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

AbstractPrimary 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

Paraneoplastic SIADH and Dermatomyositis in Cervical Cancer: A Case Report and Literature Review

We present the first known case of a patient with cervical squamous cell carcinoma complicated by paraneoplastic syndromes of both dermatomyositis and inappropriate secretion of antidiuretic hormone (SIADH). The patient in this case presented with generalized body pain and vaginal bleeding. Her cervical cancer was diagnosed as stage IIB by physical exam, imaging, and cervical biopsy, her dermatomyositis was confirmed by muscle and skin biopsy, and her SIADH was diagnosed based on laboratory findings

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

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. 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. 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. 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

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

<div><p>Antiretrovirals suppress HIV-1 production yet spare the <i>sites</i> 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.</p><p><b><i>Trial Registration</i>:</b> ClinicalTrial.gov <a href="https://clinicaltrials.gov/ct2/show/NCT02191657?term=NCT02191657&rank=1" target="_blank">NCT02191657</a></p></div

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 downregulate bcl-2 may decrease tumor cell threshold and sensitize tumor cells to chemotherapy. The objective of this multi-institutional phase II 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. METHODS/MATERIALS: 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(2), days 1-4, and intravenous paclitaxel 175 mg/m(2), 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% (six complete responses, four partial responses). Furthermore, seven 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% CI, 2.0-7.4 months), and overall survival was 11.2 months (95% CI, 7.5-26.2 months). Of six patients with complete responses, five survived more than two 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

Persistent HIV-1 suppression after deferiprone cessation in treatment-naive HIV-infected subjects.

<p>Discontinuation trial design (DTD) is used to analyze long-term rebound following HIV-1 RNA—based segregation into a ‘Decrease’ and a ‘No decrease’ cohort, defined by viral load post-drug on Day 7 relative to viral load pre-drug on Day 1. S1, first stage of protocol (one-week treatment); S2, second stage of protocol (eight-week observation). Left: HIV-1 RNA levels in each trial subject immediately before and after the one-week treatment period (S1). Subject 22 discontinued oral intake on Day 3 (after the 7^th dose) and Subject 2 discontinued oral intake on Day 5 (after the 13^th dose), as indicated by the white line segments (for clinical details, see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0154842#sec002" target="_blank">Results</a>). Right: Presence or absence of a decrease in HIV-1 RNA after the one-week treatment period (S1) segregates subject into the two subsets for the eight-week observation period (S2). Horizontal arrows (at C in S2 of upper panel) delineate the pre-drug viral load on Day 1 (at A in S1 of upper panel), color-coded to an individual’s post-drug viral load on Day 35 and Day 63 (28 and 56 days after drug cessation). Subject 2 did not enter S2 analysis. Subject 22 did enter S2 analysis and reacquired the pre-medication viral load at 4 weeks post-treatment, verified at 8 weeks post treatment (open circles, S2 of upper panel). <b>A</b> and <b>D</b>, HIV-1 RNA copies immediately before the intake of the first dose of deferiprone on Day 1; <b>B</b> and <b>E</b>, HIV-1 RNA copies immediately after the last dose of deferiprone on Day 7; <b>C</b> and <b>F</b>, HIV-1 RNA copies on Day 63 of protocol, i.e. day 56 off-drug. Two-letter combinations indicate the period of the intra-cohort response (ICR). Extent and significance of the inter-cohort differences (ICDs) are indicated for the identified periods.</p

Effect of deferiprone in transwell-cultured confluent ECC-1 cells: Epithelial monolayer integrity.

<p>Cultures at maximal luminal barrier function (TER ≥ 1000 ohms / cm²) were left untreated, or were treated with deferiprone at the indicated concentrations, every day <i>via</i> the apical chamber and every other day <i>via</i> the basolateral chamber. To document the spontaneous TER fluctuation in the untreated cultures, and any drug-induced deviation from those fluctuations reflective of epithelial monolayer disruption [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0154842#pone.0154842.ref066" target="_blank">66</a>], TER measurements of untreated and treated wells were made on consecutive days for a week. <i>P</i> values for untreated <i>vs</i>. treated cultures are shown at 96, 120, and 144 hours after start of deferiprone. In this system, chemicals that cause TER collapse are evident within the first 24 hours of exposure, as shown earlier (e.g. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0154842#pone.0154842.ref068" target="_blank">68</a>]). Def, deferiprone; closed small black squares, 100 μM deferiprone; closed large black squares, 200 μM deferiprone; open cyan circles, untreated controls.</p

Effect of deferiprone on HIV-1 in the isolate-infected, long-term replenished primary cell model: Dose dependency.

<p>Cultures were infected with clinical isolate of HIV-1 on Day 0 as described [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0154842#pone.0154842.ref043" target="_blank">43</a>]. Once self-sustaining infection was established by Day 12, cultures were treated with 100 μM or 200 μM deferiprone for the indicated duration, with a post-treatment observation period of 11 days. Controls were identically maintained without drug. Each p24 value in Panel A is expressed relative to the respective p24 control on the day of each measurement. Upon complete inhibition of p24 (Panel A), HIV-1 RNA measurements commenced (Panel B). Smaller triangles connected by thin line, 100 μM deferiprone; larger triangles connected by thicker line, 200 μM deferiprone; closed symbols, treatment period; open symbols, pre- and post-treatment periods; black asterisks, cessation of medication; bright green line segments, rebound of HIV-1 protein (as p24) and HIV-1 RNA (as copy number) during the post-treatment period at 100 μM deferiprone; red line segment, HIV-1 RNA decline off-drug at the on-drug rate achieved by 200 μM deferiprone; arrowheads, half of culture replenished with fresh medium, drug, and primary cells; blue, control parameters.</p