RFWD3 promotes ZRANB3 recruitment to regulate the remodeling of stalled replication forks.

Replication fork reversal is an important mechanism to protect the stability of stalled forks and thereby preserve genomic integrity. While multiple enzymes have been identified that can remodel forks, their regulation remains poorly understood. Here, we demonstrate that the ubiquitin ligase RFWD3, whose mutation causes Fanconi Anemia, promotes recruitment of the DNA translocase ZRANB3 to stalled replication forks and ubiquitinated sites of DNA damage. Using electron microscopy, we show that RFWD3 stimulates fork remodeling in a ZRANB3-epistatic manner. Fork reversal is known to promote nascent DNA degradation in BRCA2-deficient cells. Consistent with a role for RFWD3 in fork reversal, inactivation of RFWD3 in these cells rescues fork degradation and collapse, analogous to ZRANB3 inactivation. RFWD3 loss impairs ZRANB3 localization to spontaneous nuclear foci induced by inhibition of the PCNA deubiquitinase USP1. We demonstrate that RFWD3 promotes PCNA ubiquitination and interaction with ZRANB3, providing a mechanism for RFWD3-dependent recruitment of ZRANB3. Together, these results uncover a new role for RFWD3 in regulating ZRANB3-dependent fork remodeling.

Diagnosis and management of pharyngoesophageal stenosis: A comprehensive approach to prophylactic, endoscopic, and reconstructive treatment options.

BACKGROUND: Pharyngoesophageal stenosis (PES) is a serious complication that substantially impacts functional outcomes and quality of life (QOL) for up to a third of head and neck cancer patients who undergo radiotherapy. Dysphagia is often multifactorial in nature and is a devastating complication of treatment that impacts patients' QOL, general health and overall wellbeing. The authors detail the clinical presentation, risk factors, imaging characteristics, preventive measures, and multimodality treatment options for PES. METHODS: The authors present a comprehensive management algorithm for PES, including treatment by dilation, stenting, spray cryotherapy and dilation, and reconstructive treatment options utilizing different pedicled and free flaps. RESULTS: The authors advocate for a thorough assessment of the extent and degree of pharyngoesophageal involvement of PES to determine the optimal management strategy. CONCLUSIONS: The development of post treatment dysphagia requires appropriate imaging and biopsy, when indicated, to rule out the presence of persistent/recurrent cancer. Multidisciplinary management by a team of physicians well-versed in the range of diagnostic and therapeutic interventions available for PES is critical to its successful management.

Primary Hyperparathyroidism During Pregnancy Treated With Parathyroidectomy: A Systematic Review.

OBJECTIVES/HYPOTHESIS: The primary objective of this study was to assess the safety of parathyroidectomy during pregnancy as treatment for hyperparathyroidism (HPTH) in comparison to nonsurgical management plans. Secondary outcomes involved analyzing the safety of surgery in the third trimester and the benefit of operating on asymptomatic pregnant patients. STUDY DESIGN: Systematic review. METHODS: PRISMA-guided systematic review of all cases of primary hyperparathyroidism during pregnancy published in peer-reviewed English journals on PubMed/MEDLINE, EMBASE, and SCOPUS from 1980 to 2020. RESULTS: A total of 75 manuscripts were included in this review describing 382 cases of gestational hyperparathyroidism. The median maternal age was 31 years. Overall, 108 cases (28.3%) underwent parathyroidectomy during pregnancy while 274 cases (71.7%) were treated nonsurgically. The majority of surgeries took place during the second trimester (67.6%). Complications and/or deaths were less likely to occur after surgery in the second trimester (4.48%) as compared to surgery in the third trimester (21.1%). Nine surgically treated cases resulted in infant complications and/or death; however, none of these nine cases had any surgical complications. Despite these complications, the overall infant complication rate for patients who underwent surgical treatment remained lower than that of patients treated with conservative therapy (9.1% vs. 38.9%). CONCLUSIONS: This review suggests that for all pregnant patients with diagnosed HPTH, parathyroidectomy should be considered regardless of symptomatology. Our data suggest that parathyroidectomy is associated with fewer risks than more conservative treatments and results in better fetal outcomes. Surgery during the third trimester is feasible and surgery should be considered in both symptomatic and asymptomatic patients. Laryngoscope, 131:1915-1921, 2021.

Metastatic thyroid carcinoma to the parapharyngeal and retropharyngeal spaces: Systematic review with seven newly reported cases describing an uncommon presentation of a common disease.

BACKGROUND: Metastatic thyroid carcinoma to retropharyngeal and parapharyngeal (RP/PP) lymph nodes is rare. Literature suggests previous lateral neck dissection (LND) may alter patterns of lymphatic drainage in the neck, predisposing to these less common sites of spread. METHODS: PRISMA-guided systematic search for all published cases detailing RP/PP metastases of well-differentiated thyroid carcinoma from 1970 to 2019. RESULTS: Seventy articles were identified and 44 were included, along with seven cases treated at our institution, totaling 239 cases. Cases represented both retropharyngeal (60.7%) and parapharyngeal (39.3%) metastases identified in the initial (27.6%) and recurrent (72.4%) setting. CONCLUSION: RP/PP metastases generally present in the recurrent setting. RP/PP metastases often represent high-risk disease, and surgical treatment is recommended.

Incongruent radiographic indication of calvarial metastatic diploic space invasion with absent histologic findings in a patient with basal cell carcinoma of the scalp.

BACKGROUND: Radiographic imaging is often used to determine basal cell carcinoma (BCC) extension and invasion and to define a surgical plan. However, imaging modalities may overestimate tumor invasion and lead to unnecessarily aggressive treatment. METHODS: A 77-year-old woman was seen with a growing BCC of the scalp with MRI imaging indicative of calvarial diploic space invasion. The patient underwent Mohs surgery followed by a parietal craniectomy. RESULTS: Contrary to the MRI findings, histological evaluation of the cortical parietal calvarium and the diploic space did not demonstrate BCC. CONCLUSIONS: Surgeons should be wary of diploic space changes in the absence of cortical erosion demonstrated in MRI as it may not explicitly indicate tumor invasion. Biopsy of the diploe is necessary in such cases to determine the surgical course and to avoid morbidity associated with calvarium removal.

Assessment of efficacy and tolerability of once-daily extended release metformin in patients with type 2 diabetes mellitus.

AIMS: To determine prospectively the efficacy, tolerability and patient satisfaction of an extended release formulation of metformin (metformin XR) in hospital based outpatients with type 2 diabetes mellitus currently treated with standard metformin. METHODS: Patients on immediate release standard metformin either alone or combined with other oral agents were switched to extended release metformin XR 500 mg tablets and titrated to a maximum dose of 2000 mg/day Measurements to include glucose and lipid control, blood pressure, body weight, waist circumference, C-reactive protein, adverse events and patient satisfaction were recorded at baseline, three and six months. RESULTS: Complete data were obtained for 35 of the 61 patients enrolled to the study. At three and six months no changes were reported for any of the cardiovascular risk factors except for lipids where there was a modest rise in plasma triglycerides. These effects were achieved with a reduced dose of metformin XR compared to pre-study dosing with standard metformin (1500 mg +/- 402 vs 1861 +/- 711 p = 0.004). A total of 77% of patients were free of gastrointestinal side effects and 83% of patients stated a preference for metformin XR at the end of the study. Ghost tablets were reported in the faeces by the majority of the patients (54.1%). CONCLUSIONS: Patients switched to extended release metformin XR derived the same clinical and metabolic benefits as for standard metformin but with reduced dosage, fewer gastrointestinal side effects and a greater sense of well being and satisfaction on medication.