Citations

Abstract Mantle cell lymphoma (MCL) is an incurable rare subtype of non-Hodgkin lymphoma and is subject to relapse and therapeutic resistance. Molecular aberrations in MCL affect pathogenesis, prognosis, and therapeutic response. In this systematic review, we searched 3 databases and selected 32 articles that described mutations in MCL patients. We then conducted a meta-analysis using a Bayesian multiregression model to analyze patient-level data in 2127 MCL patients, including prevalence of mutations. In tumor or bone marrow samples taken at diagnosis or baseline, ATM was the most frequently mutated gene (43.5%) followed by TP53 (26.8%), CDKN2A (23.9%), and CCND1 (20.2%). Aberrations were also detected in IGH (38.4%) and MYC (20.8%), primarily through cytogenetic methods. Other common baseline mutations were NSD2 (15.0%), KMT2A (8.9%), S1PR1 (8.6%), and CARD11 (8.5%). Our data also show a change in mutational status from baseline samples to samples at disease progression and present mutations of interest in MCL that should be considered for future analysis. The genes with the highest mutational frequency difference (>5%) are TP53, ATM, KMT2A, MAP3K14, BTK, TRAF2, CHD2, TLR2, ARID2, RIMS2, NOTCH2, TET2, SPEN, NSD2, CARD11, CCND1, SP140, CDKN2A, and S1PR1. These findings provide a summary of the mutational landscape of MCL. The genes with the highest change in mutation frequency should be included in targeted next-generation sequencing panels for future studies. These findings also highlight the need for analysis of serial samples in MCL. Patient-level data of prevalent mutations in MCL provide additional evidence emphasizing molecular variability in advancing precision medicine initiatives in MCL.

Context.— Controversies and uncertainty persist in prostate cancer grading. Objective.— To update grading recommendations. Data Sources.— Critical review of the literature along with pathology and clinician surveys. Conclusions.— Percent Gleason pattern 4 (%GP4) is as follows: (1) report %GP4 in needle biopsy with Grade Groups (GrGp) 2 and 3, and in needle biopsy on other parts (jars) of lower grade in cases with at least 1 part showing Gleason score (GS) 4 + 4 = 8; and (2) report %GP4: less than 5% or less than 10% and 10% increments thereafter. Tertiary grade patterns are as follows: (1) replace “tertiary grade pattern” in radical prostatectomy (RP) with “minor tertiary pattern 5 (TP5),” and only use in RP with GrGp 2 or 3 with less than 5% Gleason pattern 5; and (2) minor TP5 is noted along with the GS, with the GrGp based on the GS. Global score and magnetic resonance imaging (MRI)-targeted biopsies are as follows: (1) when multiple undesignated cores are taken from a single MRI-targeted lesion, an overall grade for that lesion is given as if all the involved cores were one long core; and (2) if providing a global score, when different scores are found in the standard and the MRI-targeted biopsy, give a single global score (factoring both the systematic standard and the MRI-targeted positive cores). Grade Groups are as follows: (1) Grade Groups (GrGp) is the terminology adopted by major world organizations; and (2) retain GS 3 + 5 = 8 in GrGp 4. Cribriform carcinoma is as follows: (1) report the presence or absence of cribriform glands in biopsy and RP with Gleason pattern 4 carcinoma. Intraductal carcinoma (IDC-P) is as follows: (1) report IDC-P in biopsy and RP; (2) use criteria based on dense cribriform glands (>50% of the gland is composed of epithelium relative to luminal spaces) and/or solid nests and/or marked pleomorphism/necrosis; (3) it is not necessary to perform basal cell immunostains on biopsy and RP to identify IDC-P if the results would not change the overall (highest) GS/GrGp part per case; (4) do not include IDC-P in determining the final GS/GrGp on biopsy and/or RP; and (5) “atypical intraductal proliferation (AIP)” is preferred for an intraductal proliferation of prostatic secretory cells which shows a greater degree of architectural complexity and/or cytological atypia than typical high-grade prostatic intraepithelial neoplasia, yet falling short of the strict diagnostic threshold for IDC-P. Molecular testing is as follows: (1) Ki67 is not ready for routine clinical use; (2) additional studies of active surveillance cohorts are needed to establish the utility of PTEN in this setting; and (3) dedicated studies of RNA-based assays in active surveillance populations are needed to substantiate the utility of these expensive tests in this setting. Artificial intelligence and novel grading schema are as follows: (1) incorporating reactive stromal grade, percent GP4, minor tertiary GP5, and cribriform/intraductal carcinoma are not ready for adoption in current practice.

AbstractBackgroundEndobronchial ultrasound‐guided transbronchial lung biopsy (EBUS‐TBLB) and fluorodeoxyglucose positron emission tomography (FDG‐PET) have been widely used in the diagnosis of peripheral pulmonary lesions (PPLs). This study was conducted to determine the diagnostic value of EBUS‐TBLB combined with FDG‐PET in the assessment of PPLs.MethodsThe clinical data of 76 patients with PPLs who received both FDG‐PET and EBUS‐TBLB from January 2016 to February 2018 were retrospectively evaluated. Further subgroup analysis was performed according to lesion diameter (≤20 mm or >20 mm). Related diagnostic indices were calculated and compared between groups.ResultsWhen combining EBUS‐TBLB with FDG‐PET, the diagnostic accuracy rate, sensitivity, specificity, Youden's index, positive predictive value, and negative predictive value for PPLs were 86.8%, 90.2%, 73.3%, 63.5%, 93.2%, and 64.7%, respectively. In addition, the diagnostic accuracy rate of the combined approach was significantly higher than the single EBUS‐TBLB and FDG‐PET (P < 0.01 and P < 0.05, respectively), and its Youden's index was also at a higher level. When stratified by lesion diameter, the combined approach showed a significantly higher diagnostic accuracy rate (P < 0.05) and a higher Youden's index for PPLs >20 mm than PPLs ≤20 mm. In addition, we found that positive bronchus sign and probe within the probe were two important factors conducing to enhancing the diagnostic accuracy rate for EBUS‐TBLB.ConclusionsAn integrated approach combining EBUS‐TBLB with FDG‐PET is particularly useful for diagnosing PPLs, and the improved diagnostic yields were especially evident for PPLs >20 mm.

GPR15 expression is promoted by Ahr in an evolutionarily conserved manner via cooperation with Foxp3 but inhibited by RORγt.

Background Lymphedema treatment is an ongoing challenge. It impacts quality of life due to pain, loss of range of motion of the extremity, and repeated episodes of cellulitis. Different modalities have been used to evaluate lymphedema; some are more error-prone and some are more invasive. However, these measurements are poorly standardized, and intrarater and interrater reliabilities are difficult to achieve. This pilot study aims to assess the feasibility of ultrasound vibroelastography for assessing patients with extremity lymphedema via measuring shear wave speeds of subcutaneous tissues. Methods Patients with clinical and lymphoscintigraphic diagnosis of secondary lymphedema in the extremities without prior surgical treatment were included. A 0.1-s harmonic vibration was generated at three frequencies (100, 150, and 200 Hz) by the indenter of a handheld shaker on the skin. An ultrasound probe was used for noninvasively capturing of wave propagation in the subcutaneous tissue. Wave speeds were measured in the subcutaneous tissues of both the control and affected extremities. Results A total of 11 female patients with secondary lymphedema in the extremities were enrolled in this study. The magnitudes of the wave speeds of the region of interest in the subcutaneous tissue at lymphedema sites in the upper extremity (3.9 ± 0.17 m/s, 5.96 ± 0.67 m/s, and 7.41 ± 1.09 m/s) were statistically higher than those of the control sites (2.1 ± 0.27 m/s, 2.93 ± 0.57 m/s, and 3.56 ± 0.76 m/s) at 100, 150, and 200 Hz (P < 0.05), and at 100 and 200 Hz (P < 0.05) between lymphedema (4.33 ± 0.35 m/s, 4.17 ± 1.00 m/s, and 4.56 ± 0.37 m/s) and controls sites (2.48 ± 0.43 m/s, 2.77 ± 0.55 m/s, and 3.06 ± 0.29 m/s) in the lower extremity. Conclusions These preliminary data suggest that ultrasound vibroelastography may be useful in the evaluation of secondary lymphedema and can be a valuable tool to noninvasively track treatment progress.

Background Immune checkpoint inhibitors (ICIs) to date have demonstrated limited activity in advanced ovarian cancer (OC). Folate receptor alpha (FRα) is overexpressed in the majority of OCs and presents an attractive target for a combination immunotherapy to potentially overcome resistance to ICI in OCs. The current study sought to examine clinical and immunologic responses to TPIV200, a multiepitope FRα vaccine administered with programmed death ligand 1 (PD-L1) inhibitor durvalumab in patients with advanced platinum-resistant OC. Methods Following Simon two-stage phase II trial design, 27 patients were enrolled. Treatment was administered in 28-day cycles (intradermal TPIV200 and granulocyte-macrophage colony-stimulating factor (GM-CSF) for 6 cycles and intravenous durvalumab for 12 cycles). Primary endpoints included overall response rate and progression-free survival at 24 weeks. Translational parameters focused on tumor microenvironment, PD-L1 and FRα expression, and peripheral vaccine-specific immune responses. Results Treatment was well tolerated, with related grade 3 toxicity rate of 18.5%. Increased T cell responses to the majority of peptides were observed in all patients at 6 weeks (p<0.0001). There was one unconfirmed partial response (3.7%) and nine patients had stable disease (33.3%). Clinical benefit was not associated with baseline FRα or PD-L1 expression. One patient with prolonged clinical benefit demonstrated loss of FRα expression and upregulation of PD-L1 in a progressing lesion. Despite the low overall response rate, the median overall survival was 21 months (13.5–∞), with evidence of benefit from postimmunotherapy regimens. Conclusions Combination of TPIV200 and durvalumab was safe and elicited robust FRα-specific T cell responses in all patients. Unexpectedly durable survival in this heavily pretreated population highlights the need to investigate the impact of FRα vaccination on the OC biology post-treatment.

9543 Background: Lung cancer is the leading cause of cancer related death in the United States in all racial groups. However, the overall death rate from lung cancer is different among white, black and Asian. Although differences in socioeconomic status and treatments received might be the contributing factors, the biology, particularly genomic alteration of cancer might also have an important impact. To date, the differences of genomic alterations among all racial patients are poorly understood. Methods: The American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE, version 7.0) database was analyzed. A total of 8908 patients with lung adenocarcinoma (LUAD) were identified. Among them, 5652 patients who had comprehensive sequencing results (gene panel ≥ 275) were selected for further analysis. Patients with unknown race, undefined and Pacific Island (only 3 patients) were excluded. Finally, 5360 patients were included in the study. The prevalence and distribution of genomic alteration cross all racial groups were analyzed. Results: Overall 5951 samples from 5360 patients were collected (85.7% white, 7.9% Asian, 4.7% black, 0.2% Native American and 1.4% other). Most patients have only one sample. The median mutation counts in white, black, Asian, Native American and others are 7, 6, 5, 5, 7 respectively (Kruskal–Wallis test, P< 0.001). Asian have significantly higher rates of insertion and deletions than other races (14.8% of Asian versus 9.8% of white, 10.7% of black, 10.4% of Native American, 11.1% of other; Pearson’s chi-square test, < 0.001). TP53, EGFR, KRAS and STK11 are the most frequent alterations in white, black and other. EGFR, TP53, KRAS and APC are the most frequent alterations in Asian. STK11 mutations are rare in both Asian and Native American. Native Americans have more alterations of LRP1B, ARID2 and ATM, although the patients’ number remains small. ATM and KEAP1 mutations are also common in white and black. EGFR is the highest discrepancy gene in racial distribution. 78.9% Asian, 47.7% black, 36.4% of native American had EGFR alteration in comparison to 29.6% in white (Fisher's exact test, P < 0.001). KRAS is the second highest discrepancy gene in racial distribution. 11.6% Asian, 26.3% black, 27.3% of Native American had KRAS alteration in comparison to 36.1% in white (Fisher's exact test, P< 0.001). Conclusions: Our study demonstrated the potential diversity of genomic alterations across all racial groups with potential impact on therapeutic decisions.

6016 Background: The role of HIPEC for recurrent EOC is not well defined. The aim of this phase II study was to determine the proportion of pts without evidence of disease progression at 24 months post SCS +/- intraoperative carboplatin HIPEC. Methods: After SCS to ≤ 0.5 cm residual visible disease pts were intraoperatively randomized to carboplatin HIPEC (800mg/m2 for 90 minutes) or no HIPEC. The HIPEC arm received 5 additional and the standard arm received 6 postoperative cycles of IV platinum-based chemotherapy without maintenance treatment. Based on an exact binomial single stage “pick the winner” design, each arm is considered “winner” if ≥ 17/49 pts are without evidence of disease progression at 24 months post SCS. Secondary objectives include postoperative grade ≥ 3 toxicity and complications within 4 weeks post SCS, and pharmacokinetics of carboplatin HIPEC. Results: Of 98 pts, 49 (50%) were randomized to the HIPEC arm. The arms were well balanced for age, stage, histology, BRCA mutation status, prior chemotherapy, and disease-free interval. Complete gross SCS was achieved in 94% of the standard and 82% of the HIPEC arm (p = 0.12). Bowel resection was performed more frequently in the standard (65%) compared to the HIPEC arm (37%; p = 0.008). Median operative time was shorter in the standard (296 minutes) compared to the HIPEC arm (475 minutes; p < 0.001). There was no perioperative mortality and no difference in use of ostomies, length of stay or postoperative toxicity. At a median follow-up of 27.7 months (range: 8.8-81.8 months) 70 of 98 pts progressed and 26 died with a median progression free survival (PFS) of 14.3 months (12.1-16 months) and a median overall survival (OS) of 55.2 months (47.7-not reached). At 24 months post SCS 32 pts progressed within 24 months in the standard versus 35 in the HIPEC arm. There was no statistically significant difference in median PFS (15.4 vs 12.3 months, p = 0.173) or median OS (69.2 vs 53.1 months, p = 0.317) between arms. These are preliminary efficacy estimates as 83/98 pts have a minimum of 24 months follow-up. Conclusions: The HIPEC arm did not reach the predefined “winner” endpoint; the standard arm is still undetermined as 6 pts did not reach 24 months follow-up. No perioperative mortality, and no increased perioperative morbidity or toxicity was seen with HIPEC. SCS with carboplatin HIPEC followed by 5 cycles of platinum-based chemotherapy was not superior to SCS without HIPEC followed by 6 cycles of platinum-based chemotherapy. Clinical trial information: NCT01767675.

1506 Background: Hereditary breast and ovarian cancer (HBOC) is preventable when genetic risk is identified. We aimed to test whether pre and/or post-test genetic counseling is needed to optimally deliver online accessible genetic testing. Methods: MAGENTA (Making GENetic Testing Accessible) is a four-arm non-inferiority trial evaluating electronic genetic education and results delivery alone or combined with pre-test only, or post-test only telephone genetic counseling compared to mandatory pre- and post-test counseling (control arm) in women at risk of HBOC (NCT02993068). Regardless of assigned arm, all subjects with a pathogenic mutation received post-test telephone counseling. All subjects were enrolled electronically as part of either a family history cohort (FHC) or a cascade cohort (CC, known familial mutation). The primary outcome was cancer risk distress at 3 months and the trial was powered for the FHC. Secondary outcomes included completion of testing (i.e., received results), anxiety, depression, quality of life, and decisional regret, all measured by standardized scales. Results: Enrollment is complete and a total of 3,822 participants were randomized, 3,111 in FHC and 711 in CC. Participants were enrolled from all 50 states, but most were white/non-Hispanic (88%). Among participants that completed genetic testing, 173 (7.2%) had a mutation in a breast or ovarian cancer gene, with 114 (5.7%) of FHC and 59 (14.2%) of CC. In the primary intention-to-treat analysis of FHC, each of the three experimental arms was non-inferior to the control arm for distress at 3 months (p < 0.025/3 = 0.0083). In the CC, no and pre-test only counseling were also non-inferior (p < 0.025/3 = 0.0083). Distress was lowest in the arm with neither pre nor post-test counseling. Overall, 318 (18%) participants had very high distress at three month follow-up, and this rate was not significantly different across arms. Anxiety, depression and decisional regret did not have statistically significant differences across arms at follow-up. Test completion was highest in the no counseling arm (86.4%) and lowest in the control arm (60.6%). Conclusions: Electronic genetic education and results release without genetic counseling was non-inferior with regard to patient distress and was associated with higher test completion and lower distress. These results support use of a genetic testing paradigm providing individualized genetic counseling only for patients with positive test results. Clinical trial information: NCT02993068.

Abstract Splicing alterations are common in diseases such as cancer, where mutations in splicing factor genes are frequently responsible for aberrant splicing. Here we present an alternative mechanism for splicing regulation in T-cell acute lymphoblastic leukemia (T-ALL) that involves posttranslational stabilization of the splicing machinery via deubiquitination. We demonstrate there are extensive exon skipping changes in disease, affecting proteasomal subunits, cell-cycle regulators, and the RNA machinery. We present that the serine/arginine-rich splicing factors (SRSF), controlling exon skipping, are critical for leukemia cell survival. The ubiquitin-specific peptidase 7 (USP7) regulates SRSF6 protein levels via active deubiquitination, and USP7 inhibition alters the exon skipping pattern and blocks T-ALL growth. The splicing inhibitor H3B-8800 affects splicing of proteasomal transcripts and proteasome activity and acts synergistically with proteasome inhibitors in inhibiting T-ALL growth. Our study provides the proof-of-principle for regulation of splicing factors via deubiquitination and suggests new therapeutic modalities in T-ALL. Significance: Our study provides a new proof-of-principle for posttranslational regulation of splicing factors independently of mutations in aggressive T-cell leukemia. It further suggests a new drug combination of splicing and proteasomal inhibitors, a concept that might apply to other diseases with or without mutations affecting the splicing machinery. This article is highlighted in the In This Issue feature, p. 1241