RED BREAST SYNDROME (RBS) ASSOCIATED TO THE USE OF POLYGLYCOLIC MESH IN BREAST RECONSTRUCTION: A CASE REPORT.

Some patients undergoing breast reconstruction with acellular dermal matrices (ADMs) develop postoperative erythema overlying their ADM grafts named red breast syndrome (RBS). To the best of our knowledge this entity has never been related to the use of a synthetic mesh. We present a case of a 61-year-old patient who underwent bilateral nipple-sparing prophylactic mastectomy because of BRCA-1 gene mutation. The patient was reconstructed with a direct-to-implant approach, and the implants were covered with a polyglycolic acid mesh. Twenty days after the reconstruction, she presented with a blanching erythema of both reconstructed breasts without signs of infection on the area covered by the mesh. The patient denied symptoms like fever or tenderness and presented with no clinical signs of infection. Her laboratory tests were within normal range. We decided to watch and wait. The patient continued strict controls in the outpatient setting. Gradually, the erythema begun to disappear and it resolved spontaneously. RBS has only been described with the use of ADMs, but since in this case the mesh was made of polyglycolic acid, we suggest RBS should be considered either with the use of biological or synthetic meshes. The importance of its differential diagnosis resides in distinguishing it from an infection.

The importance of oral health to prevent aspiration pneumonia.

No abstract provided.

Development and external validation of a machine learning model for prediction of survival in undifferentiated pleomorphic sarcoma.

PURPOSE: Machine learning (ML) algorithms to predict cancer survival have recently been reported for a number of sarcoma subtypes, but none have investigated undifferentiated pleomorphic sarcoma (UPS). ML is a powerful tool that has the potential to better prognosticate UPS. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was queried for cases of histologically confirmed undifferentiated pleomorphic sarcoma (UPS) (n = 665). Patient, tumor, and treatment characteristics were recorded, and ML models were developed to predict 1-, 3-, and 5-year survival. The best performing ML model was externally validated using an institutional cohort of UPS patients (n = 151). RESULTS: All ML models performed best at the 1-year time point and worst at the 5-year time point. On internal validation within the SEER cohort, the best models had c-statistics of 0.67-0.69 at the 5-year time point. The Multi-Layer Perceptron Neural Network (MLP) model was the best performing model and used for external validation. Similarly, the MLP model performed best at 1-year and worst at 5-year on external validation with c-statistics of 0.85 and 0.81, respectively. The MLP model was well calibrated on external validation. The MLP model has been made publicly available at https://rachar.shinyapps.io/ups_app/ . CONCLUSION: Machine learning models perform well for survival prediction in UPS, though this sarcoma subtype may be more difficult to prognosticate than other subtypes. Future studies are needed to further validate the machine learning approach for UPS prognostication.

DIY Flap Monitoring: The Glucose Index.

Background: Flap loss is reduced by monitoring, which detects vascular compromise. Glucose levels vary in suffering flaps; therefore, we aimed to show that monitoring flaps with glucose pinprick test is a cheap, reliable, ubiquitous, and easy method. Methods: We reviewed a prospectively kept database. A pinprick test was performed to measure systemic and flap glucose levels. A glucose index (GI; flap glucose/systemic glucose) was calculated. Comparison between the groups (with occlusive event, and without occlusive event) was done. Results: In total, 32 flaps in 29 consecutive patients were included. Eleven (34%) were free flaps. Of these, one (9%) was explored twice. Initially, salvage was achieved. However, 36 hours later, a second exploration was needed but was unsuccessful. Of the 21 pedicled flaps (66%), one (5%) needed exploration (suture release), and three (14%) had partial losses that were not clinically relevant. On the ROC curve, we found a cut-off value for a GI of 0.49 or less with a sensitivity of 95% [95% confidence interval (CI): 75.1 to 99.9%] and a specificity of 100% (95% CI: 98.5 to 100%), with a positive predictive value of 100% (95% CI: 81.5 to 100%) and a negative predictive value of 99.6% (95% CI: 97.8 to 100%) for flap suffering. Conclusions: The GI, as a complement, assists in defining treatment approach. It is an easy, reliable, accessible method that can be performed by nonmedical personnel. Its main drawback is the inability to monitor buried or hard to reach flaps.

The management of cervical lymph nodes in patients with cutaneous melanoma.

BACKGROUND: The aim of this study was to review the management of cervical lymph nodes in patients with cutaneous melanoma and to analyze factors influencing prognosis. METHODS: This was a retrospective cohort study of patients who had cervical node surgery at the Sydney Melanoma Unit from 1990 to 2004. RESULTS: Of 716 patients who met the study criteria, 339 had a sentinel node biopsy (SNB) and 396 had a neck dissection. Locoregional recurrence occurred in 27.6 % of those undergoing therapeutic neck dissection and 60 % eventually developed distant metastases. Radiotherapy was given as adjuvant treatment in 110 of the patients who had a therapeutic neck dissection (41 %), but this was not associated with improved regional control (p = .322). Multivariate analysis showed that nodal positivity (p < .001) and primary tumor ulceration (p = < .027) were the most important predictors of locoregional recurrence and that primary tumor Breslow thickness (p = .009) and node positivity (p = .046) were the most important factors predicting survival. SNB-positive patients who underwent immediate completion lymphadenectomy had a 5-year survival advantage over those who had a therapeutic neck dissection for macroscopic disease (54 % vs 47 %, p = .028). CONCLUSIONS: Nodal status was the most important factor predicting disease-free and overall survival in patients with melanoma of the head and neck. Adjuvant radiotherapy was not associated with better locoregional control in the non-randomized cohorts of patients in this study.

Increased SERCA2a sub-cellular heterogeneity in right-ventricular heart failure inhibits excitation-contraction coupling and modulates arrhythmogenic dynamics.

The intracellular calcium handling system of cardiomyocytes is responsible for controlling excitation-contraction coupling (ECC) and has been linked to pro-arrhythmogenic cellular phenomena in conditions such as heart failure (HF). SERCA2a, responsible for intracellular uptake, is a primary regulator of calcium homeostasis, and remodelling of its function has been proposed as a causal factor underlying cellular and tissue dysfunction in disease. Whereas adaptations to the global (i.e. whole-cell) expression of SERCA2a have been previously investigated in the context of multiple diseases, the role of its spatial profile in the sub-cellular volume has yet to be elucidated. We present an approach to characterize the sub-cellular heterogeneity of SERCA2a and apply this approach to quantify adaptations to the length-scale of heterogeneity (the distance over which expression is correlated) associated with right-ventricular (RV)-HF. These characterizations informed simulations to predict the functional implications of this heterogeneity, and its remodelling in disease, on ECC, the dynamics of calcium-transient alternans and the emergence of spontaneous triggered activity. Image analysis reveals that RV-HF is associated with an increase in length-scale and its inter-cellular variability; simulations predict that this increase in length-scale can reduce ECC and critically modulate the vulnerability to both alternans and triggered activity. This article is part of the theme issue 'The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease'.

Antibiotic prescriptions in the context of suspected bacterial respiratory tract superinfections in the COVID-19 era: a retrospective quantitative analysis of antibiotic consumption and identification of antibiotic prescription drivers.

This study aims to quantify antibiotic consumption for suspected respiratory tract superinfections in COVID-19 patients, while investigating the associated drivers of antibiotic prescribing in light of the current signs of antibiotic overuse. Adult patients with a positive COVID-19 diagnosis admitted to a Belgian 721-bed university hospital were analyzed retrospectively (March 11th-May 4th, 2020), excluding short-term admissions (< 24 h). Antibiotic prescriptions were analyzed and quantified, using Defined Daily Doses (DDD) per admission and per 100 bed days. Possible drivers of antibiotic prescribing were identified by means of mixed effects logistic modelling analysis with backwards selection. Of all included admissions (n = 429), 39% (n = 171) were prescribed antibiotics for (presumed) respiratory tract superinfection (3.6 DDD/admission; 31.5 DDD/100 bed days). Consumption of beta-lactamase inhibitor-penicillin combinations was the highest (2.55 DDD/admission; 23.3 DDD/100 bed days). Four drivers were identified: fever on admission (OR 2.97; 95% CI 1.42-6.22), lower SpO2/FiO2 ratio on admission (OR 0.96; 95% CI 0.92-0.99), underlying pulmonary disease (OR 3.04; 95% CI 1.12-8.27) and longer hospital stay (OR 1.09; 95% CI 1.03-1.16). We present detailed quantitative antibiotic data for presumed respiratory tract superinfections in hospitalized COVID-19 patients. In addition to knowledge on antibiotic consumption, we hope antimicrobial stewardship programs will be able to use the drivers identified in this study to optimize their interventions in COVID-19 wards.

Sir2 is induced by oxidative stress in a yeast model of Huntington disease and its activation reduces protein aggregation.

Huntington disease (HD) is a neurodegenerative disorder caused by expansion of CAG trinucleotide repeats, leading to an elongated polyglutamine sequence (polyQ) in the huntingtin protein. Misfolding of mutant polyQ proteins with expanded tracts results in aggregation, causing cytotoxicity. Oxidative stress in HD has been documented in humans as important to disease progression. Using yeast cells as a model of HD, we report that when grown at high glucose concentration, cells expressing mutant polyQ do not show apparent oxidative stress. At higher cell densities, when glucose becomes limiting and cells are metabolically shifting from fermentation to respiration, protein oxidation and catalase activity increases in relation to the length of the polyQ tract. Oxidative stress, either endogenous as a result of mutant polyQ expression or exogenously generated, increases Sir2 levels. Δ sir2 cells expressing expanded polyQ lengths show signs of oxidative stress even at the early exponential phase. In a wild-type background, isonicotinamide, a Sir2 activator, decreases mutant polyQ aggregation and the stress generated by expanded polyQ. Taken together, these results describe mutant polyQ proteins as being more toxic in respiring cells, causing oxidative stress and an increase in Sir2 levels. Activation of Sir2 would play a protective role against this toxicity.

Follow-up schedules after treatment for malignant melanoma.

BACKGROUND: Existing follow-up guidelines after treatment for melanoma are based largely on dated literature and historical precedent. This study aimed to calculate recurrence rates and establish prognostic factors for recurrence to help redesign a follow-up schedule. METHODS: Data were retrieved from the Sydney Melanoma Unit database for all patients with a single primary melanoma and American Joint Committee on Cancer (AJCC) stage I-II disease, who had received their first treatment between 1959 and 2002. Recurrence rates, timing and survival were recorded by substage, and predictive factors were analysed. RESULTS: Recurrence occurred in 18.9 per cent (895 of 4748) of patients overall, 5.2 per cent (95 of 1822) of those with stage IA disease, 18.4 per cent (264 of 1436) with IB, 28.7 per cent (215 of 750) with IIA, 40.6 per cent (213 of 524) with IIB and 44.3 per cent (86 of 194) with IIC disease. Overall, the median disease-free survival time was 2.6 years, but there were marked differences between AJCC subgroups. Primary tumour thickness, ulceration and tumour mitotic rate were important predictors of recurrence. CONCLUSION: A new follow-up schedule was proposed: stage I annually, stage IIA 6-monthly for 2 years and then annually, stage IIB-IIC 4-monthly for 2 years, 6-monthly in the third year and annually thereafter.

The advantage of using a synoptic pathology report format for cutaneous melanoma.

AIMS: Although the synoptic format is being increasingly used for primary cutaneous melanoma pathology reporting, no study assessing its value has yet been reported in the literature. The aim was to determine whether the use of synoptic reports increases the frequency with which pathological features that may influence prognosis and guide management are documented. METHODS AND RESULTS: Melanoma pathology reports (n = 1692) were evaluated; 904 were in a synoptic format [671 Sydney Melanoma Unit (SMU) reports and 233 non-SMU reports] and 788 were non-synoptic (184 SMU reports and 604 non-SMU reports). Reports (n = 1354) from 677 patients who had both a SMU report and a non-SMU report were compared. Almost all features were reported more frequently in synoptic than in non-synoptic reports (P < 0.001). No significant differences were found in the frequency of reporting the main pathological features between SMU and non-SMU synoptic reports. Synoptic reports were more frequently used by SMU (78%) than by non-SMU pathologists (28%). CONCLUSIONS: This is the first study to provide objective evidence that synoptic pathology reports for melanoma are more complete than non-synoptic reports (regardless of whether the reports are generated within or outside a specialist melanoma centre). All synoptic reports should include the facility for free text, be tailored to individual institutional requirements and be updated regularly to be of maximal value.

Re-emergence of rabies virus maintained by canid populations in Paraguay.

Paraguay has registered no human cases of rabies since 2004, and the last case in dogs, reported in 2009, was due to a variant maintained in the common vampire bat "Desmodus rotundus". In 2014, a dog was diagnosed as positive for rabies with aggression towards a boy and all required measures of control were successfully adopted. Epidemiological investigation revealed that the dog was not vaccinated and had been attacked by a crab-eating fox, "zorro" (Cerdocyon thous). The sample was diagnosed by the Official Veterinary Service of the Country and sent to the Center on Rabies Research from the University of São Paulo, Brazil, for antigenic and genetic characterization. A second sample from a dog positive for rabies in the same region in 2015 and 11 samples from a rabies outbreak from Asuncion in 1996 were also characterized. The antigenic profile of the samples, AgV2, was compatible with one of the variants maintained by dogs in Latin America. In genetic characterization, the samples segregated in the canine (domestic and wild species)-related group in an independent subgroup that also included samples from Argentina. These results and the epidemiology of the case indicate that even with the control of rabies in domestic animals, the virus can still circulate in wildlife and may be transmitted to domestic animals and humans, demonstrating the importance of continuous and improved surveillance and control of rabies, including in wild species, to prevent outbreaks in controlled areas.

Regulation of urokinase-type plasminogen activator gene transcription by macrophage colony-stimulating factor.

The mouse urokinase-type plasminogen activator (uPA) gene was used as a model macrophage colony-stimulating factor 1 (CSF-1)-inducible gene to investigate CSF-1 signalling pathways. Nuclear run-on analysis showed that induction of uPA mRNA by CSF-1 and phorbol myristate acetate (PMA) was at the transcriptional level in bone marrow-derived macrophages. CSF-1 and PMA synergized strongly in the induction of uPA mRNA, showing that at least some components of CSF-1 action are mediated independently of protein kinase C. Promoter targets of CSF-1 signalling were investigated with NIH 3T3 cells expressing the human CSF-1 receptor (c-fms). uPA mRNA was induced in these cells by treatment with CSF-1, and a PEA3/AP-1 element at -2.4 kb in the uPA promoter was involved in this response. Ets transcription factors can act through PEA3 sequences, and the involvement of Ets factors in the induction of uPA was confirmed by use of a dominant negative Ets-2 factor. Expression of the DNA binding domain of Ets-2 fused to the lacZ gene product prevented CSF-1-mediated induction of uPA mRNA in NIH 3T3 cells expressing the CSF-1 receptor. Examination of ets-2 mRNA expression in macrophages showed that it was also induced synergistically by CSF-1 and PMA. In the macrophage cell line RAW264, the uPA PEA3/AP-1 element mediated a response to both PMA and cotransfected Ets-2. uPA promoter constructs were induced 60- to 130-fold by Ets-2 expression, and the recombinant Ets-2 DNA binding domain was able to bind to the uPA PEA3/AP-1 element. This work is consistent with a proposed pathway for CSF-1 signalling involving sequential activation of fms, ras, and Ets factors.

Ras-mediated phosphorylation of a conserved threonine residue enhances the transactivation activities of c-Ets1 and c-Ets2.

The Ras oncogene products regulate the expression of genes in transformed cells, and members of the Ets family of transcription factors have been implicated in this process. To determine which Ets factors are the targets of Ras signaling pathways, the abilities of several Ets factors to activate Ras-responsive enhancer (RRE) reporters in the presence of oncogenic Ras were examined. In transient transfection assay, reporters containing RREs composed of Ets-AP-1 binding sites could be activated 30-fold in NIH 3T3 fibroblasts and 80-fold in the macrophage-like line RAW264 by the combination of Ets1 or Ets2 and Ras but not by several other Ets factors that were tested in the assay. Ets2 and Ras also superactivated an RRE composed of Ets-Ets binding sites, but the Ets-responsive promoter of the c-fms gene was not superactivated. Mutation of a threonine residue to alanine in the conserved amino-terminal regions of Ets1 and Ets2 (threonine 38 and threonine 72, respectively) abrogated the ability of each of these proteins to superactivate reporter gene expression. Phosphoamino acid analysis of radiolabeled Ets2 revealed that Ras induced normally absent threonine-specific phosphorylation of the protein. The Ras-dependent increase in threonine phosphorylation was not observed in Ets2 proteins that had the conserved threonine 72 residue mutated to alanine or serine. These data indicate that Ets1 and Ets2 are specific nuclear targets of Ras signaling events and that phosphorylation of a conserved threonine residue is a necessary molecular component of Ras-mediated activation of these transcription factors.

Determinants of outcome in melanoma patients with cerebral metastases.

PURPOSE: To analyze prognostic factors, effects of treatment, and survival for patients with cerebral metastases from melanoma. PATIENTS AND METHODS: All melanoma patients with cerebral metastases treated at the Sydney Melanoma Unit between 1952 and 2000 were identified. From 1985 to 2000, patients were diagnosed and treated using consistent modern techniques and this cohort was analyzed in detail. Multivariate analysis of prognostic factors for survival was performed. RESULTS: A total of 1137 patients with cerebral metastases were identified; 686 were treated between 1985 and 2000. For these 686 patients, the median time from primary diagnosis to cerebral metastasis was 3.1 years (range, 0 to 41 years). A total of 646 patients (94%) have died as a result of melanoma. The median survival from the time of diagnosis of cerebral metastasis was 4.1 months (range, 0 to 17.2 years). Treatment was as follows: surgery and postoperative radiotherapy, 158 patients; surgery alone, 47 patients; radiotherapy alone, 236 patients; and supportive care alone, 210 patients. Median survival according to treatment received for these four groups was 8.9, 8.7, 3.4, and 2.1 months, respectively; the differences between surgery and nonsurgery groups were statistically significant. On multivariate analysis, significant factors associated with improved survival were surgical treatment (P <.0001), no concurrent extracerebral metastases (P <.0001), younger age (P =.0007), and longer disease-free interval (P =.036). Prognostic factors analysis confirmed the important influence of patient selection on treatment received. CONCLUSION: This large series documents the characteristics of patients who developed cerebral metastases from melanoma. Median survival was dependent on treatment, which in turn was dependent on patient selection.

An enhancer element responsive to ras and fms signaling pathways is composed of two distinct nuclear factor binding sites.

In order to precisely define the sequences that constitute the ras-responsive enhancers element present in the murine retrotransposon NVL3, point mutations were introduced into the previously defined minimal transcriptional enhancer DNA. Analyses of the effects of these point mutations in transient transfection experiments, in gel retention assays, and by methylation interference footprinting indicated that the enhancer element was composed of two binding sites for distinct nuclear factors. Both binding sites were required for activation of the enhancer by either ras or v-fms oncogenes, and the distinct nuclear factors were found in extracts from cells that contained either oncogene. UV cross-linking analysis revealed that the AP1-related binding site, TGACTCT, was recognized by a nuclear factor of apparent molecular size of 50 kilodaltons, that is probably c-jun. The other binding site, CAGGATAT, is very similar to sites recognized by the ets-family of transcription factors, and was recognized by the 120-kilodalton ras-responsive factor-1. Activation of the NVL3 element was reconstituted in an in vitro transcription assay. The ets-related binding site was necessary for this in vitro reconstitution of activity. Thus, the NVL3 enhancer is related to the previously described oncogene-responsive enhancer element present in polyoma virus and is also related to elements identified in several cellular genes known to be ras-responsive, including the transforming growth factor-beta 1 gene.

Simultaneous occurrence of Hodgkin's disease and Kaposi's sarcoma in a patient with the acquired immune deficiency syndrome.

Kaposi's sarcoma and Hodgkin's disease have each been associated with abnormalities in T lymphocyte function and occur with increased frequency in the immunosuppressed host. Although the association of Kaposi's sarcoma with lymphoreticular disorders has long been recognized, only sporadic cases of Hodgkin's disease have been described in patients with the acquired immune deficiency syndrome (AIDS) in contrast to the frequent occurrence of non-Hodgkin's lymphoma in these patients. The simultaneous occurrence of Kaposi's sarcoma and Hodgkin's disease in the same lymph node is described in a patient with AIDS. This case suggests an association of AIDS with both Kaposi's sarcoma and malignant lymphomas and raises the question of a common pathogenetic mechanism.

Modification of the radiation response of mouse lung by actinomycin D: dependence on interval between radiation and drug treatments.

Actinomycin D (0.6 mg/kg, i.p.) enhances the radiation response of mouse lung. The degree of enhancement varies inversely with the interval between radiation and drug treatments. The kinetics of the loss of interaction of the drug with radiation damage is similar to that observed for "slow repair" of radiation injury to the lung.

Second malignancies and Hodgkin's disease--the Royal Marsden Hospital experience.

The frequency of secondary malignant neoplasms occurring in patients treated for Hodgkin's disease at the Royal Marsden Hospital between 1963 and 1978 is reported and the literature is reviewed. 730 patients were reviewed and 583 patients permanently resident in the United Kingdom were included in the analysis. The frequency of leukaemia and solid tumors was determined from age- and sex-corrected data from the South Thames Cancer Registry. Thirty-seven malignancies were recorded in 36 patients including 9 leukaemias, 10 lung cancers, 6 skin cancers and 2 non-Hodgkin's lymphoma, all of which were observed in significant excess. When all remaining sites are combined, there was a slight excess but no one site is individually significant.

An analysis of prognostic factors in early stage Hodgkin's disease.

An analysis of prognostic factors has been carried out in 398 patients presenting with clinical Stage I and II Hodgkin's disease treated between 1963 and 1979. By life table analysis older age, lymphocyte depletion histology, systemic symptoms, mediastinal node bulk, and erythrocyte sedimentation rate (ESR) greater than 40 mm/h were associated with a significantly worse survival probability. On multiple factor regression analysis only age and stage were independent prognostic variables for survival, with systemic symptoms having borderline significance. Using this information, together with other analyses of prognosis in early Hodgkin's disease three groups of patients are defined. The first with a predicted 5-year survival of 78% would include patients possessing at least one of the following features; age greater than 60, lymphocyte depletion, greater than 3 sites involved, systemic symptoms, mediastinal/thoracic ratio of greater than 1/3. The second groups present with at least two of the following factors; ESR greater than 40 mm/h, male sex, 3 involved sites, or mixed cellularity histology, and the 5 year survival probability is 84%. The remaining Stage I and II patients would constitute a good prognosis group with a predicted 5-year survival of 92%.