Available Systemic Treatments and Emerging Therapies for Breast Cancer Brain Metastases.

OPINION STATEMENT: In 2023, breast cancer brain metastases (BCBrM) remain a major clinical challenge gaining well-deserved attention. Historically managed with local therapies alone, systemic therapies including small molecule inhibitors and antibody-drug conjugates (ADCs) have shown unprecedented activity in recent trials including patients with brain metastases. These advancements stem from efforts to include patients with stable and active BCBrM in early- and late-phase trial design. Tucatinib added to trastuzumab and capecitabine improves intracranial and extracranial progression-free survival and overall survival in stable and active human epidermal growth factor receptor 2 (HER2+)-positive brain metastases. Trastuzumab deruxtecan (T-DXd) has both shown impressive intracranial activity in stable and active HER2+ BCBrMs challenging historical thinking of ADCs' inability to penetrate the central nervous system (CNS). T-DXd has shown potent activity in HER2-low (immunohistochemistry scores of 1+ or 2+, non-amplified by fluorescence in situ hybridization) metastatic breast cancer and will be studied in HER2-low BCBrM as well. Novel endocrine therapies including oral selective estrogen downregulators (SERDs) and complete estrogen receptor antagonists (CERANs) are being studied in hormone receptor-positive BCBrM clinical trials due to robust intracranial activity in preclinical models. Triple-negative breast cancer (TNBC) brain metastases continue to portend the worst prognosis of all subtypes. Clinical trials leading to the approval of immune checkpoint inhibitors have enrolled few BCBrM patients leading to a lack of understanding of immunotherapies contribution in this subgroup. Data surrounding the use of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in patients with germline BRCA mutation carriers with CNS disease is hopeful. ADCs including those targeting low-level HER2 expression and TROP2 are under active investigation in triple-negative BCBrMs.

Clues from hands Part 1: personal details about patients revealed by hand examination.

This is the first part of a two-part article on personal details revealed by the hand examination. Daily activities revealed by hand examination are the focus of Part 1, while personal details including nutrition and psychological assessment are presented in Part 2. These clues enable the examiner to discern hobbies, vocation, sporting activities, dietary information, and psychosocial information of the patient. We describe signs that may aid the clinician in determining these activities, enabling us to provide better patient care by establishing good patient rapport. Part 1, presented here, focuses on detection of visible traces on the hands of sporting activities, hobbies, and vocation. The patient through long familiarity may be oblivious to these features or may find them too insignificant to mention, yet they can provide meaningful social details for the

Obtundation and Myocardial Infarction in a Case of Systemic Loxoscelism.

We report an atypical course of a likely brown recluse spider bite in a 79-year-old male. The Rader scale and Loxosceles reclusa venom detection by ELISA provide supporting evidence for a loxoscelism diagnosis. Obtundation and myocardial infarction occurred following a drop in hemoglobin to 6.5g/dL. The rapid loss of blood volume was considered a significant etiologic factor for both the obtundation and myocardial infarction. The neurological symptoms reversed rapidly after packed red blood cell transfusion.

Safety and Efficacy Outcomes in Immune Checkpoint Inhibitor-Treated Patients With Metastatic Urothelial Carcinoma Requiring Treatment Interruption or Discontinuation Due to Immune-Related Adverse Events.

INTRODUCTION: As most patients with metastatic urothelial carcinoma (mUC) will be treated with immune checkpoint inhibitors (ICI), familiarity with their associated immune-related adverse events (irAEs) is critical. We describe the characteristics and outcomes of ICI-treated mUC patients who experienced irAEs requiring treatment interruption (TI) or permanent discontinuation. MATERIALS AND METHODS: ICI-treated mUC patients who developed grade ≥2 irAEs were reviewed. Clinical-, treatment-, and toxicity-related data were evaluated. Toxicity was graded per common terminology for categorization of adverse events v5.0. Cohorts were divided into patients who underwent ICI rechallenge and those who required permanent ICI discontinuation. Time to treatment interruption (TTI), time to next treatment, and duration of clinical benefit were assessed descriptively. Progression-free survival and overall survival (OS) were estimated using Kaplan-Meier methodology. RESULTS: Of 200 ICI-treated mUC patients at Cleveland Clinic between October 2015 and October 2020, 16 (8%) experienced ≥ grade 2 irAEs necessitating TI. Median TTI among all patients was 6.5 months (range, 1-19). Eleven patients (69%) required corticosteroids. ICI were held and rechallenged in 10 patients (62%) and permanently discontinued in 6 patients (38%). Of the 10 ICI-rechallenged patients, 7 (70%) experienced another irAE upon rechallenge with median time to irAE recurrence of 2.9 months (range, 0.1-10.9); 3 (30%) eventually discontinued ICI due to recrudescent irAEs. Four (40%) of the 10 ICI-rechallenged patients received subsequent therapy. Five (83%) of the 6 patients who permanently discontinued ICI demonstrated durable clinical benefit off therapy with median duration of clinical benefit 17.7 months (range, 14.2-55.2). Two-year OS was 40% (95% CI: 19%-86%) in the ICI rechallenge cohort and 67% (95% CI: 38%-100%) in the permanent discontinuation cohort. CONCLUSION: ICI-treated mUC patients who developed irAEs requiring TI had a high rate of subsequent irAEs upon ICI rechallenge. Importantly, patients who permanently discontinued ICI due to irAE demonstrated durable clinical benefit off treatment.

Region growing by sector analysis for detection of blue-gray ovoids in basal cell carcinoma.

Blue-gray ovoids (B-GOs) are critical dermoscopic structures in basal cell carcinomas (BCCs) that pose a challenge for automatic detection. Due to variation in size and color, B-GOs can be easily mistaken for similar structures in benign lesions. Analysis of these structures could help further accomplish the goal of automatic BCC detection. This study introduces an efficient sector-based method for segmenting B-GOs. Four modifications of conventional region-growing techniques are presented: (i) employing a seed area rather than a seed point, (ii) utilizing fixed control limits determined from the seed area to eliminate re-calculations of previously-added regions, (iii) determining region growing criteria using logistic regression, and (iv) area analysis and expansion by sectors. Contact dermoscopy images of 68 confirmed BCCs having B-GOs were obtained. A total of 24 color features were analyzed for all B-GO seed areas. Logistic regression analysis determined blue chromaticity, followed by red variance, were the best features for discriminating B-GO edges from surrounding areas. Segmentation of malignant structures obtained an average Pratt's figure of merit of 0.397. The techniques presented here provide a non-recursive, sector-based, region-growing method applicable to any colored structure appearing in digital images. Further research using these techniques could lead to automatic detection of B-GOs in BCCs.

Analysis of clinical and dermoscopic features for basal cell carcinoma neural network classification.

BACKGROUND: Basal cell carcinoma (BCC) is the most commonly diagnosed cancer in the USA. In this research, we examine four different feature categories used for diagnostic decisions, including patient personal profile (patient age, gender, etc.), general exam (lesion size and location), common dermoscopic (blue-gray ovoids, leaf-structure dirt trails, etc.), and specific dermoscopic lesion (white/pink areas, semitranslucency, etc.). Specific dermoscopic features are more restricted versions of the common dermoscopic features. METHODS: Combinations of the four feature categories are analyzed over a data set of 700 lesions, with 350 BCCs and 350 benign lesions, for lesion discrimination using neural network-based techniques, including evolving artificial neural networks (EANNs) and evolving artificial neural network ensembles. RESULTS: Experiment results based on 10-fold cross validation for training and testing the different neural network-based techniques yielded an area under the receiver operating characteristic curve as high as 0.981 when all features were combined. The common dermoscopic lesion features generally yielded higher discrimination results than other individual feature categories. CONCLUSIONS: Experimental results show that combining clinical and image information provides enhanced lesion discrimination capability over either information source separately. This research highlights the potential of data fusion as a model for the diagnostic process.

Sector expansion and elliptical modeling of blue-gray ovoids for basal cell carcinoma discrimination in dermoscopy images.

BACKGROUND: Blue-gray ovoids (B-GOs), a critical dermoscopic structure for basal cell carcinoma (BCC), offer an opportunity for automatic detection of BCC. Due to variation in size and color, B-GOs can be easily mistaken for similar structures in benign lesions. Analysis of these structures could afford accurate characterization and automatic recognition of B-GOs, furthering the goal of automatic BCC detection. This study utilizes a novel segmentation method to discriminate B-GOs from their benign mimics. METHODS: Contact dermoscopy images of 68 confirmed BCCs with B-GOs were obtained. Another set of 131 contact dermoscopic images of benign lesions possessing B-GO mimics provided a benign competitive set. A total of 22 B-GO features were analyzed for all structures: 21 color features and one size feature. Regarding segmentation, this study utilized a novel sector-based, non-recursive segmentation method to expand the masks applied to the B-GOs and mimicking structures. RESULTS: Logistic regression analysis determined that blue chromaticity was the best feature for discriminating true B-GOs in BCC from benign, mimicking structures. Discrimination of malignant structures was optimal when the final B-GO border was approximated by a best-fit ellipse. Using this optimal configuration, logistic regression analysis discriminated the expanded and fitted malignant structures from similar benign structures with a classification rate as high as 96.5%. CONCLUSIONS: Experimental results show that color features allow accurate expansion and localization of structures from seed areas. Modeling these structures as ellipses allows high discrimination of B-GOs in BCCs from similar structures in benign images.

Dermoscopy of black-spot poison ivy.

Black-spot poison ivy is an uncommon presentation of poison ivy (Toxicodendron) allergic contact dermatitis. A 78-year-old sought evaluation of a black spot present on her right hand amid pruritic vesicles. The presentation of a black spot on the skin in a clinical context suggesting poison ivy is indicative of black-spot poison ivy. Dermoscopy revealed a jagged, centrally homogeneous, dark brown lesion with a red rim. A skin sample was obtained and compared against a poison ivy standard using ultra-fast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS). This finding confirmed the presence of multiple urushiol congeners in the skin sample. Black-spot poison ivy may be added to the list of diagnoses that show a specific dermoscopic pattern.

Persistent edematous-plaque photosensitivity observed with sitagliptin phosphate (Januvia®).

Photosensitivity to sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is reported. No previous reports of photosensitivity to any DPP-4 inhibitors are known. Physical examination of the patient revealed edematous plaques confined to sun-exposed areas of the skin. An unusual finding in this case was the spongy sensation upon palpation of the plaques. Histopathology revealed parakeratosis and abundant eosinophils, supporting the clinical impression of cutaneous drug sensitivity. The eruption finally cleared, approximately two years after onset.

Opportunities to reduce children's excessive consumption of calories from beverages.

OBJECTIVE: To describe children's consumption of sugar-sweetened beverages (SSBs) and 100% fruit juice (FJ), and identify factors that may reduce excessive consumption. DESIGN: A total of 830 parents of young children completed a 36-item questionnaire at the pediatricians' office. RESULTS: Children consumed soda (62.2%), other SSBs (61.6%), and FJ (88.2%): 26.9% exceeded the American Academy of Pediatrics' recommended daily FJ intake. 157 (18.9%) children consumed excessive calories (>200 kcal/d) from beverages (median = 292.2 kcal/d, range 203.8-2177.0 kcal/d). Risk factors for excessive calorie consumption from beverages were exceeding recommendations for FJ (odds ratio [OR] = 119.7, 95% confidence interval [CI] = 52.2-274.7), being 7 to 12 years old (OR = 4.3, 95%CI = 1.9-9.9), and having Medicaid insurance (OR = 2.6, 95%CI = 1.1-6.0). Parents would likely reduce beverage consumption if recommended by the physician (65.6%). CONCLUSIONS: About 1 in 5 children consumes excessive calories from soda, other SSBs and FJ, with FJ the major contributor.

The pink rim sign: location of pink as an indicator of melanoma in dermoscopic images.

Background. In dermoscopic images, multiple shades of pink have been described in melanoma without specifying location of these areas within the lesion. Objective. The purpose of this study was to determine the statistics for the presence of centrally and peripherally located pink melanoma and benign melanocytic lesions. Methods. Three observers, untrained in dermoscopy, each retrospectively analyzed 1290 dermoscopic images (296 melanomas (170 in situ and 126 invasive), 994 benign melanocytic nevi) and assessed the presence of any shade of pink in the center and periphery of the lesion. Results. Pink was located in the peripheral region in 14.5% of melanomas and 6.3% of benign melanocytic lesions, yielding an odds ratio of 2.51 (95% CI: 1.7-3.8, P < 0.0001). Central pink was located in 12.8% of melanomas and 21.8% of benign lesions, yielding an odds ratio of 0.462 (95% CI: 0.67, P = 0.204). Pink in melanoma in situ tended to be present throughout the lesion (68% of pink lesions). Pink in invasive melanoma was present in 17% of cases, often presenting as a pink rim. Conclusions. The presence of pink in the periphery or rim of a dermoscopic melanocytic lesion image provides an indication of malignancy. We offer the "pink rim sign" as a clue to the dermoscopic diagnosis of invasive melanoma.

Extreme pain from brown recluse spider bites: model for cytokine-driven pain.

IMPORTANCE: Bites from the brown recluse spider (BRS) can cause extreme pain. We propose cytokine release as a cause of the discomfort and a central mechanism through glial cell upregulation to explain measured pain levels and time course. OBSERVATIONS: Twenty-three BRS bites were scored at a probable or documented level clinically, and an enzyme-linked immunosorbent assay was used to confirm the presence of BRS venom. The mean (SD) pain level in these cases 24 hours after the spider bite was severe: 6.74 (2.75) on a scale of 0 to 10. Narcotics may be needed to provide relief in some cases. The difference in pain level by anatomic region was not significant. Escalation observed in 22 of 23 cases, increasing from low/none to extreme within 24 hours, is consistent with a cytokine pain pattern, in which pain increases concomitantly with a temporal increase of inflammatory cytokines. CONCLUSIONS AND RELEVANCE: These findings in BRS bites support the hypothesis of cytokine release in inflammatory pain. A larger series is needed to confirm the findings reported here. The extreme pain from many BRS bites motivates us to find better prevention and treatment techniques.

Fuzzy logic color detection: Blue areas in melanoma dermoscopy images.

Fuzzy logic image analysis techniques were used to analyze three shades of blue (lavender blue, light blue, and dark blue) in dermoscopic images for melanoma detection. A logistic regression model provided up to 82.7% accuracy for melanoma discrimination for 866 images. With a support vector machines (SVM) classifier, lower accuracy was obtained for individual shades (79.9-80.1%) compared with up to 81.4% accuracy with multiple shades. All fuzzy blue logic alpha cuts scored higher than the crisp case. Fuzzy logic techniques applied to multiple shades of blue can assist in melanoma detection. These vector-based fuzzy logic techniques can be extended to other image analysis problems involving multiple colors or color shades.