Postradioiodine Graves' management: The PRAGMA study.

OBJECTIVE: Thyroid status in the months following radioiodine (RI) treatment for Graves' disease can be unstable. Our objective was to quantify frequency of abnormal thyroid function post-RI and compare effectiveness of common management strategies. DESIGN: Retrospective, multicentre and observational study. PATIENTS: Adult patients with Graves' disease treated with RI with 12 months' follow-up. MEASUREMENTS: Euthyroidism was defined as both serum thyrotropin (thyroid-stimulating hormone [TSH]) and free thyroxine (FT4) within their reference ranges or, when only one was available, it was within its reference range; hypothyroidism as TSH ≥ 10 mU/L, or subnormal FT4 regardless of TSH; hyperthyroidism as TSH below and FT4 above their reference ranges; dysthyroidism as the sum of hypo- and hyperthyroidism; subclinical hypothyroidism as normal FT4 and TSH between the upper limit of normal and <10 mU/L; and subclinical hyperthyroidism as low TSH and normal FT4. RESULTS: Of 812 patients studied post-RI, hypothyroidism occurred in 80.7% and hyperthyroidism in 48.6% of patients. Three principal post-RI management strategies were employed: (a) antithyroid drugs alone, (b) levothyroxine alone, and (c) combination of the two. Differences among these were small. Adherence to national guidelines regarding monitoring thyroid function in the first 6 months was low (21.4%-28.7%). No negative outcomes (new-onset/exacerbation of Graves' orbitopathy, weight gain, and cardiovascular events) were associated with dysthyroidism. There were significant differences in demographics, clinical practice, and thyroid status postradioiodine between centres. CONCLUSIONS: Dysthyroidism in the 12 months post-RI was common. Differences between post-RI strategies were small, suggesting these interventions alone are unlikely to address the high frequency of dysthyroidism.

Upregulation of C/EBPα Inhibits Suppressive Activity of Myeloid Cells and Potentiates Antitumor Response in Mice and Patients with Cancer.

PURPOSE: To evaluate the mechanisms of how therapeutic upregulation of the transcription factor, CCAAT/enhancer-binding protein alpha (C/EBPα), prevents tumor progression in patients with advanced hepatocellular carcinoma (HCC) and in different mouse tumor models. EXPERIMENTAL DESIGN: We conducted a phase I trial in 36 patients with HCC (NCT02716012) who received sorafenib as part of their standard care, and were given therapeutic C/EBPα small activating RNA (saRNA; MTL-CEBPA) as either neoadjuvant or adjuvant treatment. In the preclinical setting, the effects of MTL-CEBPA were assessed in several mouse models, including BNL-1ME liver cancer, Lewis lung carcinoma (LLC), and colon adenocarcinoma (MC38). RESULTS: MTL-CEBPA treatment caused radiologic regression of tumors in 26.7% of HCC patients with an underlying viral etiology with 3 complete responders. MTL-CEBPA treatment in those patients caused a marked decrease in peripheral blood monocytic myeloid-derived suppressor cell (M-MDSC) numbers and an overall reduction in the numbers of protumoral M2 tumor-associated macrophages (TAM). Gene and protein analysis of patient leukocytes following treatment showed CEBPA activation affected regulation of factors involved in immune-suppressive activity. To corroborate this observation, treatment of all the mouse tumor models with MTL-CEBPA led to a reversal in the suppressive activity of M-MDSCs and TAMs, but not polymorphonuclear MDSCs (PMN-MDSC). The antitumor effects of MTL-CEBPA in these tumor models showed dependency on T cells. This was accentuated when MTL-CEBPA was combined with checkpoint inhibitors or with PMN-MDSC-targeted immunotherapy. CONCLUSIONS: This report demonstrates that therapeutic upregulation of the transcription factor C/EBPα causes inactivation of immune-suppressive myeloid cells with potent antitumor responses across different tumor models and in cancer patients. MTL-CEBPA is currently being investigated in combination with pembrolizumab in a phase I/Ib multicenter clinical study (NCT04105335).

Gene activation of CEBPA using saRNA: preclinical studies of the first in human saRNA drug candidate for liver cancer.

Liver diseases are a growing epidemic worldwide. If unresolved, liver fibrosis develops and can lead to cirrhosis and clinical decompensation. Around 5% of cirrhotic liver diseased patients develop hepatocellular carcinoma (HCC), which in its advanced stages has limited therapeutic options and negative survival outcomes. CEPBA is a master regulator of hepatic function where its expression is known to be suppressed in many forms of liver disease including HCC. Injection of MTL-CEBPA, a small activating RNA oligonucleotide therapy (CEBPA-51) formulated in liposomal nanoparticles (NOV340- SMARTICLES) upregulates hepatic CEBPA expression. Here we show how MTL-CEBPA therapy promotes disease reversal in rodent models of cirrhosis, fibrosis, hepatosteatosis, and significantly reduces tumor burden in cirrhotic HCC. Restoration of liver function markers were observed in a carbon-tetrachloride-induced rat model of fibrosis following 2 weeks of MTL-CEBPA therapy. At 14 weeks, animals showed reduction in ascites and enhanced survival rates. MTL-CEBPA reversed changes associated with hepatosteatosis in non-alcoholic methionine and cholic-deficient diet-induced steaotic liver disease. In diethylnitrosamine induced cirrhotic HCC rats, MTL-CEBPA treatment led to a significant reduction in tumor burden. The data included here and the rapid adoption of MTL-CEBPA into a Phase 1 study may lead to new therapeutic oligonucleotides for undruggable diseases.

Ultrasound detection of the "sliding viscera" sign promotes safer laparoscopy.

STUDY OBJECTIVE: To estimate the feasibility of preoperative ultrasound evaluation of the umbilical region in patients undergoing laparoscopy with a previous history of abdominal surgery. DESIGN: Prospective study (Canadian Task Force Classification II-1). SETTING: Department of Obstetrics and Gynecology Fatebenefratelli Isola Tiberina Hospital. PATIENTS: Twenty-five women with a previous history of open abdominal surgery (group A) and a group of 22 women with no previous history of surgery (group B) underwent dynamic ultrasound evaluation of the umbilical field. INTERVENTION: Ultrasound Slide-By test. RESULTS: Patients were asked to take a deep inspiratory breath, which accentuated respiratory excursion. The movement of the intraabdominal contents in a vertical fashion in relation to the abdominal wall, referred to as the "viscera slide," between the bowel and peritoneum was evaluated. Abdominal wall tissue thickness, Uracus to peritoneum thickness (UTP, mm) were also evaluated. Non parametric Mann-Whitney testing was used. No major demographic differences between the 2 study groups was noted. The abdominal wall tissue thickness was not significantly different between the 2 groups. The UTP was shorter in A group than in B group (1.5 +/- 0.3 mm vs 3.5 +/- 0.9 mm, p = .002). Absence of the "sliding viscera" sign was observed in 16 patients in group A and in 1 patient in group B. Patients with an absence of the sliding viscera sign were found to have subumbilical fibrous adhesions during laparoscopy. CONCLUSIONS: Evaluation of trocar insertion sites may be difficult and remains a challenge for peritoneal endosurgical access. We have shown that absence of the "sliding viscera" sign is more likely to be linked to subumbilical adhesions and represents a quick method for preoperative assessment. The UTP may also be a useful measurement, which requires further validation.

Pelvic lymphadenectomy for cervical cancer: extraperitoneal versus laparoscopic approach.

OBJECTIVE: To compare the extraperitoneal versus the laparoscopic technique in performing pelvic lymphadenectomy in a series of patients undergoing a radical vaginal hysterectomy for locally advanced cervical cancer. STUDY DESIGN: Retrospective study with 42 patients undergoing a radical vaginal hysterectomy for cervical cancer. Patients from group A (20 patients) had a laparoscopic lymph node dissection and patients belonging to group B (22 patients) had an extraperitoneal lymphadenectomy. Historical data, clinical and surgical characteristics, perioperative and post-operative complications were analyzed. Follow-up was conducted according to the oncologic requirements. RESULTS: No significant difference was observed between the two groups in terms of blood loss, post-operative pain, transfusions, hospital stay and post-operative hematomas. The extraperitoneal group (group B) significantly showed a reduced operating time, a greater number of nodes removed (p<0.05). The only lymphocyst occurred in group B. CONCLUSIONS: Extraperitoneal pelvic lymphadenectomy can be considered an adequate technique to complement radical vaginal operations for cervical cancer.