Recurrent pembrolizumab-induced mechanical small bowel obstruction in a patient with metastatic cervical cancer.

•Adverse events of pembrolizumab have been documented, but more severe gastrointestinal effects are not as well described.•We report a case of a patient with cervical cancer treated with pembrolizumab who developed small bowel obstruction (SBO)•Histological analysis and gastrointestinal workup points to pembrolizumab as likely cause of SBO.

Phase II study of Vigil® DNA engineered immunotherapy as maintenance in advanced stage ovarian cancer.

OBJECTIVES: The majority of women with Stage III/IV ovarian cancer who achieve clinical complete response with frontline standard of care will relapse within 2years. Vigil immunotherapy, a GMCSF/bi-shRNA furin DNA engineered autologous tumor cell (EATC) product, demonstrated safety and induction of circulating activated T-cells against autologous tumor in Phase I trial Senzer et al. (2012, 2013) . Our objectives for this study include evaluation of safety, immune response and recurrence free survival (RFS). METHODS: This is a Phase II crossover trial of Vigil (1.0×107 cells/intradermal injection/month for 4 to 12 doses) in Stage III/IV ovarian cancer patients achieving cCR (normal imaging, CA-125≤35units/ml, physical exam, and no symptoms suggestive of the presence of active disease) following primary surgical debulking and carboplatin/paclitaxel adjuvant or neoadjuvant chemotherapy. Patients received Vigil or standard of care during the maintenance period. RESULTS: Forty-two patients were entered into trial, 31 received Vigil and 11 received standard of care. No≥Grade 3 toxicity related to product was observed. A marked induction of circulating activated T-cell population was observed against individual, pre-processed autologous tumor in the Vigil arm as compared to pre-Vigil baseline using IFNγ ELISPOT response (30/31 negative ELISPOT pre Vigil to 31/31 positive ELISPOT post Vigil, median 134 spots). Moreover, in correlation with ELISPOT response, RFS from time of procurement was improved (mean 826days/median 604days in the Vigil arm from mean 481days/median 377days in the control arm, p=0.033). CONCLUSION: In conjunction with the demonstrated safety, the high rate of induction of T-cell activation and correlation with improvement in RFS justify further Phase II/III assessment of Vigil.

Ovarian strumal carcinoid producing peptide YY associated with severe constipation: a case report and review of the literature.

Primary carcinoid tumors are rare neoplasms of the ovary. Of the 4 histologic subtypes, ovarian carcinoid tumors with insular patterns produce carcinoid syndrome in approximately one third of cases, versus strumal and trabecular carcinoids which very rarely cause typical carcinoid syndrome. A unique presentation of ovarian carcinoid tumors with concurrent severe constipation has been reported, which is thought to represent a new carcinoid syndrome. The proposed mechanism is the production of peptide YY by the tumor, a gastrointestinal hormone responsible for decreasing gut motility. We report a case of a 34-yr-old white woman who presented with constipation and weight loss for 1 yr, and was found to have a unilateral ovarian strumal carcinoid, which produced peptide YY as demonstrated by immunohistochemistry. The 13 previous case reports of ovarian carcinoids with constipation are reviewed and the clinicopathologic features are discussed. This report and literature review further solidifies this entity as a new type of carcinoid syndrome.

Actinomyces bacteremia in association with tubo-ovarian abscesses and hysteroscopic sterilization.

BACKGROUND: Actinomyces infection is well-documented in intrauterine devices but has not been previously associated with hysteroscopic sterilization using coil inserts. Additionally, abscesses associated with these implants have been observed in few cases. CASE: A 31-year-old multiparous woman with a history of hysteroscopic sterilization with coil inserts 18 months previously presented with several weeks of pelvic pain. Despite percutaneous drainage of intra-abdominal abscesses, her pain and fevers persisted. Blood cultures were positive for Actinomyces infection, and exploratory laparotomy demonstrated abscesses at both coil sites. CONCLUSION: When a causative organism cannot be identified or the when patient does not respond to standard antibiotic therapy, Actinomyces infection should be considered because prolonged antibiotic therapy is necessary.

Accuracy of optical spectroscopy for the detection of cervical intraepithelial neoplasia: Testing a device as an adjunct to colposcopy.

Testing emerging technologies involves the evaluation of biologic plausibility, technical efficacy, clinical effectiveness, patient satisfaction, and cost-effectiveness. The objective of this study was to select an effective classification algorithm for optical spectroscopy as an adjunct to colposcopy and obtain preliminary estimates of its accuracy for the detection of CIN 2 or worse. We recruited 1,000 patients from screening and prevention clinics and 850 patients from colposcopy clinics at two comprehensive cancer centers and a community hospital. Optical spectroscopy was performed, and 4,864 biopsies were obtained from the sites measured, including abnormal and normal colposcopic areas. The gold standard was the histologic report of biopsies, read 2 to 3 times by histopathologists blinded to the cytologic, histopathologic, and spectroscopic results. We calculated sensitivities, specificities, receiver operating characteristic (ROC) curves, and areas under the ROC curves. We identified a cutpoint for an algorithm based on optical spectroscopy that yielded an estimated sensitivity of 1.00 [95% confidence interval (CI) = 0.92-1.00] and an estimated specificity of 0.71 [95% CI = 0.62-0.79] in a combined screening and diagnostic population. The positive and negative predictive values were 0.58 and 1.00, respectively. The area under the ROC curve was 0.85 (95% CI = 0.81-0.89). The per-patient and per-site performance were similar in the diagnostic and poorer in the screening settings. Like colposcopy, the device performs best in a diagnostic population. Alternative statistical approaches demonstrate that the analysis is robust and that spectroscopy works as well as or slightly better than colposcopy for the detection of CIN 2 to cancer.

The performance of fluorescence and reflectance spectroscopy for the in vivo diagnosis of cervical neoplasia; point probe versus multispectral approaches.

OBJECTIVE: This review evaluates the diagnostic efficacy of fluorescence spectroscopy, reflectance spectroscopy, and their combination that use both point probe and multispectral imaging approaches in diagnosing cervical neoplasia in vivo. METHODS: Articles were selected for this review from a literature search which report the performance of fluorescence and reflectance spectroscopy devices in diagnosing cervical neoplasia in vivo. This analysis focused on the comparison of point probe versus multispectral approaches; the use of fluorescence, reflectance, and their combination; and finally the types of populations that have been studied for in vivo diagnosis of squamous intraepithelial lesions (SIL). RESULTS: Twenty-six studies were included and their heterogeneity precluded formal meta-analysis. Though point probes were expected to have greater specificity and multispectral approaches greater sensitivity, there was considerable overlap in the performance of point probe and multispectral devices. There were few studies that studied fluorescence spectroscopy alone and reflectance spectroscopy alone. Combined fluorescence and reflectance approaches showed considerable overlap among point probe and multispectral devices. The overlap of performance suggests that fluorescence and reflectance may have similar performance. Currently the paucity of data precludes definitive conclusions regarding the additive effect of both approaches. Only two of twenty-six trials have recruited patients with no history of an abnormal Papanicolaou smear (screening populations) and twenty-four trials include patients with a range of cervical abnormalities from atypia to cancer (diagnostic populations). DISCUSSION: Optical spectroscopy using a point probe and multispectral approaches appears to overlap in performance. Fluorescence and reflectance spectroscopies examine different aspects of epithelial-stromal biology and appear to yield similar diagnostic performance. While intuitively appealing, their combination may or may not be additive. There have been few studies of these technologies in screening populations. Better definitions of device trial design and reporting requirements would facilitate combining analyses to formally examine performance.

Classification using the cumulative log-odds in the quantitative pathologic diagnosis of adenocarcinoma of the cervix.

INTRODUCTION: This study develops a method that discriminates between normal and cancerous tissue sections (i.e., populations of cells) using a statistical model applied to high-dimensional quantitative measurements made on a sample of cells. MATERIALS AND METHODS: We use a cumulative log-odds model to create a score for a tissue section using the information from the cells within that tissue section. Then, a threshold is determined using receiver operating characteristic (ROC) curve analysis. The method was tested using data from cervical adenocarcinomas, adenocarcinoma in situ, and normal columnar tissue. RESULTS: Using 120 potential features, we analyzed the data for staining-independent features. Twenty-two features were statistically significant. We then calculated the log-odds and created a score, followed by ROC curve analysis. The operating point which maximizes the sum of the specificity and sensitivity achieved a sensitivity of 100% with a specificity of 85%. CONCLUSION: The cumulative log-odds performs well in classifying tissue sections using high-dimensional data measured at the cellular level, like that of quantitative pathology. This methodology potentially has applications in pathology, radiology, and optical technologies.

Results of a phase II double-blinded randomized clinical trial of difluoromethylornithine for cervical intraepithelial neoplasia grades 2 to 3.

PURPOSE: Our purpose was to conduct a double-blinded randomized trial of difluoromethylornithine (DFMO) at 0.125, 0.5 gm/m2, versus placebo in the treatment of cervical intraepithelial neoplasia (CIN) grades 2 to 3. A promising phase I study has shown histopathologic responses at these dose levels. EXPERIMENTAL DESIGN: Patients with histopathologically confirmed CIN 2-3 lesions were recruited from a colposcopy clinic and underwent Papanicolaou testing, human papillomavirus testing, and colpophotography. They took oral contraception and DFMO or placebo elixir for 28 days and filled out the National Cancer Institute common toxicity calendars. They returned for follow-up and a repeat Papanicolaou smear, colpophotograph, and loop excision of the cervix. RESULTS: There were no statistically significant differences among the arms in histopathologic response. This could no be explained by any biases in risk factors. The prominent toxicities were diarrhea, dizziness, nausea, and headaches. There were no differences in the toxicities among arms. The Papanicolaou smear was a poor biomarker of response and correlated poorly with the histopathology. CONCLUSIONS: DFMO is no active at 0.125 and 0.5 gm/m2 for 28 days when given orally in CIN 2-3. Higher oral doses or longer administration is necessary, supporting data from breast trials. Alternatively, a trial of topical DFMO might merit attention as activity has been noted in trials of actinic keratoses.

Use of nuclear morphometry characteristics to distinguish between normal and abnormal cervical glandular histologies.

This is a methodological study exploring the use of quantitative histopathology applied to the cervix to discriminate between normal and cancerous (consisting of adenocarcinoma and adenocarcinoma in situ) tissue samples. The goal is classifying tissue samples, which are populations of cells, from measurements on the cells. Our method uses one particular feature, the IODs-Index, to create a tissue level feature. The specific goal of this study is to find a threshold for the IODs-Index that is used to create the tissue level feature. The main statistical tool is Receiver Operating Characteristic (ROC) curve analysis. When applied to the data, our method achieved promising results with good estimated sensitivity and specificity for our data set. The optimal threshold for the IODs-Index was found to be 2.12.

Cytometric features of cell nuclei of adenocarcinoma in situ and invasive adenocarcinoma of the cervix.

OBJECTIVE: The goal of this study was to characterize adenocarcinoma in situ (ACIS) and invasive adenocarcinoma (AdCa) of the cervix by using image histometric measurements of nuclear morphometric features. STUDY DESIGN: Archival pathology slides and tissue blocks from 37 patients with ACIS, 18 with invasive AdCa, and 13 with normal cervical epithelial and glandular histology were reviewed by two pathologists. The controls were matched for age and menstrual status and as closely as possible for the age of the slides; this limited the number of normal cases available. Morphometric, photometric, and textural measurements were made on 4-microm sections of tissue stained with a thionin-SO(2) Feulgen reaction. A mixed analysis of covariance model was used for analysis. RESULTS: The Integrated Optical Density Index was found between the mean value for normal cells and that for ACIS and invasive AdCa (P <.001). Twenty-two other morphometric features were identified that exhibited differences in their means between at least two of the three tissue types. CONCLUSION: In the cell populations studied, certain nuclear image features were found to correlate with histologic diagnosis. The features can be measured objectively and could be useful to pathologists in differentiating lesions, although a larger study should be evaluated to confirm these findings. Further, these features may be important as optical technologies are developed that make diagnoses in real time.