: Thirty-one patients were enrolled in the study, of which over 90% had received prior taxane therapy. Paclitaxel was given for metastatic disease in 23% of patients. Adverse events (AEs) included anemia (grade 3: 20%), lymphopenia (grade 3: 17%), and neutropenia (grade 3: 33%, grade 4: 4%). The most frequent grade ⩾3 non-hematologic AE was diarrhea (7%). The established RP2D was 260 mg/m2 onalespib when given with paclitaxel at 80 mg/m2. PK analysis revealed a modest drug interaction profile for onalespib in the combination regimen. ORR was 20%. Three patients achieved complete responses, all of whom had received prior taxane therapy. Median DOR was 5.6 months; median PFS was 2.9 months. Conclusion: Combination treatment with onalespib and paclitaxel had an acceptable toxicity profile and RP2D was determined to be 260 mg/m2 of onalespib. Combination therapy showed antitumor activity in patients with advanced TNBC. Trial registration: Onalespib and paclitaxel in treating patients with advanced TNBC https://clinicaltrials.gov/ct2/show/NCT02474173.

Phase 1b study of HSP90 inhibitor called onalespib in combination with paclitaxel in patients with advanced triple-negative breast cancer This Phase 1b study demonstrated that treatment with a combination of onalespib and paclitaxel was reasonably well tolerated by most patients. Onalespib at 260 mg/m² given intravenously on days 1, 8 and 15 on 28-day cycles in combination with standard dose and schedule of paclitaxel was established as the recommended phase 2 dose for further clinical development. Despite minor drug-drug interactions between these 2 agents, onalespib did not alter paclitaxel exposure and paclitaxel did not affect exposure to onalespib. While onalespib with paclitaxel combination therapy did not yield durable objective responses or prolonged progression-free survival, there were several patients with long-lasting benefit from this combination including patients who previously experienced progression on taxane therapy.

An Observational Study on Cystic Alterations in Normal Dental Follicles Associated with Impacted Lower Third Molar for Early Intervention.

AIM: To evaluate the cystic changes in the radiographically normal dental follicle associated with impacted mandibular third molar. MATERIALS AND METHODS: This study was conducted on 80 patients. Samples were selected using a convenient sampling technique from the patients who had impacted mandibular third molars in Pell and Gregory's positions B and C, with follicular space less than 2.5 mm in diameter. After surgical removal of an impacted tooth, the dental follicle was sent for histopathologic evaluation. RESULTS: Pathologic alterations were found in 19% of cases out of 80 samples. Odontogenic keratocystic and dentigerous cystic changes were found in 7% of cases. A statistically significant cystic alteration was found in female patients and distoangular impacted teeth. CONCLUSION: This study shows a significant cystic alteration in the radiologically normal dental follicles. Clinical and radiographic features alone may not be a reliable indicator of the absence of pathology. Early intervention of impacted teeth will help to reduce morbidity due to the development of pathology. CLINICAL SIGNIFICANCE: This study will help educate patients on the risks of retaining impacted teeth, based on scientific facts, in order to minimize the risks and to assess the correlation of pathologic alterations with the depth of impaction and angular position of the impacted tooth.

A Study to Evaluate the Efficacy of Ultrasonography as a Diagnostic Screening Tool in Maxillofacial Fractures: A Prospective Study.

AIM: The aim of the study was to estimate the diagnostic efficacy of high-resolution ultrasonography (USG) in the diagnosis of maxillofacial fractures. MATERIALS AND METHODS: A descriptive diagnostic evaluation study was carried out on 30 patients with suspected maxillofacial fractures, out of which 26 were male (86.7%) and 4 were female (13.3%). After initial management, detailed clinical examinations were carried out and significant findings were noted. Computed tomography (CT) scans were performed in fracture-suspecting patients followed by USG examination which was done in a standardized pattern on both sides of the face. The result of USG was compared with the CT scan report. RESULT: Based on CT findings, 65 sites were found to be fractured, and this was considered the gold standard. Ultrasonography detected 58 fractures at these 780 sites, of which 54 were true fractures, while 4 were false-positive results. However, USG was not able to detect eleven fractures. The overall sensitivity and specificity of USG were 83.1% and 99%, respectively. The positive and negative predictive values were 93% and 98%, respectively. CONCLUSION: According to our study, it may be concluded that USG may be recommended as a diagnostic screening tool to detect superficial maxillofacial fractures. CLINICAL SIGNIFICANCE: Ultrasonography provides a safe, cost-effective, reliable, non-invasive, easily available, and portable imaging modality to screen for maxillofacial fractures.

Retrospective cohort study of CDK4/6-inhibitor-induced alopecia in breast cancer patients.

PURPOSE: Dermatologic adverse events commonly result in the interruption of oncologic treatment, and targeted therapies are the most frequently interrupted class of anticancer agents. Alopecia is a common cutaneous adverse event reported with CK4/6i therapy. Though the clinical characteristics and therapeutic response of EIA have been well documented, few studies have characterized alopecia in patients treated with CDK4/6i. METHODS: This study analyzed a retrospective cohort of 28 breast cancer patients diagnosed with endocrine-induced alopecia (EIA) or CDKiA. Comparative analysis of the clinical characteristics of alopecia and therapeutic response to minoxidil was conducted. Therapeutic response to minoxidil (LDOM or topical [5%] solution or foam) was assessed by both Dean Scale and qualitative clinical improvement by comparison of pretreatment and posttreatment clinical images by single-blinded, board-certified academic dermatologists (ST and BD). RESULTS: CDKiA was clinically similar to androgenetic alopecia and specific vertex involvement was more common in patients treated with CDK4/6i + ET than endocrine monotherapy (n = 7 [70.0%] vs n = 4 [36.4%]; p = 0.04), respectively. After 4-6 months of minoxidil, there was a moderate to significant qualitative alopecia improvement in 80% of CDKiA patients versus 94.4% of EIA patients. Additionally, superior improvement of mean Dean Score grade was observed in EIA (with change from pre- to posttreatment - 0.44; p = 0.0002). CONCLUSION: Compared to endocrine monotherapy, patients on combination CDK4/6i + ET had greater extent of vertex involvement and were more recalcitrant to minoxidil. The preferential vertex involvement observed in CDKiA suggests that combination therapy with minoxidil and topical antiandrogens with poor systemic absorption should be studied in this setting.

Survival outcomes seen with neoadjuvant chemotherapy in the management of locally advanced inflammatory breast cancer (IBC) versus matched controls.

Inflammatory breast cancer (IBC) poses an ongoing challenge as rates of disease recurrence and mortality remain high compared to stage-matched controls. However, frontline therapy has evolved through the years, including the widespread use of neoadjuvant chemotherapy (NAC) given the prognostic importance of pathologic complete response (pCR). Due to these sweeping changes, we need new data to assess current recurrence and survival outcomes for locally advanced IBC in the context of matched non-inflammatory controls. We conducted a retrospective analysis of institutional IBC data from 2010 to 2016 with the primary objective of comparing overall survival (OS), relapse-free survival (RFS), and distant relapse-free survival (DRFS). We matched IBC patients to non-inflammatory controls based on age, receptor status, tumor grade, clinical stage, and receipt of prior NAC. Secondary objectives included assessing pCR rates and identifying prognostic factors. Among NAC recipients, we observed similar pCR rates (47.6 % vs. 49.4 %, p = 0.88) between IBC (n = 84) and matched non-IBC (n = 81) cohorts. However, we noted a significant worsening of OS (p = 0.0001), RFS (p = 0.0001), and DRFS (p = 0.001) in the IBC group. Specifically, 5-year OS in the IBC cohort was 58.9 % vs. 86.7 % for matched controls (p = 0.0003). Older age was a weak negative predictor for OS (HR 1.03, p = 0.001) and RFS (HR 1.02, p = 0.01). For DRFS, older age was also a weak negative predictor (HR 1.02, p = 0.02), whereas the use of NAC was a positive predictor (HR 0.47, p = 0.02). Despite no clear difference in pCR, survival outcomes remain poor for IBC compared to matched non-inflammatory controls.

Evaluating the Clinical Efficacy of Maxillary Labial Frenectomy Procedure Using Diode Laser (980 nm) and Conventional Scalpel: An Observational Study.

Aim: This is an era of minimally invasive and least traumatic surgical interventions being focused on. The traditional scalpel frenectomy technique offers an increase in post-operative sequelae. To unravel this scenario a comparative evaluation is carried out to find out the clinical outcomes and quality of life after maxillary labial frenectomy using a conventional scalpel and diode laser frenectomy of 980 nm. Materials and Methods: Thirty-six subjects age ranging between 18 and 45 years reported to the Department of Oral and Maxillofacial Surgery, MES Dental College, Perinthalmanna with an aberrant frenal attachment of maxillary labial frenum were randomly assigned into two groups. Group A underwent the conventional scalpel technique and group B for the diode laser-assisted (980 nm) frenectomy technique. The post-operative parameters of ooze from the surgical site, pain, wound healing, and discomfort or acceptance of the procedure were assessed on day 1, day 7, and day 14, respectively. Results: The diode laser group exhibited statistically significant clinical and healing outcomes. Less pain, minimal or absent ooze, increased healing, and better acceptance of the procedure with diode laser at 1, 7, and 14 days recall visit. Conclusion: Surgical interventions involving needle puncture and the associated post-operative sequelae are the most dreaded experiences that make patients indifferent toward surgical treatments. Thus in terms of better clinical outcomes and improved quality of life diode laser frenectomy is an excellent alternative wherein a needleless anesthetic success followed by minimal surgical intervention and less post-operative sequelae with fast recovery is possible.

Depression, Inflammation, and Intestinal Permeability: Associations with Subjective and Objective Cognitive Functioning throughout Breast Cancer Survivorship.

About one-in-three breast cancer survivors have lingering cognitive complaints and objective cognitive impairment. Chronic inflammation and intestinal permeability (i.e., leaky gut), two risk factors for cognitive decline, can also fuel depression-another vulnerability for cognitive decline. The current study tested whether depression accompanied by high levels of inflammation or intestinal permeability predicted lower subjective and objective cognitive function in breast cancer survivors. We combined data from four breast cancer survivor studies (n = 613); some had repeated measurements for a total of 1015 study visits. All participants had a blood draw to obtain baseline measures of lipopolysaccharide binding protein-a measure of intestinal permeability, as well as three inflammatory markers that were incorporated into an inflammatory index: C-reactive protein, interleukin-6, and tumor necrosis factor-α. They reported depressive symptoms on the Center for Epidemiological Studies depression scale (CES-D), and a binary variable indicated clinically significant depressive symptoms (CES-D ≥ 16). The Kohli (749 observations) and the Breast Cancer Prevention Trial (591 observations) scales assessed subjective cognitive function. Objective cognitive function tests included the trail-making test, Hopkins verbal learning test, Conners continuous performance test, n-back test, FAS test, and animal-naming test (239-246 observations). Adjusting for education, age, BMI, cancer treatment type, time since treatment, study visit, and fatigue, women who had clinically elevated depressive symptoms accompanied by heightened inflammation or intestinal permeability reported poorer focus and marginally poorer memory. However, poorer performance across objective cognitive measures was not specific to inflammation-associated depression. Rather, there was some evidence of lower verbal fluency; poorer attention, verbal learning and memory, and working memory; and difficulties with visuospatial search among depressed survivors, regardless of inflammation. By themselves, inflammation and intestinal permeability less consistently predicted subjective or objective cognitive function. Breast cancer survivors with clinically significant depressive symptoms accompanied by either elevated inflammation or intestinal permeability may perceive greater cognitive difficulty, even though depression-related objective cognitive deficits may not be specific to inflammation- or leaky-gut-associated depression.

Inflamed but not impulsive: Acute inflammatory cytokine response does not impact prepotent response inhibition.

BACKGROUND: Prior evidence has linked inflammation with impulsivity, but most of this evidence is cross-sectional. In this study, we provoked an acute inflammatory cytokine response to see whether it lowered prepotent response inhibition on three cognitive tasks. METHOD: This study features secondary analyses from a randomized crossover trial in which 171 postmenopausal breast cancer survivors (Stage I-IIIA) each received a typhoid capsular polysaccharide vaccination and a saline placebo injection in a random sequence at two separate visits at least one month apart. Participants completed the Stroop Color-Discrepant Task, the 2-back, and the Conners Continuous Performance Test (CPT) on the computer between 5 and 7 h after the injections. They had their blood drawn once before and repeatedly after the injection to measure interleukin-1 receptor antagonist and interleukin-6 responses. RESULTS: Women committed marginally fewer errors on the Stroop color-discrepant trials after the typhoid vaccine (M = 0.36, SE = 0.08), compared to placebo (M = 0.54, SE = 0.09, p = .076). Injection type did not predict 2-back accuracy (p = .80) or CPT commission errors (p = .47). Inflammatory cytokine responses were also unrelated to the outcomes of interest (ps>.16). CONCLUSION: We found no evidence that an acute inflammatory cytokine response provokes response disinhibition - an important facet of impulsivity. In fact, our only marginally non-significant result suggested that women were better able to inhibit their prepotent responses on the Stroop after receiving the typhoid vaccine, compared to placebo. Further experimental tests of the acute inflammatory cytokine response's effect on other aspects of impulsivity are warranted. LIMITATIONS: The sample was female, primarily White, highly educated cancer survivors, and recruitment was not premised on impulsive traits or diagnosis with an impulsive-related disorder. Also, there are many facets of impulsivity, and this study only measured response inhibition.

The role of heparan sulfate in enhancing the chemotherapeutic response in triple-negative breast cancer.

Background: 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 current therapies do not facilitate long-lasting responses. Thus, there is a demand for more innovative therapies that induce durable 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. Polysulfated polysaccharide 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 enhanced cell death in response to chemotherapy. Methods: 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 the heparanase inhibitor OGT 2115 while analyzing eATP release and cell viability. Moreover, to verify that the effects of OGT 2115 are mediated through eATP, we applied specific antagonists to the purinergic receptors P2RX4 and P2RX7. In addition, the protein expression of heparanase was compared in the cell lines by Western blot analysis. We also evaluated the consequences of this therapeutic strategy on the breast cancer-initiating cell population in the treated cells using flow cytometry and tumorsphere formation efficiency assays. Results: Heparanase was found to be highly expressed in immortal mammary epithelial cells in comparison to TNBC cell lines. The heparanase inhibitor OGT 2115 augmented chemotherapy-induced TNBC cell death and eATP release. Conclusion: These results demonstrate that inhibiting the degradation of heparan sulfate in the tumor microenvironment augments the susceptibility of TNBC cell lines to chemotherapy by increasing extracellular ATP concentrations. This strategy could potentially be applied to induce more enhanced and enduring responses in TNBC patients.

Sulfatase 2 Inhibition Sensitizes Triple-Negative Breast Cancer Cells to Chemotherapy Through Augmentation of Extracellular ATP.

Background: Breast cancer is the leading cause of cancer-related death among women worldwide. Patients diagnosed with triple-negative breast cancer (TNBC) have limited therapeutic options that produce durable responses. Hence, a diagnosis of TNBC is associated with a poor prognosis compared to other types of breast cancer. As a result, there is a critical need for novel therapies that can deepen and prolong responses.We previously found that chemotherapy causes the release of extracellular adenosine triphosphate (eATP). Augmenting eATP release can boost the response of TNBC cells to chemotherapy and cause increased cell death. However, eATP concentrations are limited by several families of extracellular ATPases, which complicates the design of compounds that attenuate eATP degradation.In this study, we hypothesized that heparan sulfate (HS) would inhibit extracellular ATPases and accentuate chemotherapy-induced cytotoxicity in TNBC by augmenting eATP. HS can be desulfated by sulfatase 1 and 2; sulfatase 2 is consistently highly expressed in a variety of cancers including breast cancer, whereas sulfatase 1 is not. We hypothesized that the sulfatase 2 inhibitor OKN-007 would exacerbate chemotherapy-induced eATP release and TNBC cell death. Methods: TNBC cell lines and nontumorigenic immortal mammary epithelial cells were treated with paclitaxel in the presence of heparan sodium sulfate and/or OKN-007; eATP content and cell viability were evaluated. In addition, protein and cell surface expression of sulfatases 1 and 2 were determined in all examined cell lines via ELISA, Western blot, and flow cytometry analyses. Results: Sulfatase 2 was highly expressed in TNBC cell lines and human breast cancer samples but not in immortal mammary epithelial cells and much less so in normal human breast tissue and ductal carcinoma in situ samples. OKN-007 exacerbated chemotherapy-induced eATP release and chemotherapy-induced TNBC cell death. When combined with chemotherapy, OKN-007 attenuated cells with a cancer-initiating cell phenotype. Conclusions: These results suggest that sulfatase 2 inhibitors in combination with chemotherapy attenuate the viability of TNBC cells more than chemotherapy alone by exacerbating eATP release. These effects, as well as their capacity to attenuate the cancer-initiating cell fraction, may translate into combination therapies for TNBC that induce deeper and more durable responses.

Mortality in individuals with COPD on long-term home non-invasive ventilation.

BACKGROUND: Real-world evidence regarding survival of patients with chronic obstructive pulmonary disease (COPD) using chronic non-invasive ventilation (NIV) is scarce. RESEARCH QUESTION: How do obesity and other factors relate to mortality in patients with COPD on chronic NIV? STUDY DESIGN: and Methods: We retrospectively analyzed data from COPD patients enrolled in a home ventilation program between 2014 and 2018. Survival was compared between obese and non-obese groups using the Kaplan-Meier method. Factors associated with mortality were identified using multivariable Cox proportional regression analyses with Least Absolute Selection and Shrinkage Operator (LASSO) regularization. Univariable analyses were also done stratified by obesity. RESULTS: Median survival was 80.0 (95% CI: 71.0-NA) months among obese (n = 205) and 30.0 (95%CI: 19.0-42.0) months in non-obese (n = 61) patients. NIV adherence was high in both groups. Mortality was associated with male gender [HR 1.44], chronic opioids or benzodiazepines use [HR 1.07], home oxygen use [HR 1.82], fixed pressure mode of ventilation [HR 1.55], NIV inspiratory pressure [HR 1.05], and thoracic cancer [HR 1.27]; obesity [HR: 0.43], age [HR 0.99] and NIV expiratory pressure [HR 0.94] were associated with decreased mortality. In the obese, univariable analyses revealed that chest wall disease, thoracic cancer, home oxygen use, FEV1% predicted, and ventilation parameters were associated with mortality. In the non-obese, male gender and respiratory comorbidities were related to mortality. INTERPRETATION: Obesity is associated with improved survival in COPD patients highly adherent to NIV. Other factors associated with mortality reflect disease severity and ventilator parameters, with differences between obese and non-obese patients.

Worry and Mindfulness Differentially Impact Symptom Burden Following Treatment Among Breast Cancer Survivors: Findings From a Randomized Crossover Trial.

BACKGROUND: Breast cancer survivors often experience many somatic and cognitive side effects resulting from their cancer diagnosis and treatment, including higher rates of pain, fatigue, and memory/concentration problems. Emotion regulation offers opportunities to either enhance or dampen physical health. PURPOSE: In a secondary analysis of a double-blind randomized controlled trial (RCT) using a typhoid vaccine to assess factors associated with breast cancer survivors' inflammatory responses, we assessed how two specific aspects of emotion regulation, mindfulness, and worry, corresponded to acute changes in focus problems, memory problems, and fatigue along with performance on pain sensitivity and cognitive tasks across two visits among breast cancer survivors. METHODS: Breast cancer survivors (N = 149) completed two 8.5-hr visits at a clinical research center. Survivors were randomized to either the vaccine/saline placebo or a placebo/vaccine sequence. Worry and mindfulness questionnaires provided data on trait-level emotion regulation abilities. Fatigue, memory problems, and focus difficulties were assessed via Likert scales six times-once before the injections and then every 90 min for 7.5 hr thereafter. Women also completed a pain sensitivity task and several cognitive tasks at each visit. RESULTS: Findings from this study showed that breast cancer survivors who worried more and were less mindful experienced subjective memory problems, focus problems, and cold pain sensitivity across two visits and irrespective of injection type. Lower mindfulness also corresponded to higher subjective fatigue and hot pain sensitivity and objective ratings. Emotion regulation skills did not predict objective pain sensitivity or cognitive problems. CONCLUSION: Results from this study highlight the benefits of adaptive emotion regulation in helping mitigate symptoms associated with breast cancer survivorship.

Breast cancer survivors experience side effects resulting from their cancer diagnosis and treatment, including higher rates of pain, fatigue, and memory/concentration problems. Emotion regulation offers the possibility to either better or worse physical health. This study assessed how two emotion regulation strategies, mindfulness and worry, corresponded to changes in focus problems, memory problems, and fatigue along with performance on pain sensitivity and cognitive tasks across two visits among breast cancer survivors. A total of 149 survivors completed 2 day-long visits in the laboratory where they rated their fatigue and memory problems six times across the day, completed cognitive tests, and a pain sensitivity test. Findings from this study showed that breast cancer survivors who worried more and were less mindful experienced subjective memory problems, focus problems, and cold pain sensitivity across two visits. Emotion regulation skills did not predict objective pain sensitivity or cognitive problems. Results from this study highlight the benefits of adaptive emotion regulation skills like mindfulness in helping improve the cognitive and physical symptoms commonly experienced by breast cancer survivorship.

Conventional Rotary Technique and Piezosurgical Technique in the Removal of Impacted Mandibular Third Molar: A Comparative Study.

AIM: To compare the operating time, postoperative pain, edema, trismus, and patient acceptance following surgical removal of impacted third molar using piezosurgery and conventional rotary technique. MATERIALS AND METHODS: About 42 patients with impacted mesioangular mandibular third molars were included in this study. Subjects are divided into two groups: group I (treated with conventional rotary technique) and group II (treated with piezosurgery). Duration of surgery, pain, trismus, and swelling were assessed. The patients were evaluated on the 1st, 3rd, and 7th postoperative days. RESULTS: Postoperative pain, trismus, and edema were reduced with piezosurgery compared with conventional technique. Even though the duration of time was longer with piezosurgery, patient comfort was found to be better. CONCLUSION: Piezosurgery is a meticulous and innovative ultrasonic technique with selective bone cutting and better postoperative outcomes. However, it is expensive, and the operating time is prolonged. CLINICAL SIGNIFICANCE: Piezosurgery is an alternative in the surgical removal of third molars as it ensures precise and selective cutting, with no injury to the surrounding soft tissues. Postoperative outcome and patient acceptance are improved with piezosurgery.

Operational Metrics for the ELAINE 2 Study Combining a Traditional Approach With a Just-in-TIME Model.

PURPOSE: There are numerous barriers to enrollment in oncology biomarker-driven studies. METHODS: The ELAINE 2 study (ClinicalTrials.gov identifier: NCT04432454) is an open-label phase 2 study of lasofoxifene combined with abemaciclib in patients with advanced or metastatic estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer with an ESR1 mutation. ELAINE 2 opened clinical sites by using a Traditional approach, which activated a site before patient identification, and the Tempus TIME Trial network, which opened a site only after identifying an eligible patient. This manuscript presents the operational metrics comparing the Traditional and TIME Trial site data. RESULTS: The study enrolled patients over 34 weeks and 16 sites (six Traditional and 10 TIME Trial) participated. Duration for full clinical trial agreement execution for Traditional sites and TIME Trial sites averaged 200.5 (range, 142-257) and 7.6 days (range, 2-14), respectively. Institutional review board approval time for Traditional sites and TIME Trial sites was 27.5 (range, 12-71) and 3.0 days (range, 1-12), respectively. Duration from study activation to first consent was 33.3 (range, 18-58) and 8.8 days (range, 1-35) for Traditional and TIME Trial sites, respectively. The first patient on study was at a TIME Trial site 115 days before a Traditional site and the first seven patients enrolled were at TIME Trial sites. Traditional sites consented 23 and enrolled 16 patients, while TIME Trial sites consented 16 and enrolled 13. The trial enrolled 29 patients in 8.5 months with the anticipated enrollment duration being 12-18 months. CONCLUSION: The TIME Trial network opened earlier and enrolled the first study patients. These results demonstrate that the Just-in-TIME model, along with a Traditional model, can improve enrollment in biomarker-driven studies.