Stabilised Hyaluronic Acid (sHA) gel as a novel marker for breast cancer tumour bed cavity: Surgical feasibility.

Introduction: Consistent delineation of the breast conserving surgery (BCS) tumour bed (TB) for breast cancer remains a challenge for radiation oncologists. Accurate delineation allows for better local control and reduces toxicity when planning partial breast or TB boost radiation therapy (RT). Methods: In the operating theatre (OT) breast surgeons inserted stabilised hyaluronic acid (sHA) gel as small drops approximately one cm into the walls surrounding the resection cavity. Surgical feasibility was determined by the rate of successful sHA gel insertion procedure, the ease of insertion as rated by surgeons, the time required for insertion procedure, the quantity used, and any adverse events (AE) relating to sHA gel insertion. Results: Thirty-five patients were enrolled. All patients underwent sHA gel insertion successfully. The procedure added a median of 2.8 min to the OT time and was rated as 'easy' in 89 % of patients. There were no immediate AE in OT. Five (14 %) patients experienced a grade 2 or higher AE. Three of the five patients were prescribed oral antibiotics for breast infection. Two of the five patients experienced a grade 3 AE - haematoma which required evacuation in OT day 1 post-BCS, and infected seroma which required drainage and washout in OT 2 months post-BCS. All five patients recovered and underwent the planned adjuvant therapies for their BC. The AE data reflects common risks with standard BCS and are not clearly attributed to sHA gel insertion alone. Conclusion: We show that sHA gel is surgically feasible as a marker to help define the TB cavity for post-BCS adjuvant MRI-based RT planning.

Sex and age differences in the incidence of acute myocardial infarction during the COVID-19 pandemic in a Swedish health-care region without lockdown: a retrospective cohort study.

BACKGROUND: The incidence of acute myocardial infarction has decreased during the COVID-19 pandemic, but sex and age differences in this change in incidence have not been tested. Thus, we aimed to compare the incidence of acute myocardial infarction in a health-care region in Sweden during the COVID-19 pandemic with previous years and to evaluate sex and age differences. METHODS: We did a retrospective, observational cohort study using data from a national registry of patients admitted to coronary care units in Sweden. All patients admitted to one of three hospitals in Region Jönköping County with a diagnosis of acute myocardial infarction during the COVID-19 pandemic (March 1 to July 31, 2020) or reference period (March 1 to July 31, 2017-19) were included. The incidence of acute myocardial infarction (ST-elevation and non-ST-elevation) was calculated for both study periods. Participants were grouped according to sex and age (<70 years vs ≥70 years). The incidence and the incidence rate ratio (IRR) between the two study periods was calculated for each group and compared between groups using the Breslow-Day test. FINDINGS: The study included 1088 participants, 846 who were admitted for acute myocardial infarction during the reference period and 242 who were admitted during the COVID-19 pandemic period. The IRR of acute myocardial infarction for the COVID-19 period compared with the reference period was 0·85 (95% CI 0·73-0·98). The IRR for acute myocardial infarction was significantly lower among women aged 70 years or older (0·56 [0·40-0·78]) than among men aged 70 years or older (0·97 [0·77-1·23]; p=0·0074). INTERPRETATION: The incidence of acute myocardial infarction decreased predominantly among women aged 70 years or older during the COVID-19 pandemic. This highlights potential sex differences in health effects of the COVID-19 pandemic, which should be further elucidated. FUNDING: None.

Liver dysfunction and anti-thyroid therapy.

Thioamides have been used in the management of hyperthyroidism for over 50 years. Liver dysfunction is a rare but important side effect associated with their use. Recently, cases of liver failure associated with propylthiouracil have prompted the Federal Drug Administration to issue a Boxed Warning to the label of propylthiouracil regarding its risk of potentially fatal liver injury and acute liver failure in adults and children. Herein, we present a case to underline the importance of recognising the similar potential for severe hepatic dysfunction with the use of other thioamides.

Challenging the glucose challenge test.

BACKGROUND: To reduce the number of patients needing oral glucose tolerance test (OGTT), screening options have been considered, balancing patient comfort, cost and risk of missed diagnosis. Australian Diabetes in Pregnancy Society (ADIPS) recommends glucose challenge test (GCT) as screening for gestational diabetes mellitus (GDM), while others suggest fasting plasma glucose (FPG). International Association of Diabetes and Pregnancy Study Group (IADPSG) recently recommended new diagnostic criteria for GDM using one-step OGTT. AIM: (i) To determine how many GDM patients would be missed with GCT/OGTT or FPG/OGTT compared to OGTT alone. (ii) To assess GCT in screening for GDM using new IADPSG criteria. METHODS: Austin Pathology database was searched from 2005 to 2007; 8486 episodes of GCT and OGTT were found. Test characteristics were determined for: (i) Simulated GCT/OGTT, where the 60-min OGTT value was regarded as equivalent to 60-min GCT value; (ii) Simulated FPG/OGTT, investigating the utility of different FPG values to indicate need for OGTT. RESULTS: Oral glucose tolerance test (one-step procedure): Of 5473 patients who had OGTT alone, 14% had GDM (ADIPS criteria). Actual GCT/OGTT: Of 2407 GCT, 17.3% were abnormal, with 75% having normal follow-up OGTT. Simulated studies: In the simulated GCT/OGTT, using ADIPS criteria, GCT had a sensitivity of 87%, specificity of 74% and would miss 13% of cases. Although simulated FG/OGTT had similar sensitivity of 82% for FPG ≥4.4 mmol/L, specificity was 42%. Using IADPSG criteria, 19% were diagnosed with GDM, screening GCT had a sensitivity of 83%, specificity of 75% and would miss 17% of cases. CONCLUSION: Oral glucose tolerance test alone is the best procedure without prior preliminary testing.

Calcitonin gene-related peptide stimulates mitosis in the tip of the rat gubernaculum in vitro and provides the chemotactic signals to control gubernacular migration during testicular descent.

BACKGROUND/AIMS: We investigated whether calcitonin gene-related peptide (CGRP) released from sensory genitofemoral nerve branches could stimulate rodent gubernacular growth and provide chemotactic signals for directing inguinoscrotal gubernaculum migration in vitro. MATERIALS AND METHODS: Neonatal rat gubernacula containing a developing cremaster sac (n = 60) were removed at days 0, 2, 4, 6, 8, and 10 (n = 10 per age; n = 5 per experimental group) and placed in organ culture for 24 hours with or without added CGRP (720 nmol/L). The gubernacula were stained for bromodeoxyuridine (BrdU) immunohistochemistry. Cells were counted (3 x 100 cells) in the mesenchymal tip of the gubernaculum to find the percentage of BrdU uptake. A further group of neonatal rat gubernacula (n = 21 per group) were placed in organ culture on an agar platform with 5 agarose beads soaked in either PBS or 10(-6) mol/L CGRP placed approximately 0.8 to 1 mm on each side of the tip of the cremaster sac. After 72 hours, the position of the gubernaculum was compared with its starting position and any deviation measured. RESULTS: Exogenous CGRP caused a significant increase in BrdU uptake in the tip of the gubernaculum in 0-day-old rats compared with control cultures. Two-way analysis of variance in the cellular proliferation pattern between gubernacula cultured +/- CGRP between 0 and 10 days showed a significant difference (P < .001). The cultures containing CGRP-impregnated beads caused significant (P < .01) deviation of the tip of the gubernaculum toward the beads, whereas the controls demonstrated no net movement of the tip. CONCLUSIONS: These studies demonstrate that mitosis in the tip of the rat gubernaculum is significantly increased in response to CGRP in vitro. Also, CGRP may provide chemotactic signals to control inguinoscrotal gubernacular migration in the rat.

Signalling molecules: clues from development of the limb bud for cryptorchidism?

Recent studies of testicular descent suggest not only that the gubernaculum does not initially attach to the scrotum, but also that it must migrate from the groin. Two findings suggest that the gubernaculum may behave like an embryonic limb bud during this phase. First, the active growth centre is at the distal tip of the gubernaculum. Secondly, the gubernaculum is loose in the subcutaneous tissues beneath Scarpa's fascia. The free protrusion of the gubernaculum from the abdominal wall was so reminiscent of a developing embryonic limb bud, we thought that the biological controls of both processus may be similar. This review examines what is known about vertebrate limb bud development, and compares the mechanisms to what has recently been discovered in the gubernaculum. The hypothesis that both processes may be similar is initially consistent with the current facts, encouraging us to investigate this further experimentally.

A new role for androgen in testicular descent: permitting gubernacular cell proliferation in response to the neuropeptide, calcitonin gene-related peptide.

BACKGROUND/PURPOSE: Cell proliferation at the gubernacular tip increases in response to exogenous calcitonin gene-related peptide (CGRP) during migration into the scrotum. Calcitonin gene-related peptide is contained in the masculinized sensory branches of the genitofemoral nerve. We tested the independent effects of chemical sensory nerve disruption and prenatal androgen blockade on the in vitro gubernacular proliferative response to CGRP. METHODS: Neonatal Sprague-Dawley rats were injected with capsaicin, a sensory nerve toxin, and gubernacula dissected 2 days later (D2). Sprague-Dawley dams were injected with flutamide, an androgen receptor antagonist, between days 15 and 19 of gestation. Flutamide pretreated males, and normal neonatal rats, were dissected at D0 and D2. Gubernacula were cultured for 24 hours +/- CGRP, pulse-labelled for the last 4 hours of culture with bromodeoxyuridine, a thymidine analogue marker for DNA replication, sectioned, and stained using immunohistochemistry. The percentage of positively staining cells in the gubernacular tip was calculated from three separate counts by a blinded observer and compared using analysis of variance. RESULTS: Normal D0 gubernacular tips showed a significant response of cell proliferation to exogenous CGRP (34% vs 9% in controls, P < .001), which resolved by day 2 (16% vs 12%, P > .05). Calcitonin gene-related peptide markedly increased cell proliferation in D2 capsaicin pretreated gubernacula compared with controls (25% vs 14%, P < .01) and normal D2 gubernacula cultured with CGRP (P < .01). D0 flutamide pretreated cultured with CGRP showed no increase in cell proliferation compared with controls (16% vs 11%), but a small response was seen by D2 (19% vs 9%, P < .05). There was no significant difference between proliferation rates in the control groups. CONCLUSIONS: Sensory innervation interruption sensitises the gubernaculum to exogenous CGRP, suggesting upregulation of CGRP receptors. In contrast, androgen blockade abolishes the increased rate of cell proliferation within the gubernacular tip. We conclude that androgens are necessary to "preprogramme" the proliferative response of the gubernaculum to CGRP.

The role of hepatocyte growth factor in the humoral regulation of inguinal hernia closure.

BACKGROUND: Calcitonin gene-related peptide (CGRP) is proposed to indirectly cause inguinal hernia closure via hepatocyte growth factor (HGF). Studies have shown that CGRP and HGF cause processus vaginalis (PV) fusion in vitro. We localized the HGF receptor in the PV and tested whether CGRP was responsible for HGF release. METHOD: Hernial sacs collected from 20 children (15 males, 4 females, 1 XY female) undergoing inguinal hernia repair were immunohistochemically stained for HGF receptor (c-met). Parietal peritoneum was stained for comparison. Hernial sacs from another 16 children (12 males, 4 females), with each sac divided into 4, were cultured, with and without CGRP, for 24 and 48 hours. Hepatocyte growth factor content was then assayed in the culture medium (4/16 children) and tissue extracts (12/16 children), using enzyme-linked immunosorbent assay. Children were aged 1 month to 10 years. Data were analyzed using paired Student t tests. RESULTS: C-met localized to the PV epithelial surface in 17 of 20 hernial sacs and in the parietal peritoneum. Hepatocyte growth factor levels increased over time in 4 of 4 culture medium assays, with a significant difference in 1 of 4. Seven of 12 tissue extract assays had significant differences; however, 3 of 7 had decreased HGF levels. CONCLUSION: The presence of HGF receptors in the PV is consistent with a role for HGF in triggering epithelial-mesenchymal transformation during inguinal hernia closure. The presence of HGF receptors in the parietal peritoneum suggests that regulation of this process is complex. Enzyme-linked immunosorbent assay results indicate that, in a subset of patients, exogenous CGRP may be responsible for HGF elevation and potentially implicates deficient endogenous CGRP as one cause for inguinal hernia patency.

Testicular descent, cryptorchidism and inguinal hernia: the Melbourne perspective.

Cryptorchidism is the commonest congenital genitourinary anomaly in males and results when the testis does not descend into its normal intrascrotal position during development. In full-term infants, the incidence is approximately 3% at birth. Cryptorchidism results in several abnormalities, including attenuated spermatogenesis, infertility and a greater risk of malignancy. The normal mechanism of testicular descent appears to be multi-staged, with various anatomical factors and hormonal influences, but the exact process is still unclear. In this article we review the current theories of normal testicular descent, with a focus on the hormones and anatomical factors, and current treatments for undescended testis.

The gubernaculum in testicular descent and cryptorchidism.

The gubernaculum plays an essential role in the complex mechanism of testicular descent and inguinal hernia closure. Understanding this complex developmental process is gradually allowing us insight into how to regulate normal descent and also treat maldescended testes.