Real-World Clinical Outcomes With Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer.

PURPOSE: Sacituzumab govitecan (SG) is approved for the treatment of metastatic triple-negative breast cancer (mTNBC). We report the real-world clinical effectiveness and toxicity data of SG in patients with mTNBC. METHODS: A multi-institution retrospective study of patients with mTNBC treated with SG from January 2021 to May 2023 was conducted. Demographic and clinicopathologic variables were collected. Univariate and multivariate Cox regression models were used for survival analysis. RESULTS: A total of 115 patients were included. The median age at SG initiation was 60 years (range, 31-85). All patients were female; 73 (63.5%) were White and 31 (27.0%) were Black. The median number of previous therapies in the metastatic setting was two (range, 0-8). Sixty-one (56.0%) patients had primary refractory disease. Median relative dose intensity was 92% (range, 33%-100%). Grade 3 or higher adverse events (AEs) were seen in 50.9% of patients, which included neutropenia (35.7%), anemia (27.0%), vomiting (16.5%), fatigue (8.7%), and diarrhea (7.0%). Dose reductions and treatment discontinuation due to AEs were required in 51.3% and 13.2%, respectively. The objective response rate (ORR) was 27.8%. Median overall survival was 9.6 months (95% CI, 7.8 to 12.9) and median progression-free survival (PFS) was 4.8 months (95% CI, 3.6 to 5.9). In patients with human epidermal growth factor receptor 2 (HER2)-low mTNBC who received trastuzumab deruxtecan (T-DXd) after SG, the ORR to T-DXd was 34.8% and median PFS was 7 months (95% CI, 4.6 to 10.1). CONCLUSION: In a real-world cohort of heavily pretreated patients with mTNBC, SG retains its clinical activity. In a subgroup with HER2-low disease, T-DXd continues to demonstrate promising clinical activity after SG, supporting the use of sequential antibody-drug conjugates in this population.

Multimodality Evaluation of Persistent Hyperparathyroidism in a Rare Case of Ectopic Submandibular Parathyroid Adenoma.

ABSTRACT: A 53-year-old woman of primary hyperparathyroidism with both ultrasound neck examination and planar 99mTc-MIBI scan being negative revealed a tracer-avid focus in the left submandibular region in early (15 minutes postinjection) 99mTc-MIBI SPECT/CT views, raising a suspicion of rare ectopic parathyroid adenoma. This finding was correlated on 4D-CT and confirmed on histopathology following surgical excision. Submandibular region is an unusual location for ectopic parathyroid adenoma. Nevertheless, high degree of suspicion with utilization of multimodality imaging including 99mTc MIBI-SPECT/CT and 4D-CT improves preoperative detection of parathyroid adenoma at rare ectopic sites as seen in this case of persistent hyperparathyroidism.

Detrimental Impact of Chemotherapy Dose Reduction or Discontinuation in Early Stage Triple-Negative Breast Cancer Treated With Pembrolizumab and Neoadjuvant Chemotherapy: A Multicenter Experience.

BACKGROUND: Pembrolizumab combined with neoadjuvant chemotherapy (NAC) is the current standard of care in early stage triple-negative breast cancer (TNBC) based on higher event-free survival and pathological complete response (pCR) in Keynote-522 (KN-522) clinical trial. However, this aggressive five-drug regimen is associated with increased risks for immune-related adverse events (irAEs). We investigated real-world clinical outcomes and toxicity of this regimen as well as factors predictive of pCR and irAEs. METHODS: We identified and abstracted data from 153 early-stage TNBC patients treated with the KN-522 regimen between July 1, 2021, and December 31, 2023, at 4 academic institutions in the U.S. Descriptive analysis was conducted, univariate and multivariate analyses were performed to identify factors associated with pCR and irAEs. RESULTS: The median age was 52 years (interquartile range, 42-60years), with 66% White and 24% Black patients with stage I/II (67%), node-negative disease (58%), grade 3 (86%) tumors, and ≥1 comorbidities (68%). Approximately 21% discontinued pembrolizumab, because of toxicity; ∼50% received a lower relative dose intensity (RDI) of chemotherapy (dose reduction or discontinuation). Of the 153 patients, 99 (64.7%) achieved pCR and 83 (54%) experienced an irAE, with 18 (12%) having ≥ grade 3 irAE. The majority (90%) of the irAEs were observed during neoadjuvant phase. Stage I/II versus stage III disease (OR 1.55, CI 1.04-2.33, P = .03), age (OR 0.96, CI 0.93-0.99, P = .01) and full versus reduced RDI of NAC (OR 1.53, CI 1.04-2.26, P = .03) were associated with higher pCR rates on multivariate analyses. Fewer cycles of pembrolizumab were associated with a higher likelihood of irAEs (OR 1.52, CI 1.07-2.16, P = .02), likely explained by the early discontinuation and receipt of less than 8 cycles of pembrolizumab in patients who experienced irAEs. CONCLUSIONS: Our study validates the clinical efficacy of KN-522 regimen; however, we observed a higher incidence of irAEs (54%) in this real-world population. Lower stage and younger age were associated with higher likelihood of achieving pCR. Toxicity-related chemotherapy dose reduction or discontinuation was observed to adversely impact the likelihood of achieving pCR.

Navigating the practical-knowledge gap in deep margin elevation: A step towards a structured case selection - a review.

The deep margin elevation (DME) technique has gained popularity because of numerous supporting case reports. However, some clinicians are cautious regarding using this technique owing to the lack of clear case selection criteria for DME application. This review aimed to analyze case reports and a series of DME cases to determine pre-/post-operative evaluation methods that could be used to suggest a pre-operative case selection checklist for DME. An electronic database search was conducted in June 2021 and updated by June 2023 using selected terms from PubMed, Cochrane Library, Google Scholar, EBSCO, and Scopus. The search was limited to English-language publications and was not restricted to the date. The inclusion criteria were case reports/series addressing periodontal and restorative outcomes of DME. The search identified 217 articles, 76 of which were pertinent. However, only six case reports and one case series satisfied the inclusion criteria. None of the selected studies followed any reporting guidelines, which led to significant information gaps. While the reviewed studies reported favorable outcomes, standardized protocols for evaluating pre-/post-operative restorative and periodontal status were lacking. The post-operative follow-up period varied from 3 months to 6 years. Designing and implementing pre-/post-operative guidelines hold the potential for ensuring the safe application of the DME technique. This may enhance our understanding of the suitability and efficacy of such non-invasive technique in future clinical trials. Clinical significance: Handling deep cavities and preparing crowns are challenging. However, a lack of understanding of when to perform DME can lead to missed opportunities for conservative treatment, thereby a disservice to the patient. Provision of safe guidelines should be employed by clinicians until further evidence either supports or contradicts this treatment method.

An improved method for measuring catalase activity in biological samples.

Catalase (CAT) is an important enzyme that protects biomolecules against oxidative damage by breaking down hydrogen peroxide (H2O2) into water and oxygen. CAT is present in all aerobic microbes, animals, and plants. It is, however, absent from normal human urine but can be detected in pathological urine. CAT testing can thus help to detect such urine. This study presents a novel spectrophotometric method for determining CAT activity characterized by its simplicity, sensitivity, specificity, and rapidity. The method involves incubating enzyme-containing samples with a carefully chosen concentration of H2O2 for a specified incubation period. Subsequently, a solution containing ferrous ammonium sulfate (FAS) and sulfosalicylic acid (SSA) is added to terminate the enzyme activity. A distinctive maroon-colored ferrisulfosalicylate complex is formed. The formation of this complex is a direct result of the reaction between FAS and any residual peroxide present. This leads to the generation of ferric ions when coordinated with SSA. The complex has a maximum absorbance of 490 nm. This advanced method eliminates the need for concentrated acids to stop CAT activity, making it safer and easier to handle. A comparative analysis against the standard ferrithiocyanate method showed a correlation coefficient of 0.99, demonstrating the new method's comparable effectiveness and reliability. In conclusion, a simple and reliable protocol for assessing CAT activity, which utilizes a cuvette or microplate, has been demonstrated in this study. This interference-free protocol can easily be used in research and clinical analysis with considerable accuracy and precision.

Acquired disorders of phosphaturia: Beyond tumor-induced osteomalacia.

Phosphate is an integral part of human cellular structure and function. Though most recognised disorders of phosphaturia are genetic in origin, phosphate loss due to acquired conditions is commonly encountered in clinical practice. Acquired hypophosphatemia is most commonly due to renal phosphate wasting and can produce significant morbidity. It also heralds future kidney damage, and continued exposure can lead to progressive kidney injury and potentially renal failure. These conditions are a diverse group of disorders with common shared mechanisms causing loss of phosphate in the urine. Renal phosphate loss can occur as an isolated entity or as a part of generalised proximal tubular dysfunction, i.e., Fanconi's syndrome. An insight into the pathophysiological mechanisms of acquired phosphaturia can help clinicians monitor their patients better and avoid potential harms.

Should patients with hormone receptor-positive, HER2-negative breast cancer and one or two positive sentinel nodes undergo axillary dissection to determine candidacy for adjuvant abemaciclib?

BACKGROUND: The monarchE trial demonstrated improved outcomes with the use of adjuvant abemaciclib in patients with high-risk hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer defined as ≥4 positive lymph nodes (+LNs) or one to three +LNs with one or more additional high-risk features (HRFs). The proportion of patients with one or two positive sentinel lymph nodes (+SLNs) without HRFs who had ≥4 +LNs at the time of completion axillary lymph node dissection (cALND), and who therefore qualified for receipt of abemaciclib, was investigated. METHODS: Females with pathologically node-positive nonmetastatic HR+/HER2- breast cancer stratified by the number of +SLNs and +LNs and the presence of one or more HRFs were identified from the National Cancer Database (2018-2019). The proportion of patients meeting the criteria for abemaciclib both before and after ALND was assessed. RESULTS: Of the 22,048 patients identified, 1578 patients underwent upfront surgery, had one or two +SLNs without HRFs, and went on to cALND. Only 213 (13%) of these patients had ≥4 +LNs; thus, cALND performed solely to determine abemaciclib candidacy would have constituted surgical overtreatment in 1365 patients (87%). When stratified by the number of +SLNs, only 10% of those with one +SLN and 24% of those with two +SLNs had ≥4 +LNs after cALND, which meets the criteria for abemaciclib. CONCLUSIONS: Patients with one +SLN without HRFs are unlikely to have ≥4 +LNs and should not be subjected to the morbidity of ALND in order to inform candidacy for abemaciclib. An individualized multidisciplinary discussion should be undertaken about the risk:benefit ratio of ALND and abemaciclib for those with two +SLNs.

Adrenal Venous Sampling in Primary Aldosteronism: Single-Centre Experience from Western India.

Introduction: The protocols and criteria used for adrenal venous sampling (AVS) differ across centres. There are no studies from the Indian subcontinent describing AVS-based outcomes in primary aldosteronism (PA). We aim to describe our experience from a single centre. Methods: Retrospective records from 2018 to 2020 of patients with confirmed PA who underwent AVS were reviewed. Clinical, imaging, AVS data and outcomes (as per PASO criteria) were recorded. AVS was performed by sequential sampling with cosyntropin stimulation with intraprocedural cortisol and cut-off of selectivity >5 and lateralization >4 by a single radiologist. Results: Fifteen patients with median age of 50 years (41-58) and duration of hypertension of 156 (36-204) months were included. Ten had grade 3 hypertension, 13 had hypokalaemia and 3 had hypokalaemic paralysis. On CT scan, eight patients had bilateral adrenal lesions, four had unilateral adenoma and three patients had normal adrenals. AVS was bilaterally successful in all and showed lateralization of disease in 10 patients and was bilateral in the remaining 5 patients. Overall concordance of CT and AVS was 5/15 (33.3%). Among seven patients who underwent surgery, complete clinical success was seen in two and partial clinical success in the remaining five. Complete biochemical success was seen in two and partial in one. There were no major complications. Conclusions: AVS performed by a single radiologist with defined protocols has a good success rate. AVS has additional value over CT scan in lateralization, especially when CT shows bilateral disease.

Early Detection and Prognostic Assessment of Cutaneous Melanoma: Consensus on Optimal Practice and the Role of Gene Expression Profile Testing.

Importance: Therapy for advanced melanoma has transformed during the past decade, but early detection and prognostic assessment of cutaneous melanoma (CM) remain paramount goals. Best practices for screening and use of pigmented lesion evaluation tools and gene expression profile (GEP) testing in CM remain to be defined. Objective: To provide consensus recommendations on optimal screening practices and prebiopsy diagnostic, postbiopsy diagnostic, and prognostic assessment of CM. Evidence Review: Case scenarios were interrogated using a modified Delphi consensus method. Melanoma panelists (n = 60) were invited to vote on hypothetical scenarios via an emailed survey (n = 42), which was followed by a consensus conference (n = 51) that reviewed the literature and the rationale for survey answers. Panelists participated in a follow-up survey for final recommendations on the scenarios (n = 45). Findings: The panelists reached consensus (≥70% agreement) in supporting a risk-stratified approach to melanoma screening in clinical settings and public screening events, screening personnel recommendations (self/partner, primary care provider, general dermatologist, and pigmented lesion expert), screening intervals, and acceptable appointment wait times. Participants also reached consensus that visual and dermoscopic examination are sufficient for evaluation and follow-up of melanocytic skin lesions deemed innocuous. The panelists reached consensus on interpreting reflectance confocal microscopy and some but not all results from epidermal tape stripping, but they did not reach consensus on use of certain pigmented lesion evaluation tools, such as electrical impedance spectroscopy. Regarding GEP scores, the panelists reached consensus that a low-risk prognostic GEP score should not outweigh concerning histologic features when selecting patients to undergo sentinel lymph node biopsy but did not reach consensus on imaging recommendations in the setting of a high-risk prognostic GEP score and low-risk histology and/or negative nodal status. Conclusions and Relevance: For this consensus statement, panelists reached consensus on aspects of a risk-stratified approach to melanoma screening and follow-up as well as use of visual examination and dermoscopy. These findings support a practical approach to diagnosing and evaluating CM. Panelists did not reach consensus on a clearly defined role for GEP testing in clinical decision-making, citing the need for additional studies to establish the clinical use of existing GEP assays.

Phase I trial of pembrolizumab plus vemurafenib and cobimetinib in patients with metastatic melanoma.

Background: Preclinical and translational evidence suggest BRAF/MEK inhibitors modulate the tumor microenvironment (TME), providing rationale for combination with immunotherapy. Methods: This investigator-initiated, phase I trial evaluated pembrolizumab, vemurafenib, and cobimetinib in patients with untreated, BRAFV600E/K mutant advanced melanoma. The first 4 patients received vemurafenib with pembrolizumab, and the next 5 patients received vemurafenib and cobimetinib with pembrolizumab. Primary endpoints: safety and maximum tolerated dose of the triplet. Secondary endpoints: objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and quality of life (QoL). The trial was closed after enrollment of 9 (planned 30) patients due to dose-limiting toxicity (DLT). Study NCT02818023 was approved by the IRB, and all patients provided informed consent. Results: Patients received a median of 6 cycles of therapy. 8 of 9 experienced drug-related grade 3/4 AEs. DLTs included dermatitis (n=8), hepatitis (n=1), QTc prolongation (n=1), and arthralgias (n=1 each). QoL assessments identified a clinically significant decrease in self assessed QoL at 1 year compared to baseline (0.38 v 0.43). Median PFS was 20.7 months and median OS was 23.8 months for vemurafenib with pembrolizumab. Median PFS and OS were not reached for patients receiving triple therapy. ORR in the overall cohort was 78% (7/9). 2 patients experienced a complete response, 5 had a partial response, 1 had stable disease, and 1 had progressive disease. 4 patients had ongoing responses at data analysis. Peripheral blood flow cytometry identified significantly decreased PD1 expression on CD4+ T-cells at 3 and 9 weeks compared to baseline, not corresponding to clinical response. Conclusions: Triple therapy with vemurafenib, cobimetinib and pembrolizumab is associated with high response rates but significant adverse events, leading to early study closure.