Systemic Therapy for Melanoma: ASCO Guideline Update Q and A.

This Q&A answers questions regarding ASCO's recent Systemic Therapy for Melanoma guideline.

Systemic Therapy for Melanoma: ASCO Guideline Update.

PURPOSE: To provide guidance to clinicians regarding the use of systemic therapy for melanoma. METHODS: American Society of Clinical Oncology convened an Expert Panel and conducted an updated systematic review of the literature. RESULTS: The updated review identified 21 additional randomized trials. UPDATED RECOMMENDATIONS: Neoadjuvant pembrolizumab was newly recommended for patients with resectable stage IIIB to IV cutaneous melanoma. For patients with resected cutaneous melanoma, adjuvant nivolumab or pembrolizumab was newly recommended for stage IIB-C disease and adjuvant nivolumab plus ipilimumab was added as a potential option for stage IV disease. For patients with unresectable or metastatic cutaneous melanoma, nivolumab plus relatlimab was added as a potential option regardless of BRAF mutation status and nivolumab plus ipilimumab followed by nivolumab was preferred over BRAF/MEK inhibitor therapy. Talimogene laherparepvec is no longer recommended as an option for patients with BRAF wild-type disease who have progressed on anti-PD-1 therapy. Ipilimumab- and ipilimumab-containing regimens are no longer recommended for patients with BRAF-mutated disease after progression on other therapies.This full update incorporates the new recommendations for uveal melanoma published in the 2022 Rapid Recommendation Update.Additional information is available at www.asco.org/melanoma-guidelines.

Systemic therapy for melanoma: ASCO guideline update

To provide guidance to clinicians regarding the use of systemic therapy for melanoma. American Society of Clinical Oncology convened an Expert Panel and conducted an updated systematic review of the literature. The updated review identified 21 additional randomized trials. Neoadjuvant pembrolizumab was newly recommended for patients with resectable stage IIIB to IV cutaneous melanoma. For patients with resected cutaneous melanoma, adjuvant nivolumab or pembrolizumab was newly recommended for stage IIB-C disease and adjuvant nivolumab plus ipilimumab was added as a potential option for stage IV disease. For patients with unresectable or metastatic cutaneous melanoma, nivolumab plus relatlimab was added as a potential option regardless of BRAF mutation status and nivolumab plus ipilimumab followed by nivolumab was preferred over BRAF/MEK inhibitor therapy. Talimogene laherparepvec is no longer recommended as an option for patients with BRAF wild-type disease who have progressed on anti­PD-1 therapy. Ipilimumab- and ipilimumab-containing regimens are no longer recommended for patients with BRAF-mutated disease after progression on other therapies. This full update incorporates the new recommendations for uveal melanoma published in the 2022 Rapid Recommendation Update. Additional information is available at www.asco.org/melanoma-guidelines

Systemic Therapy for Melanoma: ASCO Guideline.

PURPOSE: To provide guidance to clinicians regarding the use of systemic therapy for melanoma. METHODS: ASCO convened an Expert Panel and conducted a systematic review of the literature. RESULTS: A systematic review, one meta-analysis, and 34 additional randomized trials were identified. The published studies included a wide range of systemic therapies in cutaneous and noncutaneous melanoma. RECOMMENDATIONS: In the adjuvant setting, nivolumab or pembrolizumab should be offered to patients with resected stage IIIA/B/C/D BRAF wild-type cutaneous melanoma, while either of those two agents or the combination of dabrafenib and trametinib should be offered in BRAF-mutant disease. No recommendation could be made for or against the use of neoadjuvant therapy in cutaneous melanoma. In the unresectable/metastatic setting, ipilimumab plus nivolumab, nivolumab alone, or pembrolizumab alone should be offered to patients with BRAF wild-type cutaneous melanoma, while those three regimens or combination BRAF/MEK inhibitor therapy with dabrafenib/trametinib, encorafenib/binimetinib, or vemurafenib/cobimetinib should be offered in BRAF-mutant disease. Patients with mucosal melanoma may be offered the same therapies recommended for cutaneous melanoma. No recommendation could be made for or against specific therapy for uveal melanoma. Additional information is available at www.asco.org/melanoma-guidelines.

Burnout and Emotional Well-Being among Nephrology Fellows: A National Online Survey.

BACKGROUND: Physician burnout and emotional distress are associated with work dissatisfaction and provision of suboptimal patient care. Little is known about burnout among nephrology fellows. METHODS: Validated items on burnout, depressive symptoms, and well being were included in the American Society of Nephrology annual survey emailed to US nephrology fellows in May to June 2018. Burnout was defined as an affirmative response to two single-item questions of experiencing emotional exhaustion or depersonalization. RESULTS: Responses from 347 of 808 eligible first- and second-year adult nephrology fellows were examined (response rate=42.9%). Most fellows were aged 30-34 years (56.8%), male (62.0%), married or partnered (72.6%), international medical graduates (62.5%), and pursuing a clinical nephrology fellowship (87.0%). Emotional exhaustion and depersonalization were reported by 28.0% and 14.4% of the fellows, respectively, with an overall burnout prevalence of 30.0%. Most fellows indicated having strong program leadership (75.2%), positive work-life balance (69.2%), presence of social support (89.3%), and career satisfaction (73.2%); 44.7% reported a disruptive work environment and 35.4% reported depressive symptoms. Multivariable logistic regression revealed a statistically significant association between female gender (odds ratio [OR], 1.90; 95% confidence interval [95% CI], 1.09 to 3.32), poor work-life balance (OR, 3.97; 95% CI, 2.22 to 7.07), or a disruptive work environment (OR, 2.63; 95% CI, 1.48 to 4.66) and burnout. CONCLUSIONS: About one third of US nephrology fellows surveyed reported experiencing burnout and depressive symptoms. Further exploration of burnout-especially that reported by female physicians, as well as burnout associated with poor work-life balance or a disruptive work environment-is warranted to develop targeted efforts that may enhance the educational experience and emotional well being of nephrology fellows.

Use of Larynx-Preservation Strategies in the Treatment of Laryngeal Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update.

Purpose To update the guideline recommendations on the use of larynx-preservation strategies in the treatment of laryngeal cancer. Methods An Expert Panel updated the systematic review of the literature for the period from January 2005 to May 2017. Results The panel confirmed that the use of a larynx-preservation approach for appropriately selected patients does not compromise survival. No larynx-preservation approach offered a survival advantage compared with total laryngectomy and adjuvant therapy as indicated. Changes were supported for the use of endoscopic surgical resection in patients with limited disease (T1, T2) and for initial total laryngectomy in patients with T4a disease or with severe pretreatment laryngeal dysfunction. New recommendations for positron emission tomography imaging for the evaluation of regional nodes after treatment and best measures for evaluating voice and swallowing function were added. Recommendations Patients with T1, T2 laryngeal cancer should be treated initially with intent to preserve the larynx by using endoscopic resection or radiation therapy, with either leading to similar outcomes. For patients with locally advanced (T3, T4) disease, organ-preservation surgery, combined chemotherapy and radiation, or radiation alone offer the potential for larynx preservation without compromising overall survival. For selected patients with extensive T3 or large T4a lesions and/or poor pretreatment laryngeal function, better survival rates and quality of life may be achieved with total laryngectomy. Patients with clinically involved regional cervical nodes (N+) who have a complete clinical and radiologic imaging response after chemoradiation do not require elective neck dissection. All patients should undergo a pretreatment baseline assessment of voice and swallowing function and receive counseling with regard to the potential impact of treatment options on voice, swallowing, and quality of life. Additional information is available at www.asco.org/head-neck-cancer-guidelines and www.asco.org/guidelineswiki .

Language complexity differs between doctors and patients during contraceptive counseling: A mixed-method study.

The purpose of this study was to assess differences in language complexity for physician and patient speech and describe differences in speech content and literacy for medical office visits related to contraception. In a cross-sectional, mixed-methods study, we invited clinic faculty, residents, and consecutive patients to participate in simulated clinical encounters. Two investigators independently transcribed the recordings of these encounters. We calculated Flesch-Kincaid Reading Level (FKRL) and Flesch Reading Ease (FRE) scores as proxy measures for language complexity related to physician and patient speech. We also performed content analysis of the office visit transcriptions. Thirty-one of 33 physicians and 51 of 61 patients participated in the study, yielding response rates of 94% and 84%, respectively. Student Independent t-tests revealed differences in language complexity for providers and patients. On average, physicians spoke at an Eighth-Grade (13 to 14 years old) reading level, while patients spoke at a Fourth-Grade (nine to ten years old) level. Physicians gave primary importance to physiologic mechanisms. Patients focused on efficacy and side effects. We interpret the findings from the theoretical perspective of language and culture as inseparable components of communication. Both language and culture communicate, but at different levels of analysis. We explore both dimensions of communication with the same data set. Although this paper is theoretically exploratory, we believe it broadens inquiry of language use in medicine for subsequent investigation.

Experimental traumatic brain injury alters ethanol consumption and sensitivity.

Altered alcohol consumption patterns after traumatic brain injury (TBI) can lead to significant impairments in TBI recovery. Few preclinical models have been used to examine alcohol use across distinct phases of the post-injury period, leaving mechanistic questions unanswered. To address this, the aim of this study was to describe the histological and behavioral outcomes of a noncontusive closed-head TBI in the mouse, after which sensitivity to and consumption of alcohol were quantified, in addition to dopaminergic signaling markers. We hypothesized that TBI would alter alcohol consumption patterns and related signal transduction pathways that were congruent to clinical observations. After midline impact to the skull, latency to right after injury, motor deficits, traumatic axonal injury, and reactive astrogliosis were evaluated in C57BL/6J mice. Amyloid precursor protein (APP) accumulation was observed in white matter tracts at 6, 24, and 72 h post-TBI. Increased intensity of glial fibrillary acidic protein (GFAP) immunoreactivity was observed by 24 h, primarily under the impact site and in the nucleus accumbens, a striatal subregion, as early as 72 h, persisting to 7 days, after TBI. At 14 days post-TBI, when mice were tested for ethanol sensitivity after acute high-dose ethanol (4 g/kg, intraperitoneally), brain-injured mice exhibited increased sedation time compared with uninjured mice, which was accompanied by deficits in striatal dopamine- and cAMP-regulated neuronal phosphoprotein, 32 kDa (DARPP-32) phosphorylation. At 17 days post-TBI, ethanol intake was assessed using the Drinking-in-the-Dark paradigm. Intake across 7 days of consumption was significantly reduced in TBI mice compared with sham controls, paralleling the reduction in alcohol consumption observed clinically in the initial post-injury period. These data demonstrate that TBI increases sensitivity to ethanol-induced sedation and affects downstream signaling mediators of striatal dopaminergic neurotransmission while altering ethanol consumption. Examining TBI effects on ethanol responsitivity will improve our understanding of alcohol use post-TBI in humans.

Postnatal ethanol exposure simplifies the dendritic morphology of medium spiny neurons independently of adenylyl cyclase 1 and 8 activity in mice.

BACKGROUND: Fetal exposure to alcohol can have multiple deleterious effects, including learning disorders and behavioral and executive functioning abnormalities, collectively termed fetal alcohol spectrum disorders. Neonatal mice lacking both calcium-/calmodulin-stimulated adenylyl cyclases (ACs) 1 and 8 demonstrate increased vulnerability to ethanol (EtOH)-induced neurotoxicity in the striatum compared with wild-type (WT) controls. However, the developmental impact on surviving neurons is still unclear. METHODS: WT and AC1/8 double knockout (DKO) mice were administered 1 dose of EtOH (2.5 g/kg) between postnatal days 5 to 7 (P5-7). At P30, brains were removed and processed for Golgi-Cox staining. Medium spiny neurons (MSNs) from the caudate putamen were analyzed for changes in dendritic complexity; number of branches, branch points and terminals, total and average dendritic length; spine density and soma size. RESULTS: EtOH significantly reduced the dendritic complexity and soma size in surviving MSNs regardless of genotype without affecting spine density. In the absence of EtOH, genetic deletion of AC1/8 reduced the dendritic complexity, number of branch points, spine density, and soma size of MSNs compared with WT controls. CONCLUSIONS: These data indicate that neonatal exposure to a single dose of EtOH is sufficient to cause long-term alterations in the dendritic complexity of MSNs and that this outcome is not altered by the functional status of AC1 and AC8. Therefore, although deletion of AC1/8 demonstrates a role for the ACs in normal morphologic development and EtOH-induced neurodegeneration, loss of AC1/8 activity does not exacerbate the effects of EtOH on dendritic morphology or spine density.

A paleontology primer for oncologists.

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