Citations

Abstract Introduction. Voyager-V1 (VV1) is an oncolytic vesicular stomatitis virus engineered to express human interferon beta (IFNβ) to enhance cellular antitumor immune responses and tumor selectivity. VV1 also contains the human sodium iodide symporter (NIS) as an imaging gene. We report here the novel use of virus-encoded IFNβ as a PD marker using correlative data from three Phase I trials of VSV-IFNβ-NIS in patients with refractory cancers (n=46). Methods. 46 patients with solid tumors (n=34) and hematological malignancies (n=12) received 1 dose of VV1 either intratumorally (ITu) or intravenously (IV) at doses ranging from 3 x 106 to 5 x 1010 TCID50. Plasma IFNβ levels were collected pre-treatment, 4 hours post-infusion, Day 2 (24-hour), Day 3, 8, 15 and 29 (IT only). Samples were processed using a standard IFNβ specific ELISA kit. Results. ITu dose escalation is complete with 27 patients treated and no DLTs. IV escalation is ongoing at 5 x 1010 TCID50 with 19 patients treated to date. In the ITu study, plasma IFNβ levels at 24h were undetected at the lowest dose levels (up to 1 x 107 TCID50), and became detectable from 3 x 107 TCID50. In the IV patients, IFNβ was detectable at all dose levels (5 x 109 through 5 x 1010 TCID50) with the highest peak and longest duration in a patient with metastatic endometrial cancer coincident with shrinkage of multiple tumors. The IFNβ produced by virus-infected cells can be differentiated from the acute innate antiviral responses by magnitude of response and AUC as the majority of the inflammatory cytokines returned to baseline by 48h. Peak IFNβ levels were variable between patients, likely reflecting heterogeneity in tumor susceptibility to VV1, ranging from 1.4pg/mL to 656pg/mL across 6 patients (mean 153pg/ml) at the highest ITu dose. Plasma IFNβ 24 hours post-therapy of >20pg/mL appears to predict for RECIST 1.1-evaluated SD vs PD, p=0.048 in the ITu patients. Peak IFNβ ranged from 18 to 1700 pg/mL across 9 patients (mean=442pg/ml) at 1.7 x 1010 in the IV study. Peak IFNβ was highest in two cases of endometrial cancer (1500 and 1700 pg/ml). The patient with the highest IFNβ levels on the IV trial showed 16.7% tumor shrinkage at the first tumor evaluation. SPECT imaging, which shows location of viral replication, was positive in 50% of ITu injected tumors, also validating of VV1 infection of target cells. To date, SPECT images were negative in the IV trial despite IFNβ positivity, reflecting IFNβ as a more sensitive PD marker of viral infection. IHC staining of tumor biopsies collected pre-treatment and 1 month after VSV showed increased numbers of CD3, CD8, CD68, PDL1 or PD1 in some injected or noninjected tumors. Other immune markers and tumor gene signatures are also being evaluated. Conclusions. Plasma IFNβ has emerged as a simple and convenient biomarker of viral replication in tumors. IFNβ will be used in future studies as a PD marker to assess the impact of immune-modulating combination drugs with VV1. Citation Format: Timothy P. Cripe, Jamie Bakkum-Gamez, Jaime R. Merchan, Martha Q. Lacy, Manish R. Patel, Steven Powell, James Strauss, Lianwen Zhang, Toshie Sakuma, Memy Diaz, Nandakumar Packiriswamy, Deepak Upreti, Bethany Brunton, Dragan Jevremovic, Stephen J. Russell, Alice Bexon, Kah-Whye Peng. Rational design of an oncolytic virus permits use of interferon beta as a pharmacodynamic marker for clinical application [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT090.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years from diagnosis. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. The best outcomes are observed in patients whose primary treatment includes complete resection of all visible disease plus combination platinum-based chemotherapy. Research efforts are focused on primary neoadjuvant treatments that may improve resectability, as well as systemic therapies providing improved long-term survival. These NCCN Guidelines Insights focus on recent updates to neoadjuvant chemotherapy recommendations, including the addition of hyperthermic intraperitoneal chemotherapy, and the role of PARP inhibitors and bevacizumab as maintenance therapy options in select patients who have completed primary chemotherapy.

INTRODUCTION: To compare two published risk stratification criteria (Milwaukee Model vs. Mayo Criteria) to predict lymphatic dissemination (LD) in endometrioid endometrial cancer (EC). METHODS: Patients who underwent surgery for EC between 1/1/2004-9/30/2013 and had endometrioid histology without stage IV disease were included and classified as either low-risk or at-risk for LD using two independent risk stratification systems. LD was defined as positive nodes at time of surgery or lymph node recurrence within 2 years of surgery after negative lymph node assessment (LNA) or when LNA was not performed. False positive (FP) and false negative (FN) rates for each risk model were calculated. RESULTS: Among 1103 patients, 81 (7.3%) had LD (72 positive LN and 9 LN recurrences). Most patients (90.2%) had stage I disease. Integration of the Milwaukee Model was associated with a low at-risk rate for LD (38.1%) but a relatively high FN rate (13.6%, 95% CI 7.0-23.0). Conversely, the traditional Mayo Criteria using a tumor diameter (TD) cutoff of ≤2 cm (vs >2 cm) had a higher at-risk rate for LD (69.5%) but a FN rate of 0.0% (95% CI, 0-4.5). Modifying Mayo Criteria using a TD cutoff of ≤3 cm (vs >3 cm) identified fewer women at-risk than using ≤2 cm cutoff (56.8% vs. 69.5%), but had a higher FN rate of 3.7% (95% CI, 0.8-10.4). CONCLUSIONS: The Milwaukee Model had the lowest at-risk rate of LD but an unacceptable FN rate. Modifying the Mayo Criteria by increasing the TD cutoff from the traditional ≤2 cm to ≤3 cm would spare an estimated 12.7% of patients LNA, but the accompanying FN rate is unacceptably high. The traditional Mayo Criteria for low-risk EC remains the most accurate in determining which patients LNA can be omitted.

INTRODUCTION: Leiomyomas are benign uterine smooth muscle tumors. After menopause, most women have a reduction in size and number of leiomyomas. Conversely, uterine sarcomas present as a rapidly enlarging pelvic mass in postmenopausal women. The distinction of uterine leiomyoma from sarcoma is difficult and definitive diagnosis requires pathologic examination. METHODS: A 74 year-old multiparous female with a history of ductal carcinoma in situ (DCIS) of the breast presented with significant postmenopausal bleeding, requiring blood transfusion, and a rapidly enlarging pelvic mass. Abdominal imaging including ultrasound and computerized tomography confirmed a 15 cm uterine mass. The patient underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy with concern for uterine sarcoma. Grossly, the uterus contained a 15.5 cm well demarcated intramural mass. Microscopically, the tumor was a spindle cell neoplasm with anastomosing fascicles interrupted by thick-walled blood vessels or fibrous regions. The cells exhibited uniformly mild to moderate cytologic atypia. Immunohistochemically, the tumor strongly and diffusely expressed desmin and h-caldesmon and exhibited patchy, strong expression of CD10. RNA-seq, confirmed by RT-PCR and Sanger sequencing, revealed a gene fusion involving KAT6B and KANSL1. The fusion joins exon 3 of KAT6B to exons 11 and 12 of KANSL1. The final diagnosis was a benign uterine leiomyoma. The patient remains without evidence of disease six months post-operatively. CONCLUSION: This is the first case, to our knowledge, that has identified the KAT6B-KANSL1 fusion in a uterine leiomyoma. Further efforts to classify the pathologic characteristics and prevalence of this fusion may contribute to understanding of tumorigenesis of uterine smooth muscle tumors.

Abstract Rationale The diagnostic concordance between transbronchial lung cryobiopsy (TBLC)—versus surgical lung biopsy (SLB) as the current gold standard—in interstitial lung disease (ILD) cases requiring histology remains controversial. Objectives To assess diagnostic concordance between TBLC and SLB sequentially performed in the same patients, the diagnostic yield of both techniques, and subsequent changes in multidisciplinary assessment (MDA) decisions. Methods A two-center prospective study included patients with ILD with a nondefinite usual interstitial pneumonia pattern (on high-resolution computed tomography scan) confirmed at a first MDA. Patients underwent TBLC immediately followed by video-assisted thoracoscopy for SLB at the same anatomical locations. After open reading of both sample types by local pathologists and final diagnosis at a second MDA (MDA2), anonymized TBLC and SLB slides were blindly assessed by an external expert pathologist (T.V.C.). Kappa-concordance coefficients and percentage agreement were computed for: TBLC versus SLB, MDA2 versus TBLC, MDA2 versus SLB, and blinded pathology versus routine pathology. Measurements and Main Results Twenty-one patients were included. The median TBLC biopsy size (longest axis) was 7 mm (interquartile range, 5–8 mm). SLB biopsy sizes averaged 46.1 ± 13.8 mm. Concordance coefficients and percentage agreement were: TBLC versus SLB: κ = 0.22 (95% confidence interval [CI], 0.01–0.44), percentage agreement = 38% (95% CI, 18–62%); MDA2 versus TBLC: κ = 0.31 (95% CI, 0.06–0.56), percentage agreement = 48% (95% CI, 26–70)%; MDA2 versus SLB: κ = 0.51 (95% CI, 0.27–0.75), percentage agreement = 62% (95% CI, 38–82%); two pneumothoraces (9.5%) were recorded during TBLC. TBLC would have led to a different treatment if SLB was not performed in 11 of 21 (52%) of cases. Conclusions Pathological results from TBLC and SLB were poorly concordant in the assessment of ILD. SLBs were more frequently concordant with the final diagnosis retained at MDA.

Male and female glioblastomas are biologically distinct, and improving outcomes may require sex-specific approaches to treatment.

ABSTRACT The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell‐released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV‐associated functional activities. Finally, a checklist is provided with summaries of key points.