Treatment of Anal High-Grade Squamous Intraepithelial Lesions to Prevent Anal Cancer.

BACKGROUND: The incidence of anal cancer is substantially higher among persons living with the human immunodeficiency virus (HIV) than in the general population. Similar to cervical cancer, anal cancer is preceded by high-grade squamous intraepithelial lesions (HSILs). Treatment for cervical HSIL reduces progression to cervical cancer; however, data from prospective studies of treatment for anal HSIL to prevent anal cancer are lacking. METHODS: We conducted a phase 3 trial at 25 U.S. sites. Persons living with HIV who were 35 years of age or older and who had biopsy-proven anal HSIL were randomly assigned, in a 1:1 ratio, to receive either HSIL treatment or active monitoring without treatment. Treatment included office-based ablative procedures, ablation or excision under anesthesia, or the administration of topical fluorouracil or imiquimod. The primary outcome was progression to anal cancer in a time-to-event analysis. Participants in the treatment group were treated until HSIL was completely resolved. All the participants underwent high-resolution anoscopy at least every 6 months; biopsy was also performed for suspected ongoing HSIL in the treatment group, annually in the active-monitoring group, or any time there was concern for cancer. RESULTS: Of 4459 participants who underwent randomization, 4446 (99.7%) were included in the analysis of the time to progression to cancer. With a median follow-up of 25.8 months, 9 cases were diagnosed in the treatment group (173 per 100,000 person-years; 95% confidence interval [CI], 90 to 332) and 21 cases in the active-monitoring group (402 per 100,000 person-years; 95% CI, 262 to 616). The rate of progression to anal cancer was lower in the treatment group than in the active-monitoring group by 57% (95% CI, 6 to 80; P = 0.03 by log-rank test). CONCLUSIONS: Among participants with biopsy-proven anal HSIL, the risk of anal cancer was significantly lower with treatment for anal HSIL than with active monitoring. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT02135419.).

Metastatic Neoplasms to the Vulva-A Review.

INTRODUCTION: Metastatic neoplasms to the vulva are rare and can pose a diagnostic dilemma. As identification of the primary site can influence patient treatment and prognosis, correct diagnosis is important. METHODS: PubMed was searched for applicable publications using the terms vulva, vulvar neoplasms, metastasis, and vulvar metastasis. RESULTS: Most neoplasms metastatic to the vulva originate from other genital sources; however, extragenital primary neoplasms can also metastasize to the vulva. Vulvar metastases often occur in the setting of widespread disease. CONCLUSIONS: It is important to consider biopsy for appropriate histologic and immunohistochemical studies, as well as consider patient history to establish the primary site of metastatic lesions to the vulva, allowing optimal therapy.

Phase 2 trial of paclitaxel, 13-cis retinoic acid, and interferon alfa-2b in the treatment of advanced stage or recurrent cervical cancer.

OBJECTIVE: Overexpression of bcl-2 is a mechanism of drug resistance in cervical cancer. Agents that down-regulate bcl-2 may decrease tumor cell threshold and sensitize tumor cells to chemotherapy. The objective of this multi-institutional phase 2 trial was to evaluate the efficacy and toxicity of paclitaxel and bcl-2 modulators (13-cis retinoic acid and interferon alfa-2b) in patients with advanced-stage or recurrent cervical cancer. MATERIALS AND METHODS: Patients had biopsy-proven metastatic, first relapse, or persistent cervical cancer with no prior chemotherapy except for chemosensitizing agents. The treatment consisted of oral 13-cis retinoic acid, 1 mg/kg, and subcutaneous interferon alfa-2b, 6 mU/m, days 1 to 4, and intravenous paclitaxel, 175 mg/m, day 4 until disease progression or adverse events prohibited treatment. The primary endpoint was overall response rate. RESULTS: Thirty-three patients were enrolled between March 2001 and June 2009. Thirty-one patients were eligible for evaluation of treatment response. Twenty-seven patients (82%) received prior concurrent chemoradiation or radiotherapy alone before study enrollment. The overall response rate was 30% (6 complete responses and 4 partial responses). Furthermore, 7 patients (21%) had stable disease. Grade 3 or 4 adverse events included neutropenia (n =16 [48%]), febrile neutropenia (n = 1 [3%]), and anemia (n = 1 [3%]). There were no treatment-related deaths. The median progression-free survival was 3.4 months (95% confidence interval, 2.0-7.4 months), and overall survival was 11.2 months (95% confidence interval, 7.5-26.2 months). Of 6 patients with complete responses, 5 patients survived more than 2 years. CONCLUSIONS: Combination therapy with paclitaxel, 13-cis retinoic acid, and interferon alfa-2b is feasible and safe in treating patients with advanced and recurrent cervical cancer.

Peritoneal nodules after laparoscopic surgery with uterine morcellation: review of a rare complication.

The risk of occult malignancy being present at the time of uterine morcellation has been estimated to be about 1%. Dissemination of both benign and malignant disease may occur after morcellation, leading to a variety of peritoneal nodules. These lesions are reviewed.

Massive localized lymphedema of the vulva: report of a case and review of the literature.

BACKGROUND: Massive localized lymphedema (MLL) is a recently described entity associated with obesity, most often on the thighs. It rarely occurs on the vulva, and it may pose diagnostic difficulty for both clinician and pathologist in this setting. CASE: An obese 55-year-old woman underwent excision of bilateral polypoid vulvar masses. Histology confirmed the diagnosis of MLL. CONCLUSIONS: Although MLL is not common on the vulva, with the increasing incidence of obesity in the population, more cases can be anticipated, and an awareness of this lesion is important.

Malignant female adnexal tumor of probable Wolffian origin: a case report.

BACKGROUND: Female adnexal tumor of probable Wolffian origin (FATWO) is a rare tumor arising in locations with Wolffian remnants, such as the broad ligament. It is thought to be a benign lesion, although this is not always the case, with scattered case reports of more aggressive behavior, sometimes years later. CASE: A rare case of disseminated malignant FATWO is presented and the literature reviewed. CONCLUSION: FATWO has the potential for malignant behavior. Familiarity with this lesion will enhance recognition. Patients need long-term follow-up.

Is the diagnosis of atypical glandular cells of undetermined significance associated with greater risk at an inner city hospital?

OBJECTIVE: To test the hypothesis that the high-risk patients at an inner city hospital with atypical glandular cells of undetermined significance (AGC) on their Pap smears have a higher rate of underlying significant pathology than that reported in published data. STUDY DESIGN: This was an Institutional Review Board-approved retrospective review of all AGC Pap smears performed at University Hospital, Newark, New Jersey, between January 1, 2001, and July 30, 2008. We defined significant pathology as cervical intraepithelial neoplasia 2 (CIN 2) or greater, endocervical adenocarcinoma in situ or greater, or simple hyperplasia or greater of the endometrium. RESULTS: Medical records of 126 patients were reviewed. Forty did not meet inclusion criteria; 86 patients were included in the analysis. Thirty of the 86 (34.9%) patients were found to have significant pathology. CONCLUSION: Patients with AGC Pap results at our inner city hospital have a high risk for underlying significant pathology.

Body mass index of patients with endometrial hyperplasia: comparison to patients with proliferative endometrium and abnormal bleeding.

OBJECTIVE: Endometrial hyperplasia is a known risk factor for the development of endometrial cancer, particularly atypical hyperplasia, with a subsequent risk of up to 30%. Of the known risk factors for endometrial hyperplasia, obesity is the most preventable, but there is a paucity of data addressing the association. We tested the hypothesis that patients with endometrial hyperplasia have a higher body mass index (BMI) than patients with abnormal bleeding who are found to have proliferative endometrium. STUDY DESIGN: This was an Institutional Review Board-approved retrospective study using University Hospital Department of Pathology records. All patients who had endometrial sampling performed between January 1, 2001, and July 30, 2008, were included. The experimental group consisted of patients with endometrial hyperplasia including simple, complex and atypical hyperplasia. The control group consisted of patients who underwent endometrial sampling for abnormal bleeding during the same time period and were diagnosed with proliferative endometrium. BMI was calculated based on documented height and weight within 30 days of endometrial sampling. RESULTS: Forty-two patients with hyperplasia and 103 patients with proliferative endometrium met inclusion criteria, including documented height and weight and nonexposure to hormones. The median BMI in the hyperplasia group was 38 kg/m2 (95% CI 34.8-42.4) and 30 kg/m2 (95% CI 29.9-33.3) in the proliferative group (p < 0.0001). CONCLUSION: These data suggest that higher BMI is associated with endometrial hyperplasia as compared to women with lower BMIs and abnormal bleeding.

Pitfalls of Frozen Section in Gynecological Pathology: A Case of Endometrial Tumor With Sex Cord-Like Elements.

Endometrial stromal tumor with sex cord-like elements (ESTSCLE) is a rare entity that shares similar histological features with uterine tumors resembling ovarian sex cord tumors (UTROSCT). Differentiating the 2 entities involves ample sampling of the tissue to distinguish the percentage of sex cord components within the tissue, genetic studies, and immunohistochemical staining. Frozen section provides limited information for exclusion of either tumor; and the tumor is rare enough that the diagnosis may not be considered with the limited sampling; therefore, deferral of diagnosis to permanent sections may be appropriate.

Anaplastic carcinoma arising in an ovarian mucinous cystadenocarcinoma in a 17-year-old female.

BACKGROUND: Anaplastic carcinoma arising within a mucinous ovarian neoplasm is rare, with only about 30 reported cases. Reported cases have given a broad age range, ranging from 17 to 72 years of age, but occurrence in adolescents is exceptional, with only a few cases reported. CASE: We report a case of anaplastic carcinoma arising in a mucinous cystadenocarcinoma in a 17-year-old female who presented with severe abdominal pain, an unusual symptom for an ovarian malignancy in the postmenopausal patient, but not in the adolescent. The patient had widespread metastases at the time of presentation, consistent with the aggressive behavior of this neoplasm. CONCLUSIONS: This case illustrates that, although rare, epithelial ovarian malignancy is in the differential diagnosis of abdominal pain in an adolescent.

Pseudopapillary Granulosa Cell Tumor: A Case of This Rare Subtype.

Background The pseudopapillary pattern of granulosa cell tumor is rare. Case We describe the case of a 35-year-old woman who presented with an initial diagnosis of papillary serous cystadenocarcinoma. Results Evaluation, including immunohistochemistry, led to the diagnosis of pseudopapillary granulosa cell tumor. Conclusion The pseudopapillary pattern of granulosa cell tumor is rare and must be suspected in order to utilize appropriate immunohistochemistry and reach the correct diagnosis. Inhibin positivity is particularly helpful.

Primary signet ring cell adenocarcinoma of the uterine cervix - A rare neoplasm that raises the question of metastasis to the cervix.

Primary signet ring cell adenocarcinoma is extremely rare. Signet ring cell carcinoma is more commonly primary in the stomach or breast, and the more likely metastatic disease to the cervix needs to be ruled out. We present a case of primary signet ring cell carcinoma of the cervix and review the literature.

Drug-Based Lead Discovery: The Novel Ablative Antiretroviral Profile of Deferiprone in HIV-1-Infected Cells and in HIV-Infected Treatment-Naive Subjects of a Double-Blind, Placebo-Controlled, Randomized Exploratory Trial.

UNLABELLED: Antiretrovirals suppress HIV-1 production yet spare the sites of HIV-1 production, the HIV-1 DNA-harboring cells that evade immune detection and enable viral resistance on-drug and viral rebound off-drug. Therapeutic ablation of pathogenic cells markedly improves the outcome of many diseases. We extend this strategy to HIV-1 infection. Using drug-based lead discovery, we report the concentration threshold-dependent antiretroviral action of the medicinal chelator deferiprone and validate preclinical findings by a proof-of-concept double-blind trial. In isolate-infected primary cultures, supra-threshold concentrations during deferiprone monotherapy caused decline of HIV-1 RNA and HIV-1 DNA; did not allow viral breakthrough for up to 35 days on-drug, indicating resiliency against viral resistance; and prevented, for at least 87 days off-drug, viral rebound. Displaying a steep dose-effect curve, deferiprone produced infection-independent deficiency of hydroxylated hypusyl-eIF5A. However, unhydroxylated deoxyhypusyl-eIF5A accumulated particularly in HIV-infected cells; they preferentially underwent apoptotic DNA fragmentation. Since the threshold, ascertained at about 150 µM, is achievable in deferiprone-treated patients, we proceeded from cell culture directly to an exploratory trial. HIV-1 RNA was measured after 7 days on-drug and after 28 and 56 days off-drug. Subjects who attained supra-threshold concentrations in serum and completed the protocol of 17 oral doses, experienced a zidovudine-like decline of HIV-1 RNA on-drug that was maintained off-drug without statistically significant rebound for 8 weeks, over 670 times the drug's half-life and thus clearance from circulation. The uniform deferiprone threshold is in agreement with mapping of, and crystallographic 3D-data on, the active site of deoxyhypusyl hydroxylase (DOHH), the eIF5A-hydroxylating enzyme. We propose that deficiency of hypusine-containing eIF5A impedes the translation of mRNAs encoding proline cluster ('polyproline')-containing proteins, exemplified by Gag/p24, and facilitated by the excess of deoxyhypusine-containing eIF5A, releases the innate apoptotic defense of HIV-infected cells from viral blockade, thus depleting the cellular reservoir of HIV-1 DNA that drives breakthrough and rebound. TRIAL REGISTRATION: ClinicalTrial.gov NCT02191657.

The relevance of molecular biomarkers in cervical cancer patients treated with radiotherapy.

BACKGROUND: Radiotherapy (RT) plays an integral role in the combined-modality management of cervical cancer. Various molecular mechanisms have been implicated in the adaptive cellular response to RT. Identification of these molecular processes may permit the prediction of treatment outcome and enhanced radiation-induced cancer cell killing through tailoring of the management approach, and/or the employment of selective inhibitors of these pathways. METHODS: PubMed was searched for studies presenting biomarkers of cervical cancer radioresistance validated in patient studies or in laboratory experimentation. RESULTS: Several biomarkers of cervical cancer radioresistance are validated by patient survival or recurrence data. These biomarkers fall into categories of biological function including hypoxia, cell proliferation, cell-cell adhesion, and evasion of apoptosis. Additional radioresistance biomarkers have been identified in exploratory experiments. CONCLUSIONS: Biomarkers of radioresistance in cervical cancer may allow molecular profiling of individual tumors, leading to tailored therapies and better prognostication and prediction of outcomes.

Blocking eIF5A modification in cervical cancer cells alters the expression of cancer-related genes and suppresses cell proliferation.

Cancer etiology is influenced by alterations in protein synthesis that are not fully understood. In this study, we took a novel approach to investigate the role of the eukaryotic translation initiation factor eIF5A in human cervical cancers, where it is widely overexpressed. eIF5A contains the distinctive amino acid hypusine, which is formed by a posttranslational modification event requiring deoxyhypusine hydroxylase (DOHH), an enzyme that can be inhibited by the drugs ciclopirox and deferiprone. We found that proliferation of cervical cancer cells can be blocked by DOHH inhibition with either of these pharmacologic agents, as well as by RNA interference-mediated silencing of eIF5A, DOHH, or another enzyme in the hypusine pathway. Proteomic and RNA analyses in HeLa cervical cancer cells identified two groups of proteins in addition to eIF5A that were coordinately affected by ciclopirox and deferiprone. Group 1 proteins (Hsp27, NM23, and DJ-1) were downregulated at the translational level, whereas group 2 proteins (TrpRS and PRDX2) were upregulated at the mRNA level. Further investigations confirmed that eIF5A and DOHH are required for Hsp27 expression in cervical cancer cells and for regulation of its key target IκB and hence NF-κB. Our results argue that mature eIF5A controls a translational network of cancer-driving genes, termed the eIF5A regulon, at the levels of mRNA abundance and translation. In coordinating cell proliferation, the eIF5A regulon can be modulated by drugs such as ciclopirox or deferiprone, which might be repositioned to control cancer cell growth.

Drug-induced reactivation of apoptosis abrogates HIV-1 infection.

HIV-1 blocks apoptosis, programmed cell death, an innate defense of cells against viral invasion. However, apoptosis can be selectively reactivated in HIV-infected cells by chemical agents that interfere with HIV-1 gene expression. We studied two globally used medicines, the topical antifungal ciclopirox and the iron chelator deferiprone, for their effect on apoptosis in HIV-infected H9 cells and in peripheral blood mononuclear cells infected with clinical HIV-1 isolates. Both medicines activated apoptosis preferentially in HIV-infected cells, suggesting that the drugs mediate escape from the viral suppression of defensive apoptosis. In infected H9 cells, ciclopirox and deferiprone enhanced mitochondrial membrane depolarization, initiating the intrinsic pathway of apoptosis to execution, as evidenced by caspase-3 activation, poly(ADP-ribose) polymerase proteolysis, DNA degradation, and apoptotic cell morphology. In isolate-infected peripheral blood mononuclear cells, ciclopirox collapsed HIV-1 production to the limit of viral protein and RNA detection. Despite prolonged monotherapy, ciclopirox did not elicit breakthrough. No viral re-emergence was observed even 12 weeks after drug cessation, suggesting elimination of the proviral reservoir. Tests in mice predictive for cytotoxicity to human epithelia did not detect tissue damage or activation of apoptosis at a ciclopirox concentration that exceeded by orders of magnitude the concentration causing death of infected cells. We infer that ciclopirox and deferiprone act via therapeutic reclamation of apoptotic proficiency (TRAP) in HIV-infected cells and trigger their preferential elimination. Perturbations in viral protein expression suggest that the antiretroviral activity of both drugs stems from their ability to inhibit hydroxylation of cellular proteins essential for apoptosis and for viral infection, exemplified by eIF5A. Our findings identify ciclopirox and deferiprone as prototypes of selectively cytocidal antivirals that eliminate viral infection by destroying infected cells. A drug-based drug discovery program, based on these compounds, is warranted to determine the potential of such agents in clinical trials of HIV-infected patients.

Diffuse peritoneal chlamydial infection presenting as possible ovarian peritoneal carcinomatosis in an adolescent female.

A 17-year-old girl presented with significant abdominal ascites associated with periumbilical pain. On examination, her abdomen was found to be soft and moderately distended with left lower quadrant tenderness. Abdominal computed tomographic scan demonstrated not only ascites but also diffuse peritoneal enhancement, a left-sided enhancing adnexal mass displacing the uterus to the right, as well as omental caking. Alpha fetoprotein level was normal, whereas carcinoembryonic antigen (3.4 ng/mL) and cancer antigen 125 (315 U/mL) were mildly elevated. Based on these findings, a presumptive diagnosis of peritoneal carcinomatosis of ovarian origin was made. However, intraoperative biopsy of the left adnexal mass showed only a lymphoplasmacytic infiltrate. Chlamydial polymerase chain reaction of an intraoperative cervical sample was positive, and the final diagnosis was complicated pelvic inflammatory disease. The patient responded well to a prolonged course of antibiotics.