Final outcomes analysis of the cell product SQZ-PBMC-HPV Phase 1 trial in incurable HPV16+ solid tumors shows improved overall survival in patients with increased CD8+ T cell tumor infiltration.

Cancer vaccines strive to induce robust, antigen-targeted, T-cell-mediated immune responses but have struggled to produce meaningful regression in solid tumors. An autologous cell vaccine, SQZ-PBMC-HPV, was developed by SQZ Biotechnologies using microfluidic squeezing technology to load PBMCs with HPV16 E6 and E7 antigens in HLA-A*02+ patients. The SQZ-PBMC-HPV-101 Phase 1 trial (NCT04084951) enrolled patients with incurable HPV16+ cancers. Here, we present a post hoc analysis of the relationship between Posttreatment CD8+ T cell infiltration and patient outcomes. SQZ-PBMC-HPV was administered as monotherapy every 3 weeks. Tumor samples were collected pre-dose and post-dose 4 weeks after treatment start. Biomarkers including CD8, MHC-I, E6, E7, GZMB, and Ki67 were evaluated by immunohistochemistry, immunofluorescence, and RNA in situ hybridization, and were correlated with clinical response, survival, and drug product composition. Eighteen patients had paired pre- and post-dose biopsies. Six (33%) had an increase in CD8+ T cell density in tumor parenchyma between screening and C2D8. Patients with increased CD8+ T cell density had improved disease control rate (66.7% vs 16.7%) and median overall survival (606.5 days vs 170.0 days, p = 0.0078). Drug product was significantly enriched for higher T cells and lower monocytes in the increased CD8+ T cell density group. In patients with incurable HPV16+ solid tumors treated with SQZ-PBMC-HPV, an increase in CD8+ T cell density within the tumor parenchyma was associated with superior disease control rate and overall survival. The product composition for patients with increased CD8+ T cell density was enriched for T cells.

Vulvar Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology.

Vulvar cancer is annually diagnosed in an estimated 6,470 individuals and the vast majority are histologically squamous cell carcinomas. Vulvar cancer accounts for 5% to 8% of gynecologic malignancies. Known risk factors for vulvar cancer include increasing age, infection with human papillomavirus, cigarette smoking, inflammatory conditions affecting the vulva, and immunodeficiency. Most vulvar neoplasias are diagnosed at early stages. Rarer histologies exist and include melanoma, extramammary Paget's disease, Bartholin gland adenocarcinoma, verrucous carcinoma, basal cell carcinoma, and sarcoma. This manuscript discusses recommendations outlined in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for treatments, surveillance, systemic therapy options, and gynecologic survivorship.

NCCN Guidelines® Insights: Cervical Cancer, Version 1.2024.

The NCCN Guidelines for Cervical Cancer provide recommendations for all aspects of management for cervical cancer, including the diagnostic workup, staging, pathology, and treatment. The guidelines also include details on histopathologic classification of cervical cancer regarding diagnostic features, molecular profiles, and clinical outcomes. The treatment landscape of advanced cervical cancer is evolving constantly. These NCCN Guidelines Insights provide a summary of recent updates regarding the systemic therapy recommendations for recurrent or metastatic disease.

Protein kinase RNA-activated controls mitotic progression and determines paclitaxel chemosensitivity through B-cell lymphoma 2 in ovarian cancer.

Anti-tubulin agents, such as paclitaxel, have been used extensively for treatment of several types of cancer, including ovarian, lung, breast, and pancreatic cancers. Despite their wide use in cancer treatment, however, patient response is highly variable and drug resistance remains a major clinical issue. Protein kinase RNA-activated (PKR) plays a critical role in immune response to viral infection. We identified PKR as a phospho-protein in response to anti-tubulin agents and this phosphorylation occurs independent of its own kinase activity. PKR is phosphorylated by cyclin-dependent kinase 1 (CDK1) during anti-tubulin treatment and unperturbed mitosis and that PKR regulates mitotic progression in a phosphorylation-dependent manner. Furthermore, inactivation of PKR confers resistance to paclitaxel in ovarian and breast cancer cells in vitro and in vivo. PKR expression levels and activity are decreased in chemotherapeutic recurrent ovarian cancer patients. Mechanistically, our findings suggest that PKR controls paclitaxel chemosensitivity through repressing Bcl2 expression. Pharmacological inhibition of Bcl2 with FDA-approved agent venetoclax overcomes paclitaxel resistance in preclinical animal models of ovarian cancer. Our results suggest that PKR is a critical determinant of paclitaxel cytotoxicity and that PKR-Bcl2 axis as a potential therapeutic target for the treatment of recurrent drug-resistant ovarian tumors.

Adjuvant vaginal brachytherapy alone for high risk localized endometrial cancer as defined by the three major randomized trials of adjuvant pelvic radiation.

OBJECTIVE: Controversy exists regarding optimal management of high risk localized endometrial cancer. Given that vaginal brachytherapy (VB) alone is used routinely at our institution, we retrospectively reviewed our outcomes among high risk patients defined according to the PORTEC, GOG 99, and/or Aalders randomized trials of pelvic radiation versus observation to determine if acceptable rates of locoregional control could be achieved with vaginal brachytherapy alone in this highest risk patient population. METHODS: The Roswell Park Cancer Institute hospital tumor registry was used to identify all patients with Stage I or IIA endometrial cancer treated between January 1992 and June 2006. A total of 464 patients were identified. Of 261 patients who received post-operative RT, 225 received VB alone. Of those 225, 87 met the high risk criteria as designated by PORTEC (at least 2 of the following high risk features: age>60, Grade 3, and/or myometrial invasion >or=Occurrences of the mathematical operator' (='were changed to 'OE'. Please check.-->50%), GOG 99 (any age with 3 high risk features: Grade 2-3, >66% myometrial invasion, and/or LVSI; age >or=50 with 2 high risk features; or age >or=70 with 1 high risk feature), and/or Aalders (Stage IC, Grade 3). Descriptive recurrence statistics are provided. RESULTS: Among 87 high risk patients treated with VB alone, 36, 77, and 14 were high risk per PORTEC, GOG 99, and Aalders respectively. Forty (46%) underwent pelvic lymph node dissection. With a median follow-up of 52 months, 3 (3.4%) pelvic recurrences were observed including 1 vaginal recurrence, 1 pelvic recurrence, and 1 local recurrence involving both the vagina and pelvis. All 3 local recurrences were successfully salvaged with pelvic RT+/-surgery. CONCLUSIONS: This represents one of the largest known series of high risk localized endometrial cancer treated with VB alone. The observed 3.4% locoregional recurrence compares favorably with the 5% locoregional recurrence noted among the highest risk patients receiving pelvic RT in the PORTEC, GOG 99, and Aalders randomized trials. In this single institution experience, the 3 local recurrences were salvaged. Based on these findings, we will continue to use VB alone in the adjuvant setting for patients with high risk localized endometrial cancer.

Higher regular coffee and tea consumption is associated with reduced endometrial cancer risk.

Several studies have investigated the associations between diet and endometrial cancer, but few have focused specifically on coffee and tea. In a hospital-based case-control study, we examined the associations between endometrial cancer risk and usual consumption of coffee, decaffeinated coffee, and black tea among 541 women with endometrial cancer and 541 women with an intact uterus but without a cancer diagnosis seen at Roswell Park Cancer Institute (Buffalo, New York) between 1982 and 1998. Daily frequency of consumption of coffee, decaffeinated coffee, and black tea in the few years prior to diagnosis in cases and questionnaire completion in controls was assessed with a self-administered epidemiologic questionnaire and categorized as none, 0.5 cups/d, 1-2 cups/d and >2 cups/d. Odds ratios (OR) and 95% confidence intervals (CI) for each category referent to nondrinkers were estimated with unconditional logistic regression adjusting for age, endometrial cancer risk factors and each beverage mutually adjusted for other beverages. Compared to nondrinkers, we observed a nonsignificant negative association with endometrial cancer risk among women who reported >2 cups/d regular coffee (OR 0.71, 95% CI 0.49-1.03), a significant inverse association with >2 cups/d black tea (OR 0.56, 95% CI 0.35-0.90) and a significant inverse association with >4 cups/d combined coffee and tea consumption (OR 0.47, 95% CI 0.28-0.80). These findings suggest coffee and tea may be important in reducing endometrial cancer risk.

Higher intakes of vegetables and vegetable-related nutrients are associated with lower endometrial cancer risks.

A limited number of studies have investigated diet in association with endometrial cancer (EC). We examined the association between intakes of selected food groups and nutrients with EC risk among 541 women with histologically confirmed EC and 541 women with an intact uterus and noncancer diagnoses seen at Roswell Park Cancer Institute between 1982 and 1998. Self-reported dietary and other epidemiologic data were collected by questionnaire. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% CI, adjusting for age, BMI, hormone replacement therapy use, cigarette smoking, lifetime duration of menstruation, and total energy intake. We observed significant inverse associations for women in the highest vs. lowest quartiles of intake of total vegetables (OR, 0.51; 95% CI, 0.34-0.75), vitamin E (OR, 0.44; 95% CI, 0.27-0.70), dietary fiber (OR, 0.60; 95% CI, 0.39-0.94), beta-carotene (OR, 0.55; 95% CI, 0.37-0.82), lutein (OR, 0.52; 95% CI, 0.34-0.78), and folate (OR, 0.57; 95% CI, 0.36-0.91). Our results support that vegetables and related nutrients are associated with decreased risk of EC.

Desmoplastic small round cell tumor (DSRCT) with ovarian involvement in 2 young women.

We report 2 cases of desmoplastic small round cell tumor (DSRCT) involving the ovaries in young women. The first patient presented with symptoms of acute appendicitis and the second patient presented with a mass in the lower abdomen and slightly elevated CA-125 level. In both patients, the tumor was widely metastatic at presentation. The ovarian involvement was unilateral in the first patient and bilateral in the second with tumor size ranging from 9 to 11 cm. Morphology, immunohistochemistry, and molecular cytogenetics were consistent with DSRCT. Despite tumor debulking and multiple chemotherapy regimens, the first patient died at 20 months after initial diagnosis and the second is still undergoing chemotherapy at 7 months after initial presentation. To gain additional insight on DSRCT with ovarian involvement, the literature was reviewed and summarized.

Intraobserver and interobserver variability in distinguishing between endocervical and endometrial adenocarcinoma on problematic cases of cervical curettings.

We conducted a prospective study where 4 pathologists examined patients' problematic cases of cervical curetting for adenocarcinoma to determine whether it is of endocervical or endometrial origin based on 3 parameters: age, morphology, and immunohistochemistry (IHC) panel. Our aims were to evaluate the intraobserver and interobserver variability and to compare the results using those parameters to the final hysterectomy specimens. The value of morphology, morphology+age, and the combined parameters (morphology+age+IHC) in predicting the correct origin of the tumor was evaluated. The intraobserver agreements ranged from fair to almost perfect for each of morphology, morphology+age, and the combined parameters. The interobserver agreements were fair in the first review and ranged from slight to fair in the second review. The agreements between the diagnosis based on morphology, morphology+age, and the combined parameters compared with the final diagnosis on the hysterectomy specimen were slight (kappa=0.137), fair (kappa=0.290), and moderate (kappa=0.497), respectively. We concluded that (i) discriminating between endocervical and endometrial carcinoma is highly subject to intraobserver and interobserver variability. (ii) Surprisingly, this variability is not affected by pathologists' experience. (iii) An IHC panel adds a useful piece of information to predict the tumor origin. Lastly, even though the combination of morphology, age, and IHC is far from perfect in predicting the correct origin of the tumor, it is still the best available method.

Expression characteristics of prostate-derived Ets factor support a role in breast and prostate cancer progression.

The purpose of this study was to understand the characteristics of prostate-derived Ets factor (PDEF) protein expression in breast and prostate cancer progression. A polyclonal antibody specific to PDEF was raised and reacted with tissue microarrays consisting of benign breast, in situ ductal, invasive ductal, and invasive lobular breast carcinomas. The antibody was also reacted with tissue microarrays, including benign prostate, prostate intraepithelial neoplasias (PINs), and prostate carcinomas. Increased expression of PDEF was identified in 18%, 50%, 46%, and 51% of benign breast tissues, intraductal, invasive ductal, and invasive lobular carcinomas, respectively. Importantly, in matched samples of benign breast vs tumor, 90% showed higher expression of PDEF in the tumor tissue. Moreover, in invasive breast carcinomas, increased PDEF expression tended to correlate with Her2/neu overexpression. Increased expression of PDEF was also found in 27%, 33%, and 40% of benign prostate tissues, PIN samples, and prostate adenocarcinomas, respectively. Again, in matching samples of cancer vs benign and cancer vs PIN, 68% and 70%, respectively, showed increased expression in the malignant tissue. Moreover, PDEF was found to be more highly expressed in tumors with intermediate or high Gleason score compared with low-grade tumors (P < .01). In addition, R1881 treatment induced PDEF expression in the LNCaP prostate tumor cell line, suggesting regulation of PDEF by androgens in vivo. Together, these results for the first time show frequent increased expression of PDEF protein in breast and prostate tumors and support a role for PDEF in breast and prostate cancer progression.

Uterine carcinosarcoma associated with hereditary nonpolyposis colorectal cancer.

BACKGROUND: Hereditary nonpolyposis colorectal cancer (HNPCC) was originally described as a genetic disorder predominantly involving colorectal cancer. Numerous neoplasms are known to be associated with this condition. Sarcomas have also been reported within families with HNPCC. The challenge is determining if these cancers are sporadic or hereditary. CASE: We report on a 46-year-old woman with uterine carcinosarcoma and a family history suspicious for HNPCC. Genetic testing identified a germline MLH1 mutation. Immunohistochemistry testing of the carcinosarcoma revealed loss of MLH1 expression with preservation of MSH2 expression. CONCLUSION: The loss of MLH1 protein expression suggests the germline mutation contributed to the development of the carcinosarcoma. Hereditary nonpolyposis colorectal cancer should be included in the differential diagnosis of persons with uterine carcinosarcoma when noted within a family history suspicious for HNPCC.

Phase I study of abagovomab in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer.

PURPOSE: This open-label study assessed the safety and immunogenicity of two doses and two routes of the anti-idiotypic monoclonal antibody abagovomab (formerly ACA125) in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer. EXPERIMENTAL DESIGN: Eligible patients from the three participating institutions were any stage at diagnosis, had relapsed, and had complete or partial response to additional chemotherapy. Patients were randomized to receive abagovomab at 2.0 versus 0.2 mg and i.m. versus s.c. for four immunizations every 2 weeks and then monthly for two additional immunizations. Planned evaluation included interval physical examinations and laboratory assessments with immune assessment, including HLA typing, human anti-mouse antibody, ELISA, and enzyme-linked immunospot. Patients were required to remain on study until week 10 (the first post-baseline Ab3 determination) to be considered for immunologic assessment. The primary end points were safety and immunogenicity primarily determined by Ab3 response. RESULTS: Forty-two patients received at least one vaccination and were eligible for safety analysis. Thirty-three patients were available for Ab3 analysis (removed for progression of disease, 6; withdrawal of consent, 2; unrelated adverse event, 1). The most common adverse events were self-limited pain at injection site, myalgia, and fever. No hematologic or nonhematologic toxicity grade>2 related to immunization was seen. Ab3 was detectable in all patients (median, 236,794 ng/mL); none of route of administration (P=0.6268), dose (P=0.4602), or cohort (P=0.4944) was statistically significant in terms of effect on maximum post-baseline Ab3 titer. Human anti-mouse antibody was not detectable at baseline but was present in all patients at week 16 (range, 488-45,000 ng/mL). CONCLUSIONS: Immunization with abagovomab is well tolerated and induced robust Ab3 responses at the two doses and routes tested. A phase III randomized study with abagovomab (2.0 mg s.c.) is warranted.

Regular analgesic use and risk of endometrial cancer.

BACKGROUND: Analgesic use has been implicated in the chemoprevention of a number of solid tumors, but thus far, no previous research has focused on the role of aspirin in endometrial cancer etiology. METHODS: We conducted a hospital-based case-control study of 427 women with primary, incident endometrial cancer, and 427 age- and residence-matched controls without benign or malignant neoplasms. All participants received medical services at Roswell Park Cancer Institute in Buffalo, NY, and completed a comprehensive epidemiologic questionnaire. Women who reported analgesic use at least once a week for at least 6 months were classified as regular users and served as the reference group throughout the analyses. We used unconditional logistic regression analyses to compute crude and adjusted odds ratios (OR) with corresponding 95% confidence intervals (CI). RESULTS: Compared with nonusers, regular aspirin users were not at reduced risk of endometrial cancer (adjusted OR, 0.91; 95% CI, 0.66-1.26), nor were women with the highest frequency, duration, or cumulative lifetime aspirin use. When the sample was divided by body mass index status, regular aspirin use was not associated with risk among women classified as normal weight or overweight, but a significant risk reduction was seen for obese women (adjusted OR, 0.50; 95% CI, 0.27-0.92). Significant decreases in risk were also observed for obese women with the greatest frequency, duration, and cumulative aspirin use. No significant associations in the overall sample or among obese women were noted for acetaminophen use. CONCLUSION: We observed no evidence of an overall chemoprotective effect of aspirin on endometrial cancer risk, but the significant risk reductions among obese women warrant further investigation.

The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression.

The Hippo signaling pathway controls organ size and tumorigenesis through a kinase cascade that inactivates Yes-associated protein (YAP). Here, we show that YAP plays a central role in controlling the progression of cervical cancer. Our results suggest that YAP expression is associated with a poor prognosis for cervical cancer. TGF-α and amphiregulin (AREG), via EGFR, inhibit the Hippo signaling pathway and activate YAP to induce cervical cancer cell proliferation and migration. Activated YAP allows for up-regulation of TGF-α, AREG, and EGFR, forming a positive signaling loop to drive cervical cancer cell proliferation. HPV E6 protein, a major etiological molecule of cervical cancer, maintains high YAP protein levels in cervical cancer cells by preventing proteasome-dependent YAP degradation to drive cervical cancer cell proliferation. Results from human cervical cancer genomic databases and an accepted transgenic mouse model strongly support the clinical relevance of the discovered feed-forward signaling loop. Our study indicates that combined targeting of the Hippo and the ERBB signaling pathways represents a novel therapeutic strategy for prevention and treatment of cervical cancer.

SCP-1 cancer/testis antigen is a prognostic indicator and a candidate target for immunotherapy in epithelial ovarian cancer.

SCP-1 is a novel tumor antigen that belongs to the growing family of cancer/testis (CT) antigens, and it is a potential target for immunotherapy. In an effort to determine the expression of SCP-1 in epithelial ovarian cancer (EOC), one-step RT-PCR was performed with RNA from epithelial ovarian tumor tissues and with two normal ovarian surface epithelial cell lines. We used immunohistochemistry (IHC) to investigate SCP-1 expression in paraffin-fixed EOC samples and ELISA to test sera from a subgroup of patients for SCP-1 antibody. SCP-1 was expressed in 15 out of 100 (15%) primary tumors, as determined by RT-PCR. The normal ovarian surface epithelial cell lines were negative for SCP-1 expression, as were a panel of other normal tissues. None of the patients whose tumors were determined to be SCP-1 positive by RT-PCR expressed the antigen by IHC or demonstrated a humoral immune response by ELISA. Tumors that expressed SCP-1 mRNA tended to have a higher grade than those that did not (P = 0.03). There was a significant decrease in survival time (P = 0.004) for patients with SCP-1 mRNA-positive tumors compared to those with SCP-1 mRNA-negative tumors [median 25 mo, 95% confidence interval (CI) 0-56 mo; and median 97 mo, CI 32-162 mo, respectively]. The present study shows that SCP-1 mRNA expression in patients with EOC is associated with a poorer chance of survival. These findings imply that further evaluation of SCP-1 as a potential target for vaccine therapy in EOC is warranted.

A medical-legal partnership as a component of a palliative care model.

INTRODUCTION: A medical-legal partnership (MLP) incorporated as part of a comprehensive palliative care model addresses unmet social and material needs for patients. This study retrospectively reviews the experience of one MLP and quantifies the benefits of the program for both patients and the host health care institution. METHODS: The Legal Services Program, an MLP, reviewed their program referral and outcomes from April 1, 2004 to December 31, 2007 to document legal needs resolved. The patient accounts manager in the host health care institution reported on the revenue reimbursed to date on a subset of benefits advocacy cases. RESULTS: The Legal Services Program received 297 referrals from April 1, 2004 to December 31, 2007 and resolved multiple legal issues. Seventeen benefits advocacy cases successfully overturned benefit denials, with the institution receiving $923,188 for current and past health services rendered. Two patient-client case studies are described in-depth. CONCLUSION: This MLP demonstrates the ability to help both patients and health care institutions effectively address the needs of patients with cancer and is an important component of a comprehensive palliative care model.

Instituting a robot-assisted surgery programme at a tertiary care cancer centre.

BACKGROUND: The initial experience of a gynaecological oncology robotic surgery programme at a tertiary care cancer centre is described. METHODS: A retrospective study was performed to evaluate the perioperative outcomes of 76 patients offered robot-assisted surgery. RESULTS: Seventy-three patients underwent robot-assisted surgery; three cases were converted to laparotomy; 51% of patients underwent treatment for endometrial cancer; 18% had ovarian cancer risk reduction surgery; and 8% were treated for uterine leiomyomata. Median body mass index (BMI) was 30. Median estimated blood loss, operative time, and length of stay were 150 ml, 195 min and 1 day, respectively. The total major complication rate was 6.8% and the total minor complication rate was 15.1%. CONCLUSION: Robot-assisted surgery is safe and appropriate for gynaecological patients undergoing surgical management. A gynaecological oncology robot-assisted programme can be easily established in a tertiary care cancer centre.