Taking Control of Castleman Disease: Leveraging Precision Medicine Technologies to Accelerate Rare Disease Research.

Castleman disease (CD) is a rare and heterogeneous disorder characterized by lymphadenopathy that may occur in a single lymph node (unicentric) or multiple lymph nodes (multicentric), the latter typically occurring secondary to excessive proinflammatory hypercytokinemia. While a cohort of multicentric Castleman disease (MCD) cases are caused by Human Herpes Virus-8 (HHV-8), the etiology of HHV-8 negative, idiopathic MCD (iMCD), remains unknown. Breakthroughs in "omics" technologies that have facilitated the development of precision medicine hold promise for elucidating disease pathogenesis and identifying novel therapies for iMCD. However, in order to leverage precision medicine approaches in rare diseases like CD, stakeholders need to overcome several challenges. To address these challenges, the Castleman Disease Collaborative Network (CDCN) was founded in 2012. In the past 3 years, the CDCN has worked to transform the understanding of the pathogenesis of CD, funded and initiated genomics and proteomics research, and united international experts in a collaborative effort to accelerate progress for CD patients. The CDCN's collaborative structure leverages the tools of precision medicine and serves as a model for both scientific discovery and advancing patient care.

Decision Variables for the Use of Radioactive Iodine in Patients with Thyroid Cancer at Intermediate Risk of Recurrence.

The use of radioactive iodine (RAI) after total thyroidectomy for patients at the American Thyroid Association (ATA) who are at intermediate risk of recurrence is controversial. This is due to the lack of prospective randomized trials proving a benefit to recurrence or survival of RAI therapy in this group. In the absence of such evidence, clinicians struggle to recommend for or against this therapeutic approach which frequently results in overtreatment. This review describes key elements in the decision-making process that help clinicians more comprehensively evaluate the need for RAI therapy in patients with thyroid cancer at intermediate risk of recurrence. A clear definition of the purpose of RAI therapy should be conveyed to patients. In this sense, adjuvant RAI therapy intends to decrease recurrence, and ablation therapy is used to facilitate surveillance. Better stratification of the intermediate risk category into a low-intermediate subgroup and an intermediate-high-risk subgroup results in less heterogeneity and a more precise prediction of recurrence risk. The evaluation of post-operative thyroglobulin levels may prevent the overtreatment of low-intermediate-risk patients when their thyroglobulin level is <2.5 ng/mL. the integration of tumor genomics (when available) alongside pathologic features can enhance the ability of the clinician to predict iodine concentration in thyroid cancer cells. Finally, a detailed consideration of the adverse effects of RAI, patients' comorbidities, and patient preferences will result in a patient-centered personalized approach. Systematic examination of these variables will ultimately provide a framework for making more educated decisions on the use of RAI in patients at intermediate risk of recurrence that will prevent overtreatment and minimize harm.

HPV-associated oropharyngeal Adenosquamous carcinoma with early metastatic disease detected by ctDNA.

Adenosquamous Carcinoma is a rare, aggresssive variant of squamous cell carcinoma that may HPV-driven in the oropharynx. Although it is reported to behave similar to HPV-related squamous cell carcinoma, the literature is very limited for this disease. We present a case of early T and N stage HPV + adenosquamous carcinoma of the tonsil that metastasized immediately following surgery and adjuvant therapy despite only having microscopic nodal burden. Circulating tumor DNA (ctDNA) was instrumental in recognizing and salvaging metastatic disease early with radiation.

Invasion of a Recurrent Laryngeal Nerve from Small Well-Differentiated Papillary Thyroid Cancers: Patient Selection Implications for Active Surveillance.

Background: The success of an active surveillance management approach to low-risk papillary thyroid cancer (PTC) is heavily dependent on proper patient selection. For example, primary tumors located in a subcapsular position immediately adjacent to the trachea or a recurrent laryngeal nerve (RLN) are considered to be inappropriate for active surveillance. Since preoperative imaging cannot reliably rule out extrathyroidal extension or reveal the full course of the RLN relative to the thyroid gland, it is important for clinicians to understand subcapsular tumor locations and minimum tumor sizes that are most likely to be associated with gross invasion of the RLNs. Methods: We assessed the medical records of 123 patients treated at Memorial Sloan Kettering Cancer Center (MSK) between 1986 and 2015 who had a primary PTC tumor demonstrating gross extrathyroidal extension to either the right or left RLN. Thirty patients with a primary tumor ≤2 cm in diameter demonstrating extrathyroidal extension into an RLN were included in the analysis. Results: Gross invasion of an RLN by tumors ≤2 cm is a rare event that was seen in only 0.8% (35/4334) of patients with PTC who underwent initial thyroid surgery at MSK between 1986 and 2015. Gross RLN invasion was associated with subcapsular PTC tumors located in either the right paratracheal area (60%), left paratracheal area (36.7%), or right lateral posterior lobe area not adjacent to the trachea (3.3%). Only a quarter of the patients had imaging findings suggestive of extrathyroidal extension and only 30% had clinically apparent vocal paresis/paralysis on preoperative examination. Invasion of the RLN was not observed for primary tumors <0.9 cm in diameter, regardless of tumor location. Conclusions: Well-differentiated PTC tumors ≥0.9 cm in maximal diameter that are located in the right paratracheal, left paratracheal, and right lateral posterior lobe subcapsular positions are usually not appropriate for active surveillance even in the absence of definitive evidence for nerve invasion on preoperative imaging or vocal cord examination. Patient selection for active surveillance management should take into account not only the size and growth rate of a tumor but also its location in relation to the expected course of RLNs.

CARM1 Is Essential for Myeloid Leukemogenesis but Dispensable for Normal Hematopoiesis.

Chromatin-modifying enzymes, and specifically the protein arginine methyltransferases (PRMTs), have emerged as important targets in cancer. Here, we investigated the role of CARM1 in normal and malignant hematopoiesis. Using conditional knockout mice, we show that loss of CARM1 has little effect on normal hematopoiesis. Strikingly, knockout of Carm1 abrogates both the initiation and maintenance of acute myeloid leukemia (AML) driven by oncogenic transcription factors. We show that CARM1 knockdown impairs cell-cycle progression, promotes myeloid differentiation, and ultimately induces apoptosis. Finally, we utilize a selective, small-molecule inhibitor of CARM1 to validate the efficacy of CARM1 inhibition in leukemia cells in vitro and in vivo. Collectively, this work suggests that targeting CARM1 may be an effective therapeutic strategy for AML.

Phase II Study of a Non-Platinum-Containing Doublet of Paclitaxel and Pemetrexed with Bevacizumab as Initial Therapy for Patients with Advanced Lung Adenocarcinomas.

INTRODUCTION: Many patients with lung cancers cannot receive platinum-containing regimens owing to comorbid medical conditions. We designed the PPB (paclitaxel, pemetrexed, and bevacizumab) regimen to maintain or improve outcomes while averting the unique toxicities of platinum-based chemotherapies. METHODS: We enrolled patients with untreated, advanced lung adenocarcinomas with measurable disease and no contraindications to bevacizumab. Participants received paclitaxel, 90 mg/m(2), pemetrexed, 500 mg/m(2), and bevacizumab, 10 mg/kg, every 14 days for 6 months and continued to receive pemetrexed and bevacizumab every 14 days until progression or unacceptable toxicity. RESULTS: Of the 44 patients treated, 50% were women; the median age was 61 years and 89% had a Karnofsky performance status of at least 80%. We genotyped 38 patients with the following results: Kirsten rat sarcoma viral oncogene homolog gene (KRAS), 16; anaplastic lymphoma receptor tyrosine kinase gene (ALK), three; B-Raf proto-oncogene, serine/threonine kinase gene (BRAF) V600E, two; erb-b2 receptor tyrosine kinase 2 gene (HER2)/phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA), one; epidermal growth factor receptor gene (EGFR) exon 20 insertion, one; and driver 15, none. A total of 23 patients achieved a PR (52%, 95% confidence interval: 37-68), including seven of 16 with KRAS-mutant tumors. The overall survival rate at 2 years was 43% with a median of 17 months (95% confidence interval: 10-29). Grade 3/4 treatment-related toxicities included elevated alanine transaminase level (16%), fatigue (16%), leukopenia (9%), anemia (7%), elevated aspartate transaminase level (7%), edema (5%), and pleural effusions (5%). Two patients died of respiratory failure without disease progression. CONCLUSIONS: The PPB regimen produced a high response rate in patients with lung adenocarcinomas regardless of mutational status. Survival and toxicities were comparable to those in the phase II reports testing platinum-containing doublets with bevacizumab. These results justify use of the PPB regimen in fit patients in whom three-drug regimens including bevacizumab are appropriate.