Outcomes After Treatment With Cobimetinib in Patients With Rosai-Dorfman Disease Based on KRAS and MEK Alteration Status.

Importance: Rosai-Dorfman disease (RDD) is a rare histiocytic neoplasm with recent studies showing alterations in the MAPK pathway, most commonly in the KRAS and MEK genes in about 40% of patients. Reports on the use of MEK-inhibitor therapy in RDD have been limited to small case studies. There are no approved treatments for this neoplasm, and therefore patients with RDD need efficacious treatments. Objective: To study the outcomes after treatment with cobimetinib based on MAPK pathway alterations in patients with RDD. Design, Setting, and Participants: This retrospective cohort study conducted at 2 tertiary care centers included patients with RDD who underwent treatment with cobimetinib between January 1, 2013, and December 1, 2021. Cobimetinib was administered at a dosage of 20 to 60 mg orally once daily as a single agent for 21 days in a 28-day cycle. Pathology was centrally reviewed. Response assessment was centrally conducted and was based on the established positron emission radiography response criteria used for clinical trials of targeted therapies in histiocytosis. Main Outcomes and Measures: Main outcomes were overall response rate (ORR), progression-free survival (PFS), adverse events (AEs) of cobimetinib in the entire cohort, and ORRs and PFS based on MAPK pathway alterations in patients with RDD. Results: A total of 16 patients (median [range] age at cobimetinib initiation, 57 [31-74] years; 11 [69%] women) were included in the study. The median follow-up duration was 19.0 months (95% CI, 8.4-27.8 months). The ORR was 63% (n = 10), including 5 complete responses and 5 partial responses. Somatic alterations in the KRAS or MEK genes were detected in 8 (50%) patients. Patients with KRAS or MEK alterations had significantly higher ORR (88% vs 38%; P = .03), deeper responses (complete responses among responders: 71% vs 0%; P = .002), and better PFS (at 1 year, 100% vs 29% were free from progression or death, respectively; P < .001) compared with those without such alterations. Grade 2 or higher AEs occurred in 12 (75%) patients, and 9 (56%) required dose reduction or temporary/permanent treatment discontinuation due to AEs. Conclusions and Relevance: In this cohort study, treatment with cobimetinib was associated with positive outcomes in KRAS- or MEK-variant RDD. However, AEs requiring dose modifications were common.

Cerebral Invasive Aspergillosis in a Case of Chronic Lymphocytic Leukemia with Bruton Tyrosine Kinase Inhibitor.

Bruton tyrosine kinase (BTK) inhibitors have become an important therapy for untreated and previously treated patients with chronic lymphocytic leukemia (CLL). Despite improved outcomes, rare adverse events, such as invasive fungal infections, have been reported with the use of first-generation BTK inhibitors. Invasive fungal infections carry a high morbidity and mortality risk. There have been several case reports describing the association between aspergillosis and ibrutinib treatment, but none with acalabrutinib, to our knowledge. In this case report, we describe a patient with CLL who developed an intracranial Aspergillus fumigatus infection while receiving acalabrutinib.

Clear cell papillary renal cell carcinoma: molecular profile and virtual karyotype.

Clear cell papillary renal cell carcinoma (CCP-RCC) is a recently recognized tumor that shares morphologic features of both clear cell renal cell carcinoma and papillary renal cell carcinoma but behaves in a more indolent fashion. To date, there is little molecular information available on CCP-RCC. DNA was extracted from formalin-fixed, paraffin-embedded tissue blocks of 22 cases of CCP-RCC at the University of Alabama at Birmingham. Targeted next-generation sequencing and single-nucleotide polymorphism array were performed on all cases. Next-generation sequencing analysis found 30 somatic variants across 63.3% of cases. Seventeen variants (56.7%) were predicted to be deleterious or possibly/probably damaging. Single-nucleotide polymorphism array analysis found copy number abnormalities and/or loss of heterozygosity in 22.7% of cases. We analyzed the genetic characteristics of a group of CCP-RCCs cases and found them to be genetically different from one another. Some cases were genetically similar to clear cell renal cell carcinoma.

Is the routine microscopic examination of proximal and distal resection margins in colorectal cancer surgery justified?

Microscopic examination of the proximal and distal resection margins is part of the routine pathologic evaluation of colorectal surgical specimens removed for adenocarcinoma. Anastomotic donuts are frequently received and microscopically examined. We examined 594 specimens received over a period of 10 years and found only 3 cases of definitive direct involvement of a longitudinal margin by carcinoma. All 3 cases also showed tumor at the margin grossly. One case of margin involvement by adenocarcinoma was found in which the tumor was grossly 1.7 cm away; however, this finding was likely a tumor deposit, as the patient had diffuse metastatic disease. All 242 anastomotic donuts examined were free of carcinoma. Our study suggests that the proximal and distal margins of colorectal cancer specimens need not be examined microscopically in order to accurately assess margin status in cases where the tumor is at least 2 cm away from the margin of resection. Also, in cases in which anastomotic donuts are included with the case, these should be considered the true margins of resection and may be microscopically examined in place of the bowel specimen margins when margin examination is needed. Anastomotic donuts need not be examined if the tumor is more than 2 cm away from the margin. An exception to this rule would be cases of rectal adenocarcinoma where neoadjuvant therapy is given prior to surgery. In these cases, mucosal evidence of malignancy may be absent and microscopic examination of the margins is the only way to assure complete excision.

The Soliga, an isolated tribe from Southern India: genetic diversity and phylogenetic affinities.

India's role in the dispersal of modern humans can be explored by investigating its oldest inhabitants: the tribal people. The Soliga people of the Biligiri Rangana Hills, a tribal community in Southern India, could be among the country's first settlers. This forest-bound, Dravidian speaking group, lives isolated, practicing subsistence-level agriculture under primitive conditions. The aim of this study is to examine the phylogenetic relationships of the Soligas in relation to 29 worldwide, geographically targeted, reference populations. For this purpose, we employed a battery of 15 hypervariable autosomal short tandem repeat loci as markers. The Soliga tribe was found to be remarkably different from other Indian populations including other southern Dravidian-speaking tribes. In contrast, the Soliga people exhibited genetic affinity to two Australian aboriginal populations. This genetic similarity could be attributed to the 'Out of Africa' migratory wave(s) along the southern coast of India that eventually reached Australia. Alternatively, the observed genetic affinity may be explained by more recent migrations from the Indian subcontinent into Australia.