Optimal systemic treatment and real-world clinical application of ctDNA in patients with metastatic HER2-mutant lung cancer.

INTRODUCTION: No definitive answers currently exist regarding optimal first-line therapy for HER2-mutant NSCLC. Access to rapid tissue sequencing is a major barrier to precision drug development in the first-line setting. ctDNA analysis has the potential to overcome these obstacles and guide treatment. METHODS: We retrospectively analyzed patients with metastatic HER2-mutant NSCLC who underwent prospective clinical ctDNA sequencing and received systemic therapy at Memorial Sloan Kettering Cancer Center (MSK) from January 2016 to September 2022. HER2 mutations were identified by next-generation sequencing through MSK-IMPACT, MSK-ACCESS or Resolution ctDx LungTM assay. Primary endpoints were time to the next treatment (TTNT) and overall survival (OS). RESULTS: Sixty-three patients were included in the primary analysis. Chemoimmunotherapy (33/63, 52.4 %) was the predominant first-line treatment with a median TTNT of 5.1 months (95 %CI 4.1 - 6.1) whereas 55.0 % (22/40) of patients who received second-line T-DXd obtained a median TTNT of 9.2 m (95 % CI, 0-22.2). Plasma ctDNA was tested before first-line therapy in 40 patients with a median OS of 28.0 months (95 % CI 21-34), in whom 31 patients (78.0 %) had detectable ctDNA. HER2 mutations were detected on ctDNA with a median turnaround time of 13 days, occasionally co-occurred with EGFR and MET alterations and were tracked longitudinally correlating with treatment response. Patients with detectable baseline ctDNA had significantly shorter OS (hazard ratio (HR), 5.25; 95 % CI, 1.2-23.9; p = 0.019). CONCLUSION: Chemoimmunotherapy remains a major treatment option for metastatic HER2-mutant NSCLC. ctDNA can rapidly detect HER2 and co-mutations, and it has the potential to guide and monitor optimal first-line therapy. As a negative prognostic biomarker, detectable ctDNA at baseline would need to be taken into account for patient selection in future studies.

A Review of the Clinical Features and Management of Systemic Congenital Mastocytosis through the Presentation of An Unusual Prenatal-Onset Case.

Mastocytosis is a heterogeneous group of rare hematological disorders that can occur in infancy. We report a 16-year-old girl who presented with an aggressive form of systemic congenital mastocytosis, associated with a significant global developmental delay, deafness, and multiple anomalies. At 4 years of age, she developed a germinoma presenting as an invasive spinal mass. Extensive cytogenetic, metabolic, and molecular genetic studies that included whole-exome sequencing studies revealed a KIT alteration (NM_000222.3(KIT):c2447A > 7 pAsp816Val) and likely pathogenic variant in the DNA from peripheral blood and skin lesions. C-kit was also found to be overexpressed in the spinal tumor cells. We compared the features of this child to those of six previously reported pediatric patients with cutaneous mastocytosis, microcephaly, microtia, and/or hearing loss reported in OMIM as mastocytosis, conductive hearing loss, and microtia (MIM 248910), for which the etiology has not yet been determined. This report extends the currently recognized spectrum of KIT-related disorders and provides clues as to the potential etiology of a syndromic form of congenital mastocytosis. International efforts to understand the benefits of long-term targeted therapy with tyrosine kinase inhibitors for this KIT-altered rare disease should continue to be evaluated in clinical trials.

Vesiculobullous eosinophilic annular erythema: A case report.

Eosinophilic annular erythema is a rare eosinophilic dermatosis, characterized by arcuate erythematous urticarial plaques of unclear etiology. Vesiculobullous forms are even rarer, with only few cases described in the English literature. We report a case of vesiculobullous eosinophilic annular erythema with extensive cutaneous involvement poorly responsive to prednisone but showing complete remission with dapsone.

Effect of Bow Camber and Mass Distribution on Violinists' Preferences and Performance.

Little is known about how bow mechanical characteristics objectively and quantitatively influence violinists' preferences and performance. Hypothesizing that the bow shape (i.e., camber) and mass distribution modifications would alter both violinists' appreciations of a bow and objective assessments of their performance, we recruited 10 professional violinists to play their own violin using 18 versions of a single bow, modified by combining three cambers and six mass distributions, in random order. A musical phrase, composed for this study, was played legato and spiccato at three octaves and two tempi. Each violinist scored all 18 bows. Then, experts assessed the recorded performances according to criteria inspired by basic musical analysis. Finally, 12 audio-descriptors were calculated on the same note from each trial, to objectivise potential acoustic differences. Statistical analysis (ANOVA) reveals that bow camber impacted the violinists' appreciations (p < 0.05), and that heavier bow tips gave lower scores for spiccato playing (p < 0.05). The expert evaluations reveal that playing with a lighter bow (tip or frog), or with a bow whose camber's maximum curvature is close to the frog, had a positive impact on some violinists' performance (NS to p < 0.001). The "camber-participant" interaction had significant effects on the violinists' appreciations (p < 0.01 to p < 0.001), on the expert's evaluation and on almost all the audio-descriptors (NS to p < 0.001). While trends were identified, multiple camber-participant interactions suggest that bow makers should provide a variety of cambers to satisfy different violinists.

Prevalence of the EGFR T790M and other resistance mutations in the Australian population and histopathological correlation in a small subset of cases.

We sought to review the prevalence of EGFR T790M and other EGFR mutations associated with either proven or probable tyrosine kinase inhibitor (TKI) resistance in the Australasian lung cancer population and to perform histopathological correlation in a subset of cases. Retrospective statistical analysis was performed on a set of targeted lung cancer gene mutation tests (FIND IT gene panel) performed at Sonic Healthcare during 2018 and early 2019. A total of 1833 lung adenocarcinoma tumour samples underwent somatic mutation testing. EGFR mutations were found in 28% (n=514) of patients, in whom 9.3% (n=48) T790M mutations were present (always combined with other EGFR mutations) and 4.8% (n=25) exon 20 insertions were found. We also compared the prevalence of EGFR mutations identified in our population with that of the four largest publicly available lung cancer cohorts (total n=576 samples). Finally, a subset of 38 samples of primary/and or metastatic lung adenocarcinomas from 23 patients, including five with serial biopsies, underwent detailed morphological analysis. No reproducible morphological correlates were found to be associated with T790M, exon 20 resistance mutations or rarer co-occurring EGFR mutations. Although this may be subject to referral bias towards patients with resistant disease, the incidence of EGFR and T790M mutations is higher in this series from an Australasian population than in other similar publicly available lung adenocarcinoma cohorts. We conclude that histopathological features cannot be used to predict the acquisition of EGFR resistance.

A Rare Case of Solitary Giant Congenital Juvenile Xanthogranuloma: A Case Report.

Juvenile xanthogranuloma (JXG) is the most frequent form of non-Langerhans cell histiocytosis. We present a case of giant congenital JXG in a 7-week-old boy, who had a firm and incompressible lesion, measuring 3 × 4 cm in diameter, on his right flank. The clinical appearance of the lesion and the ultrasound results suggested a vascular tumor, such as a hemangioma. Histology confirmed a JXG, although there was an absence of Touton cells, which are usually pathognomonic of JXG. In light of these findings, it would be important to include JXG in the differential diagnosis of congenital tumours, particularly vascular lesions.

Predictive factors for sentinel lymph nodes and non-sentinel lymph nodes metastatic involvement: a database study of 1,041 melanoma patients.

BACKGROUND: Sentinel lymph node (SLN) biopsy may identify patients who may need completion lymphadenectomy and adjuvant therapy. METHODS: Univariate and multivariate analysis were conducted for SLN status in a prospective cohort of 1,041 patients. A biopsy was recommended for melanoma greater than or equal to 1 mm thick or greater than or equal to .75 mm with poor prognostic features. RESULTS: For sentinel node status, mitotic rate is very significant in univariate analysis. In multivariate analysis, Breslow, lymphovascular invasion, and primary site were significant. Breslow thickness greater than or equal to 2 mm and SLN with macroscopic burden greater than or equal to 2 mm are the only statistically significant variables predicting the non-SLN status in multivariate analysis. CONCLUSIONS: The data confirm the importance of Breslow, lymphovascular invasion, and body site for SLN status. The cutoff of 2 mm for tumor load in SLN appears to be a simple technique to find the high-risk patients with further lymph node disease.

Primary Cutaneous Carcinosarcoma of the Basal Cell Subtype Should Be Treated as a High-Risk Basal Cell Carcinoma.

BACKGROUND: Cutaneous carcinosarcoma is a rare primary tumor of the skin, characterized by biphasic epithelial and mesenchymal differentiation. OBJECTIVE: Due to the limited number of cases reported, there is no consensus regarding treatment and prognosis. Some authors suggest that cutaneous carcinosarcomas should be viewed as aggressive tumors, with ancillary imaging used to evaluate potential metastatic disease. Other reports demonstrate an indolent disease course, especially with epidermal-type cutaneous carcinosarcomas. METHODS: We report a case of cutaneous carcinosarcoma, which we treated with electrodessication and curettage following a shave biopsy. The tumor had an epithelial component resembling a basal cell carcinoma and a fibrosarcomatous stroma. RESULTS: At 1-year follow-up, our patient did not show evidence of recurrence or metastasis. CONCLUSIONS: Our case suggests that a cutaneous carcinosarcoma with an epithelial component composed of basal cell carcinoma can be regarded as a high-risk nonmelanoma skin cancer.

Olmsted syndrome-palmoplantar and periorificial keratodermas: association with malignant melanoma.

BACKGROUND: Olmsted syndrome is a rare congenital disorder with mutilating palmoplantar keratoderma, periorificial keratotic plaques, and other variable features. OBJECTIVE: We describe a 65-year-old woman with Olmsted syndrome complicated by the occurrence of a malignant melanoma inside the plantar keratoderma. To our knowledge, this is the first reported case of such an occurrence in Olmsted syndrome. The published cases of this rare disorder are reviewed. CONCLUSION: An association between malignant epithelial tumors and Olmsted syndrome has already been reported. The association of malignant melanoma with other types of palmoplantar keratodermas has been reported. This may suggest a predisposition to melanocytic as well as squamous cell malignancies in congenital keratodermas. Oral retinoids appear to be the most promising treatment for Olmsted syndrome and for other symptomatic keratodermas.

Pyodermatitis-pyostomatitis vegetans: two cases and a review of the literature.

BACKGROUND: Pyodermatitis-pyostomatitis vegetans (PD-PSV) is a rare vegetating, pustular, eosinophilic, mucocutaneous dermatosis characterized by mucocutaneous lesions of the genital, axillary, and oral regions, as well as on the scalp. OBJECTIVE: We report two patients who were diagnosed with PD-PSV. The published cases of this rare disorder are reviewed. RESULTS: The first patient presented with vegetating pustular plaques of the scalp, vulva, and mouth. The second patient initially showed pustules on fingers and then on toes. Vulva and mouth were later involved. There was no gastrointestinal involvement in either case. In both cases, histology revealed eosinophilic spongiosis with eosinophilic microabscesses and pseudoepitheliomatous hyperplasia. Direct immunofluorescence was negative. CONCLUSION: Pyodermatitis-pyostomatitis vegetans is a rare disorder of unknown cause. It bears similarities to pemphigus vegetans but histology, direct immunofluorescence, and clinical history show the differences. Response to treatment is generally rapid. In several reported cases, an inflammatory gastrointestinal disorder is found in association with the mucocutaneous signs.