Chen, Longwen

Objective: We aimed to analyze the current literature for IORT in gynecological cancers and summarized clinical outcomes regarding patient selection. Methods: A systematic search was conducted utilizing PUBMED, Embase, and CINAHL to identify studies following PRISMA-ScR guidelines. A PICOS structure was utilized: population: patients with epithelial gynecological cancers; intervention: IORT; C: a comparator was not required, as we aimed to analyze patient selection; outcome: clinical outcomes and overall survival; and S: experimental and quasi-experimental analytical observational studies and descriptive observational studies, excluding case series published in English and limited to the last 10 years. Data extraction was conducted for patient selection, IORT, oncological outcomes, and morbidity. Results: A total of 707 results were identified, and 509 studies were uploaded to Covidence for screening after removing duplications. Of the 21 eligible studies, 9 were included in the final review. The total number of patients included was 348. The studies were retrospective single-institution studies, except for one. There was significant heterogeneity in their design and protocols. IORT was exclusively used for recurrent and advanced stage gynecological cancers adjunct to pelvic exenteration or laterally extended endopelvic resections with variable indications across institutions. The mean number of IORT patients per study was 2.8 per year. Survival rates were variable and dependent on the surgical margin. Endometrial cancer had a favorable outcome compared to vulvar and cervical cancers. Conclusions: Current clinical practice, as demonstrated by the research, is consistent with NCCN guidelines that endorse the application of IORT in instances of recurrent cervical, vaginal, and vulvar malignancies; however, there are no established recommendations for primary tumors. The analysis shows that there are gaps in our knowledge, mainly regarding the status of the margins, the criteria used to choose patients, and the outcomes that are specific to each histology. The standardization of protocols and prospectively powered studies are needed to refine patient selection criteria.

Objectives: Gain insights into the pathophysiology of idiopathic subglottic stenosis (iSGS) by investigating differences in transcriptome of subglottic mucosal tissue between patients with iSGS and controls, and between tracheal and subglottic tissue within patients. Methods: RNA sequencing was conducted on biopsied mucosal samples collected from subglottic and tracheal (in-patient control) regions in iSGS patients, and from subglottis in controls. The gene expression differences were validated on a protein level by (1) staining the tissue samples obtained from a second cohort of patients and controls; and (2) in vitro functional assays using primary subglottic epithelial cells from both iSGS patients and healthy donors. Results: We found 7 upregulated genes in the subglottic region of iSGS patients relative to both the tracheal mucosa and subglottic region of controls. A gene ontology enrichment analysis found that the epithelial cell differentiation and cornification pathways are significant, involving specifically 3 of the genes: involucrin ( IVL), small proline rich protein 1B ( SPRR1B), and keratin 16 ( KRT16). Involvement of these pathways suggests squamous metaplasia of the epithelium. Histological analyses of epithelium in subglottic mucosal biopsies revealed squamous metaplasia in 41% of the samples from iSGS patients and in 25% from controls. Immunohistochemical evaluation of the samples presented with squamous epithelium revealed increased expression of the protein encoded by SPRR1B, hyperproliferative basal cells, shedding of apical layers, and accompanying lesions in iSGS compared to CTRL. Cultured primary subglottic epithelial cells from iSGS patients had higher proliferation rates compared to healthy donors and squamous metaplastic differentiation formed thinner epithelia with increased expression proteins encoded by INV, SPRR1B, and KRT16, suggesting intrinsic dysfunction of basal cells in iSGS. Conclusions: Abnormal squamous differentiation of epithelial cells may contribute to the pathogenesis of iSGS. Patients having metaplastic epithelial phenotype may be sensitive to drugs that reverse it to a normal phenotype.

Abstract Lynch syndrome (LS) markedly increases risks of colorectal and endometrial cancers. Early detection biomarkers for LS cancers could reduce the needs for invasive screening and surgical prophylaxis. To validate a panel of methylated DNA markers (MDM) previously identified in sporadic colorectal cancer and endometrial cancer for discrimination of these cancers in LS. In a case–control design, previously identified MDMs for the detection of colorectal cancer and endometrial cancer were assayed by qMSP on tissue-extracted DNA. Results were normalized to ACTB values within each sample. Least absolute shrinkage and selection operator models to classify colorectal cancer and endometrial cancer were trained on sporadic cases and controls and then applied to classify colorectal cancer and endometrial cancer, in those with LS, and cross-validated. We identified colorectal cancer cases (23 with LS, 48 sporadic), colorectal controls (32 LS, 48 sporadic), endometrial cancer cases (30 LS, 48 sporadic), and endometrial controls (29 LS, 37 sporadic). A 3-MDM panel (LASS4, LRRC4, and PPP2R5C) classified LS-CRC from LS controls with an AUC of 0.92 (0.84–0.99); results were similar for sporadic colorectal cancer. A 6-MDM panel (SFMBT2, MPZ, CYTH2, DIDO1, chr10.4479, and EMX2OS) discriminated LS-EC from LS controls with an AUC of 0.92 (0.83–1.0); the AUC for sporadic endometrial cancer versus sporadic controls was nominally higher, 0.99 (0.96–1.0). MDMs previously identified in sporadic endometrial cancer and colorectal cancer discriminate between endometrial cancer and benign endometrium and colorectal cancer and benign colorectum in LS. This supports the inclusion of patients with LS within future prospective clinical trials evaluating endometrial cancer and colorectal cancer MDMs and may provide a new avenue for cancer screening or surveillance in this high-risk population. Prevention Relevance: Lynch syndrome (LS) markedly increases risks of colorectal and endometrial cancers. Early detection biomarkers for LS cancers could reduce the needs for invasive screening and surgery. Methylated DNA markers previously identified in sporadic endometrial cancer and colorectal cancer discriminate between benign and cancer tissue in LS.

Objectives: Lung cancer is an important cause of mortality in the United States. Targeted mutation analysis has the potential to alter mortality in those with non-small-cell lung cancer. As such, the importance of timely tissue turnaround time (TAT) is substantial. We evaluated TAT at Mayo Clinic Arizona and found it to be delayed relative to national standards. Material and Methods: We conducted a series of plan, do, study, and act (PDSA) cycles at a single institution to identify areas for improvement with our lung cancer genomic testing. We assembled a multidisciplinary team and held serial meetings to discuss data from each PDSA cycle. Results: Using PDSA cycles and multidisciplinary discussions, we were able to identify a number of process limitations slowing TAT. We were then able to generate enhanced and timely communication between providers and pathology, educate and enforce the order/requisition workflow, and establish pathology accessioning with lung cancer specimens top priority. Conclusion: We were able to generate and implement a standard operating procedure for genomic testing of lung cancer specimens at our institution, thereby reducing tissue TAT.

A woman in her late 20s presented with difficulty phonating and singing for the past 15 months and no improvement from prior treatment with steroids and antibiotics for chronic laryngitis. What is your diagnosis?

e17610 Background: Methylated DNA markers (MDMs) associated with sporadic ovarian cancer (OC) are detected in plasma from patients with treatment naïve tumors, but not cancer-free controls. To assess potential benefits to patients at risk for hereditary OC, the aim of this study was to measure the performance of validated sporadic OC MDMs in OC and benign ovarian tissue (BOT), surgically obtained from germline BRCA1 or BRCA2 ( BRCA1/2) mutation carriers. Methods: BRCA1/2 carriers with OC and BRCA1/2 carriers who had undergone risk-reducing salpingo-oophorectomy (SO) were identified at a comprehensive cancer center. BRCA1/2 carriers in both OC and BOT groups were balanced on age and year of surgery with non- BRCA carriers with sporadic OC or benign indications for SO. OC and BOT formalin fixed paraffin embedded (FFPE) tissues were macrodissected following pathologist selection of representative sites; DNA was extracted, and bisulfite converted. 15 OC MDMs ( GDF6, IFFO1, MAX.chr1.147790358, MAX.chr6.10382190, MAX.chr11.14926602, C2CD4D, PDRM14, NCOR2, SKI, DSCR6, SIM2, PALLD, CDO1, GPRIN1, BCAT1) previously identified in sporadic OC were assayed by quantitative methylation specific PCR, normalized by β-actin, by blinded personnel. Areas under the receiver operating characteristic curve (AUC) were generated for each MDM to assess discrimination of OC from benign tissue and compared between BRCA1/2 and sporadic (non- BRCA) patients, using a z-test. Results: Among BRCA1/2 carriers, there were 48 OC ( BRCA-OC) and 48 BOT ( BRCA-BOT); among non- BRCA, we matched 48 OC (Sporadic-OC) and 48 BOT (non- BRCA-BOT). The median AUC for OC MDM discriminated between OC and BOT with AUCs in BRCA1/2 carriers was 0.87, (IQR, 0.83-0.93). Sporadic-OC vs non- BRCA-BOT median AUC was 0.88 (IQR, 0.83-0.92). AUCs were not significantly different for each MDM when stratified by BRCA or sporadic status. MDMs with an AUC of ≥0.9 in either group are shown (Table). Conclusions: OC MDMs identified and validated in sporadic OC are highly discriminant for OC from BOT in DNA extracted from tissues of people who carry a BRCA1/2 mutation. Testing the performance of these OC MDMs in plasma from BRCA1/2 carriers with and without OC may be of clinical value for high-risk patients and inform multi-cancer early detection testing strategies.[Table: see text]

AbstractWe describe an exceedingly rare cytology case of a NUTM1‐rearranged sarcoma involving pleural fluid. A 48‐year‐old female presented with progressive abdominal pain. Computed tomography (CT) scan of the abdomen revealed a 5.6 cm soft tissue mass in the right hemi‐abdomen. Needle core biopsy of the mass showed a small round cell tumor. Extensive work‐up including next generation sequencing (NGS) demonstrated a NUTM1:MXI1 rearranged sarcoma. The patient was first treated with ifosfamide, carboplatin, and etoposide (ICE) chemotherapy. She responded initially and then progressed with multiple masses in the abdomen and pleural effusion. The cytology of the pleural effusion showed clusters and single small round blue cells. Some of them displayed rhabdoid morphology. Immunostains of NUT antibody on cell block demonstrated strong positivity of NUT. NUTM1‐rearranged sarcoma is an emerging class of mesenchymal neoplasm and the cytomorphology of this neoplasm in liquid‐based cytology (LBC) is yet to be described. We herein reported the first cytology case of NUTM1‐rearranged sarcoma in pleural fluid.