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Listeria delivers tetanus toxoid protein to pancreatic tumors and induces cancer cell death in mice

Selvanesan, Benson Chellakkan; Chandra, Dinesh; Quispe-Tintaya, Wilber; Jahangir, Arthee; Patel, Ankur; Meena, Kiran; Alves Da Silva, Rodrigo Alberto; Friedman, Madeline; Gabor, Lisa; Khouri, Olivia; Libutti, Steven K; Yuan, Ziqiang; Li, Jenny; Siddiqui, Sarah; Beck, Amanda; Tesfa, Lydia; Koba, Wade; Chuy, Jennifer; McAuliffe, John C; Jafari, Rojin; Entenberg, David; Wang, Yarong; Condeelis, John; DesMarais, Vera; Balachandran, Vinod; Zhang, Xusheng; Lin, Ken; Gravekamp, Claudia
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease. Tumors are poorly immunogenic and immunosuppressive, preventing T cell activation in the tumor microenvironment. Here, we present a microbial-based immunotherapeutic treatment for selective delivery of an immunogenic tetanus toxoid protein (TT856-1313) into PDAC tumor cells by attenuated Listeria monocytogenes. This treatment reactivated preexisting TT-specific memory T cells to kill infected tumor cells in mice. Treatment of KrasG12D,p53R172H, Pdx1-Cre (KPC) mice with Listeria-TT resulted in TT accumulation inside tumor cells, attraction of TT-specific memory CD4 T cells to the tumor microenvironment, and production of perforin and granzyme B in tumors. Low doses of gemcitabine (GEM) increased immune effects of Listeria-TT, turning immunologically cold into hot tumors in mice. In vivo depletion of T cells from Listeria-TT + GEM-treated mice demonstrated a CD4 T cell-mediated reduction in tumor burden. CD4 T cells from TT-vaccinated mice were able to kill TT-expressing Panc-02 tumor cells in vitro. In addition, peritumoral lymph node-like structures were observed in close contact with pancreatic tumors in KPC mice treated with Listeria-TT or Listeria-TT + GEM. These structures displayed CD4 and CD8 T cells producing perforin and granzyme B. Whereas CD4 T cells efficiently infiltrated the KPC tumors, CD8 T cells did not. Listeria-TT + GEM treatment of KPC mice with advanced PDAC reduced tumor burden by 80% and metastases by 87% after treatment and increased survival by 40% compared to nontreated mice. These results suggest that Listeria-delivered recall antigens could be an alternative to neoantigen-mediated cancer immunotherapy.
PMID: 35320003
ISSN: 1946-6242
CID: 5229212

Uptake and timing of risk-reducing salpingo-oophorectomy among patients with BRCA1/2 mutations

Smith, Maria J; Gerber, Deanna; Olsen, Anne; Khouri, Olivia R; Wang, Yuyan; Liu, Mengling; Smith, Julia; Pothuri, Bhavana
BACKGROUND:In women with BRCA mutations, risk-reducing bilateral salpingo-oophorectomy (RRSO) has been shown to decrease gynecologic cancer-specific and overall mortality. The National Comprehensive Cancer Network (NCCN) recommends that patients with BRCA mutations undergo RRSO between the ages of 35-40 years for BRCA1 mutation carriers and between the ages of 40-45 years for BRCA2 mutation carriers, or after childbearing is complete. Currently, uptake and timing of RRSO and reasons for delays in RRSO are not well understood. OBJECTIVE:We sought to evaluate uptake and timing of RRSO among women with BRCA1/2 mutations in relation to NCCN guidelines, and reasons for delays in RRSO. STUDY DESIGN/METHODS:In this retrospective chart review, we identified women with BRCA1/2 mutations who discussed RRSO with a provider between 2012 and 2021. Uptake of RRSO was documented, and patients were classified as having timely or delay in RRSO based on NCCN guidelines. For those with delay in RRSO, reasons cited for delay were collected. Comparative statistical analyses were performed to evaluate characteristics of those with timely vs delayed RRSO. A multivariable logistic regression model was used to evaluate the associations between factors related to timing of RRSO. RESULTS:We identified 638 BRCA1/2 mutation carriers seen between 2012 and 2021. Of these patients, 306 (48.0%) had undergone RRSO and 332 (52.0%) had not. When evaluating timing of RRSO, 136 (21.3%) underwent timely RRSO, 239 (37.5%) had delay in RRSO, and 263 (41.2%) had not undergone RRSO but were younger than NCCN age guidelines so were neither timely nor delayed. Patients with delay in RRSO were significantly older at the time of genetic testing compared to those with timely RRSO (mean 49.8 vs 36.3 years; p < 0.001). Of the 306 patients who underwent RRSO, those with delayed RRSO had a significantly shorter interval between BRCA identification and RRSO compared to those with timely RRSO (median 8.7 vs 17.6 months; p < 0.001). Patients with delay in RRSO were more likely to have a personal history of cancer than those with timely RRSO (49.8% vs 37.5%; p=0.028). Of the 239 women with delay in RRSO, reasons included: 188 (78.7%) for delayed BRCA mutation identification; 29 (12.1%) for menopausal concerns; 17 (7.1%) for ongoing cancer treatment; 12 (5.0%) for coordination with breast surgery; 20 (8.4%) for miscellaneous reasons; and 19 (7.9%) with no reasons documented. In the multivariate model, older age at BRCA diagnosis (OR 0.73; 95%CI [0.68-0.78]; p<0.001) was significantly associated with delayed RRSO timing; those with BRCA2 mutation type were 7.54 times as likely to have timely RRSO compared to BRCA1 mutation carriers (OR 7.54; 95%CI [3.70-16.42]; p<0.001). CONCLUSION/CONCLUSIONS:Nearly 38% of BRCA1/2 mutation carriers undergo or have yet to undergo RRSO beyond the NCCN recommended age. The most common reason for delay in RRSO was delayed identification of BRCA mutation, noted in 79% of patients with delayed RRSO. Timely genetic testing for eligible patients can increase appropriately timed RRSO for prevention of ovarian cancer and reduction of mortality in BRCA mutation carriers.
PMID: 34171390
ISSN: 1097-6868
CID: 4925842

Inflammatory reaction to BioGlueâ„¢ masquerading as recurrence in patients with endometrial cancer: A report of two cases [Case Report]

Fife, Alexander; Khouri, Olivia R; Grantham, Mica; DiVito, Joseph; Hébert, Tiffany; Kuo, Dennis Yi-Shin
•BioGlue™, a glutaraldehyde-based vessel sealant, can cause a foreign body reaction.•Vessel sealants may be used for IVC repair during endometrial cancer staging.•Foreign body reaction to BioGlue™ may look like a cancer recurrence on imaging.•It is important to note prior use of vessel sealants in assessing paraaortic recurrence.
PMID: 33251313
ISSN: 2352-5789
CID: 5229202

Neoadjuvant chemotherapy in patients with advanced endometrial cancer

Khouri, Olivia R; Frey, Melissa K; Musa, Fernanda; Muggia, Franco; Lee, Jessica; Boyd, Leslie; Curtin, John P; Pothuri, Bhavana
OBJECTIVES/OBJECTIVE:Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) is a treatment strategy for ovarian cancer patients with unresectable disease or poor performance status (PS). This strategy has been used in the treatment of advanced endometrial cancer and a survival benefit has been shown in patients who are subsequently able to undergo interval cytoreduction. This study sought to review our single institution experience with NACT for advanced endometrial cancer. METHODS:We conducted a retrospective review of all patients who received NACT for advanced endometrial cancer at two institutions in New York City between 2002 and 2016. RESULTS:We identified 39 patients (median age 61, range 35-89). The histologic subtype distribution was: serous (44%), endometrioid (28%), carcinosarcoma (10%), clear cell (8%), mixed (8%), neuroendocrine (3%). Contraindications to primary surgery included: unresectable disease (72%), poor PS (15%), unresectable disease and poor PS (13%). Twenty-three patients (59%) did not undergo IDS due to: progression of disease (70%), medical ineligibility (4%), unresectable disease (17%), lost to follow-up (4%), death (4%). Sixteen patients (41%) underwent IDS, 81% had an optimal cytoreduction. Disease status at NACT completion was: partial response (56%), stable disease (3%) and progression of disease (41%). There were no complete responses. Patients who responded to NACT had a significantly longer overall survival than those who did not (15 vs. 5 months. P = 0.015). IDS was also associated with an improvement in overall survival versus no surgery (16 vs. 6 months, P = 0.04). CONCLUSIONS:Unlike ovarian cancer, less than half of the patients undergoing NACT for endometrial cancer underwent IDS, none had a complete response, and 41% had disease progression during NACT. However, endometrial cancer patients who underwent IDS had a high rate of optimal cytoreduction. Both response to NACT and IDS were associated with improved survival.
PMID: 30980132
ISSN: 1432-0843
CID: 3809502

Tubal Disease and Impersonators/Masqueraders

Khouri, Olivia R; Monteagudo, Ana; Timor-Tritsch, Ilan E
Ultrasound is considered the first-line imaging modality in the evaluation of the fallopian tubes. This chapter reviews both the physiologic and pathologic sonographic findings of the fallopian tubes and how to recognize characteristic entities. Specifically, it describes how to use ultrasound techniques to distinguish between pathologic processes including chronic versus acute pelvic inflammatory disease, as well as infertility, torsion, and malignancy. It also describes how to employ modern ultrasound techniques, such as color Doppler, three-dimensional imaging, and salpingocentesis in clinical practice.
PMID: 28005596
ISSN: 1532-5520
CID: 2374432