A Diagnostic Dilemma: Clindamycin-Resistant Group A Streptococcal Toxic Shock Syndrome Leading to Acute Respiratory Distress Syndrome (ARDS) With Multiple Possible Sources.

Group A Streptococcal (GAS) infections can potentially progress into streptococcal toxic shock syndrome (STSS) with multiorgan failure. Even with a benign presentation, GAS can rapidly lead to fatal necrotizing infections. While myositis and cutaneous infections are the typical initial presentation of STSS, genitourinary infections are a less common source. This report presents a case of a previously healthy woman with the chief complaint of ankle pain who subsequently developed streptococcal toxic shock syndrome and multiorgan failure from a Group A streptococcus infection of the genitourinary tract. She was treated with antibiotics and medical management for her septic shock and required prone ventilation for her acute respiratory distress syndrome (ARDS) but eventually recovered without surgery. This case highlights the importance of recognizing unusual presentations of Group A Strep infections, which have the potential to lead to rapid deterioration in patients. Also described are antibiotic and ventilator strategies that can be used to treat these severe systemic infections.

Exposure to secondary traumatic stress and its related factors among emergency nurses in Saudi Arabia: a mixed method study.

BACKGROUND: Emergency department (ED) nurses are exposed to the risk of secondary traumatic stress (STS), which poses a threat not only to nurses' health and psychological well-being but also adversely affects the execution of their professional duties. The quality and outcome of their nursing services are negatively affected by STS. PURPOSE: The purpose of this study is to comprehensively investigate the prevalence and intensity of Secondary Traumatic Stress (STS) among Emergency Department (ED) nurses. It aims to identify and analyze the socio-demographic, occupational, and psychological factors that influence the severity and variation of STS experienced by these nurses. METHODS: The study utilized a sequential explanatory mixed methods approach, including two phases. Phase 1 employed a cross-sectional study design, utilizing a convenience sample of 181 nurses to explore the levels of STS and the factors associated with it. Following this, Phase 2 was structured as a qualitative descriptive study, which involved conducting semi-structured interviews with a purposefully selected group of ten ED nurses. Data collection took place at three major hospitals in Saudi Arabia during the period from January to June 2022. RESULTS: A total of 181 participants were included in the study. The mean STSS score reported by the nurses was 51 (SD = 13.23) out of the maximum possible score of 85, indicating severe STS among ED nurses. Factors associated with an increase in the levels of STS among ED nurses included being female, older in age, married, possessing higher education and experience, having a positive relationship with colleagues, receiving organisational support, and dealing with a higher number of trauma cases. Several themes emerged from the qualitative interviews including: ED Characteristics: Dual Impact on STS, Emotional Resonance and Vulnerability, Personal Life Stressors, The Ability to Cope, and Social Support. CONCLUSION AND IMPLICATIONS FOR PRACTICE: Future strategies and interventions targeting STS should be prioritized to effectively manage its impact on ED nurses. It is crucial to develop targeted interventions that address the specific factors contributing to STS, as identified in this study. Additionally, these findings aim to enhance awareness among nursing administrators, managers, and supervisors about the critical factors associated with STS. This awareness is essential for accurately assessing and developing interventions that mitigate STS among nursing staff.

A Critical Case of Streptococcal Toxic Shock Syndrome: A Case Report.

A 41-year-old woman with a history of asthma presented to the emergency department with complaints of progressive malaise, dyspnea, vomiting, and diarrhea for a week. Upon presentation, the patient was hemodynamically unstable and exhibited severe respiratory distress. A chest computed tomography revealed consolidation of the left upper lobe with confluence in the left perihilar region and a left pleural effusion. The patient was admitted to the intensive care unit for further management of respiratory failure, and a chest tube was placed on the left side. Despite the absence of bacteremia, the diagnosis of Streptococcal toxic shock syndrome was confirmed through a pleural fluid culture positive for Streptococcus pyogenes and evidence of multiorgan failure. Her treatment included vasopressors, broad-spectrum antibiotics, and intravenous immunoglobulin. For renal failure, the patient required continuous renal replacement therapy. Despite all these interventions, the patient continued to decline, and left-sided video-assisted thoracoscopic surgery was pursued with subsequent improvement of her condition. The incidence of invasive Group A streptococcal disease is significant, with notable mortality and morbidity among affected patients. The rapid deterioration is thought to be secondary to the highly virulent nature of the pathogen and the production of superantigens. The rapid institution of adequate antibiotic coverage with beta-lactams and clindamycin has been shown to decrease the mortality rate. Intravenous immunoglobulin has also been included with a promising positive effect.

M1UKStreptococcus pyogenes causing community-acquired pneumonia, pleural empyema and streptococcal toxic shock syndrome.

OBJECTIVES: Streptococcus pyogenes causes superficial infections but can also cause deep-seated infections and toxin-mediated diseases. In the present study, phylogenetic and in silico prediction analyses were performed on an antimicrobial resistant M1UKS. pyogenes strain causing severe clinical manifestations during the current surge of invasive group A Streptococcus (iGAS) disease. METHODS: A 40-year-old patient was admitted to the hospital with fever, chest pain and fatigue. Based on the clinical and laboratory findings, a diagnosis of sepsis with disseminated intravascular coagulation, community-acquired pneumonia, pleural empyema and streptococcal toxic shock syndrome was made. Microbial identification was performed by multiplex PCR and conventional culturing. Furthermore, antimicrobial susceptibility testing, whole genome sequencing, phylogenomic analysis and in silico prediction analysis of antimicrobial resistance genes and virulence factors were performed. RESULTS: S. pyogenes isolates were detected in pleural fluid and sputum of the patient. Both isolates belonged to the M1UK lineage of the emm1/ST28 clone, being closely related with an M1UK GAS strain from Australia. They exhibited resistance to erythromycin and clindamycin and susceptibility-increased exposure to levofloxacin and carried genes encoding for protein homologues of antibiotic efflux pumps. Moreover, several virulence factors, and a previously described single-nucleotide polymorphism in the 5' transcriptional leader sequence of the ssrA gene, which enhances expression of SpeA, were detected. CONCLUSIONS: The present antimicrobial-resistant M1UKS. pyogenes strain represents the first report of this emerging lineage associated with such manifestations of iGAS disease.

Psychometric properties of the Mongolian version of shitsu-taikan-sho (alexisomia) in young adults.

Objective: Alexisomia is characterized by difficulty in identifying and describing bodily feelings. Shitsu-taikan-sho scale (STSS) is a self-report tool that assesses alexisomia. This study aimed to validate the Mongolian version of STSS in a nonclinical student sample. Methods: A total of 593 undergraduate students (217 males, 376 females, 18-25 years), who were studying at medical universities, were recruited. Participants completed the Mongolian version of STSS, which was translated from Japanese to Mongolian, back-translated, and finalized by an expert committee. Construct validity was examined using exploratory and confirmatory factor analyses for a three-factor structure. Internal consistency and test-retest reliability were measured using Cronbach's α and the intraclass correlation coefficients (ICC), respectively. Results: The mean scores of STSS were 18.6 ± 5.7 for difficulty identifying bodily feelings (DIB), 18.8 ± 4.0 for overadaptation (OA), 23.7 ± 4.1 for lack of health management (LHM), and 61.1 ± 10.5 for the total score (possible range: 7-35 for DIB, OA, LHM, and 21-105 for the total score, respectively). Exploratory factor analysis indicated a three-factor structure consisting of 21 items that explained 40.3% of the variance (KMO = 0.916, RMSEA = 0.049, χ2 = 372, p < .001). Confirmatory factor analysis provided a good fit to the data (CFI = 0.876, TLI = 0.861, RMSEA = 0.068, χ2 = 703, p < .001). Cronbach's alpha for the STSS was 0.860, indicating good internal consistency. Test-retest reliability analysis demonstrated good reliability (ICC = 0.791). Conclusion: The 21-item Mongolian version of STSS demonstrated evidence of good reliability and validity for assessing alexisomia in a nonclinical population in Mongolia. This suggests that the Mongolian version of the STSS may allow for the comparison of alexisomia among adults in Mongolia with those in other countries.

Streptococcal Toxic Shock Syndrome Due to Invasive Coloproctitis Caused by Group G Streptococcus: A Case Report and Literature Review.

Streptococcus dysgalactiae subsp. equisimillis (SDSE) is classified as a group G streptococcus (GGS). In systemic SDSE infection, septic shock is easily induced and has a high mortality of 44%. The case was a 78-year-old man presented with fever and chills of 20 hours duration. He was in shock at the presentation and developed melena on day nine. CT images showed bowel wall thickening with emphysema and bedside colonoscopy showed active bleeding in the descending colon and rectum. Blood cultures were positive for Streptococcus dysgalactiae and a diagnosis of streptococcal toxic shock syndrome (STSS) due to SDSE was made. Urgent Hartmann procedure with laparotomy for removal of descending and rectal colon was performed to relieve his shock status. His shock status was reversed after surgery. Surgical specimens confirmed the presence of SDSE on the intestinal mucosa. This is the first case of STSS due to SDSE infection of the intestinal wall. Resection of infected tissue in the setting of multiple organ dysfunction syndrome and necrotizing enterocolitis is indicated in such cases.

Using space-time scan statistic for studying the effects of COVID-19 in Punjab, Pakistan: a guideline for policy measures in regional agriculture.

Pakistan is included in top 50 countries which are estimated to face serious agriculture and food deficiency related challenges due to the worldwide pandemic coronavirus 2019 (COVID-19). The aim of this study was to evaluate the effects of COVID-19 on food supply chain and agriculture in Punjab, Pakistan, by using space-time scan statistic (STSS). A survey was conducted at 720 points in different districts of the province. The STSS detected "active" and emerging clusters that are current at the end of our study area-particularly, 17 clusters were formed while adding the updated case data. Software ArcGIS 10.3 was used to find relative risk (RR) values; the maximum RR value was found to be 42.19 and maximum observed cases 53,265 during June 15-July 1, 2020. It was not always necessary that if the number of active cases in Punjab increased, there should be higher relative risk for more number of districts and vice versa. Due to the highest number of cases of COVID-19 and RR values during July, mostly farmers faced many difficulties during the cultivation of cotton and rice. Mostly farmers (72%) observed increase in prices of inputs (fertilizers and pesticides) during lockdown. If the supply chain of agriculture related inputs is disturbed, farmers may find it quite difficult to access markets, which could result in a decline in production and sales of crops and livestock in study area. It is suggested that to protect the food security and to decrease the effect of the lockdown, Punjab government needs to review food policy and analyse how market forces will respond to the imbalanced storage facilities and capacity, supply and demand and price control of products. The findings of this study can also help policy-makers to formulate an effective food security and agriculture adaptation strategy.

ICU Management of Invasive ß-Hemolytic Streptococcal Infections.

ß-hemolytic streptococci (BHS) are a leading cause of invasive bacterial disease worldwide. They are subtyped based on the presence of the surface polysaccharide antigens and include Group A Streptococcus (GAS; Streptococcus pyogenes), Group B Streptococcus (GBS; Streptococcus agalactiae), and non-group A, non-group B Streptococci (NABS). Invasive BHS infection is defined as isolation from the normally sterile site in patients with a compatible clinical syndrome which include, but is not limited to, streptococcal toxic shock syndrome (STSS), Necrotizing soft tissue infection (NSTI), bacteremia, meningitis lower respiratory tract, musculoskeletal and puerperal/postpartum infections. Resuscitation, source control, and ß-lactam therapy are the cornerstone of therapy.

Recombinant human soluble thrombomodulin and danaparoid combination anticoagulant therapy for disseminated intravascular coagulation in a child with streptococcal toxic shock syndrome: A case report.

Disseminated intravascular coagulation (DIC) is a common and morbid complication of streptococcal toxic shock syndrome (STSS). Because DIC with STSS progresses rapidly, prompt and proper care is critical. The present report describes the case of a 10-year-old boy who survived STSS with DIC without sequelae after treatment with combination anticoagulant therapy of recombinant human soluble thrombomodulin (rhTM) and danaparoid. RhTM and antithrombin-III were administered on day 1. RhTM administration was continued. Despite this, on day 2, his general condition remained poor, his fever persisted and his DIC score increased from an initial 5 points upon admission to 9 points. Therefore, danaparoid was additionally administered from day 2 onwards. The patient recovered without serious complications. Combination anticoagulant therapy of rhTM and danaparoid for DIC in a child with STSS was effective and safe. Therefore, this combination therapy could be used as an option for managing high-risk, rapidly progressing disease states, which predispose to morbid sequelae and death, such as DIC with STSS. RhTM and danaparoid therapy may reduce the risk of serious complications, such as organ failure, and improve the prognosis not only in STSS but also in other conditions with infection and DIC concurrence, such as sepsis.

Monitoring European data with prospective space-time scan statistics: predicting and evaluating emerging clusters of COVID-19 in European countries.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has become a pandemic infectious disease and become a serious public health crisis. As the COVID-19 pandemic continues to spread, it is of vital importance to detect COVID-19 clusters to better distribute resources and optimizing measures. This study helps the surveillance of the COVID-19 pandemic and discovers major space-time clusters of reported cases in European countries. Prospective space-time scan statistics are particularly valuable because it has detected active and emerging COVID-19 clusters. It can prompt public health decision makers when and where to improve targeted interventions, testing locations, and necessary isolation measures, and the allocation of medical resources to reduce further spread. METHODS: Using the daily case data of various countries provided by the European Centers for Disease Control and Prevention, we used SaTScan™ 9.6 to conduct a prospective space-time scan statistics analysis. We detected statistically significant space-time clusters of COVID-19 at the European country level between March 1st to October 2nd, 2020 and March 1st to October 2nd, 2021. Using ArcGIS to draw the spatial distribution map of COVID-19 in Europe, showing the emerging clusters that appeared at the end of our study period detected by Poisson prospective space-time scan statistics. RESULTS: The results show that among the 49 countries studied, the regions with the largest number of reported cases of COVID-19 are Western Europe, Central Europe, and Eastern Europe. Among the 49 countries studied, the country with the largest cumulative number of reported cases is the United Kingdom, followed by Russia, Turkey, France, and Spain. The country (or region) with the lowest cumulative number of reported cases is the Faroe Islands. We discovered 9 emerging clusters, including 21 risky countries. CONCLUSION: This result can provide timely information to national public health decision makers. For example, a country needs to improve the allocation of medical resources and epidemic detection points, or a country needs to strengthen entry and exit testing, or a country needs to strengthen the implementation of protective isolation measures. As the data is updated daily, new data can be re-analyzed to achieve real-time monitoring of COVID-19 in Europe. This study uses Poisson prospective space-time scan statistics to monitor COVID-19 in Europe.

Effects of practicing yoga on alexisomia: an open-label trial.

BACKGROUND: Alexisomia refers to difficulties in the awareness and expression of somatic feelings. This idea was proposed by Dr. Yujiro Ikemi as a characteristic observed in patients with psychosomatic diseases and is based on his observations that patients with psychosomatic diseases have difficulty in the awareness and expression of not only their emotions, i.e., alexithymia, but also somatic feelings and sensations, i.e., alexisomia. He also proposed that treating alexisomia is important in the treatment of psychosomatic diseases and that yoga might help improve alexisomia. However, no study has investigated if yoga actually affects alexisomia. This open-label pilot study investigated whether practicing yoga in a class results in change in patients with alexisomia and alexithymia. METHODS: The Shitsu-taikan-sho Scale (STSS) and the Toronto Alexithymia Scale (TAS-20) were administered to 305 participants, including 64 healthy participants, 111 participants who had subjective symptoms without abnormal findings, and 130 participants with chronic diseases. Participants were tested before and 3 months after attending yoga classes. RESULTS: Yoga practice reduced the STSS and the TAS-20 difficulty in identifying feelings (DIF) subscale scores. Multiple linear regression indicated that a reduction in the TAS-20 DIF subscale scores predicted a decrease in the STSS score, whereas reductions in the STSS difficulty in identifying bodily feelings (DIB) and the lack of health management based on bodily feelings (LHM) subscale scores predicted a decrease in the TAS-20 scores. CONCLUSION: We found that regular yoga practice improves alexisomia. Yoga-induced improvement of alexisomia may be mediated, at least in part, by an improvement of DIF in alexithymia. Yoga would be a promising therapeutic approach to improve alexisomia.

Imaging update on soft tissue sarcoma.

Soft tissue sarcomas (STS) are rare tumours presenting as soft tissue lumps. Ultrasound is often the primary modality for the initial assessment, with MRI the mainstay for lesion characterisation. PET/CT along with other emerging MRI sequences are used in certain situations as an adjunct and problem solving tool in STS staging and assessment of disease recurrence. Recent advances include the promise of whole body MRI, hybrid PET/MRI, diffusion weighted imaging, dynamic contrast enhanced MRI and advances in artificial intelligence. This article discusses current concepts in extremity STS imaging and highlights recent advances.

Next-generation sequencing of 16S rRNA for identification of invasive bacterial pathogens in a formalin-fixed paraffin-embedded placental specimen: a case report of perinatal fulminant Streptococcus pyogenes infection.

Intrauterine infection is one of the most important causes of maternal death. In perinatal emergency, we often miss an opportunity to obtain culture specimens. In this study, we tried to examine whether we investigated whether bacteria causing infection can be detected from a formalin-fixed paraffin-embedded (FFPE) placental specimen. We examined the placenta from a maternal invasive infection that resulted in infectious abortion at 18 weeks of gestation. The case was diagnosed by acute fever and abdominal pain, and the patient was cured after 3 weeks of intensive antimicrobial treatment. Four Streptococcus pyogenes strains were isolated from vaginal fluid and blood cultures of the patient. All of the strain types were emm1/ST28. We amplified the V1-V2 region of 16S rRNA from an FFPE placental specimen and sequencing was performed using a next-generation sequencer (NGS). Taxonomic analysis was then performed for sequenced data. We succeeded in detecting causative pathogens from the FFPE placenta: 69.1% of the predominantly identified bacteria were S. pyogenes and other small populations of bacteria were detected. Our results revealed the utility of NGS for 16S rRNA analysis of an FFPE placenta. This method may reveal previous perinatal invasive infections of unknown origin retrospectively.

Poor Efficacy of Postoperative Radiotherapy in Infiltrative High-grade Soft Tissue Sarcomas.

BACKGROUND/AIM: We aimed to investigate the effectiveness of postoperative radiotherapy (RT) on local recurrence-free survival (LRFS) in high-grade infiltrative soft tissue sarcomas (STSs) and determine its prognostic factors. PATIENTS AND METHODS: This was a retrospective cohort study and included 132 patients with high-grade STSs. Patients were divided into two groups: Group RT (n=48) who underwent postoperative RT and Group No-RT (n=84) who underwent only surgery. We analysed 5-year LRFS and its prognostic factors between these groups. Furthermore, 5-year LRFS in infiltrative and non-infiltrative STSs were evaluated. RESULTS: Five-year LRFS was not significantly different in Group RT (83.6%) and Group No-RT (79.6%) (p=0.698). Overall, significant prognostic factors influencing LRFS were age at diagnosis (p=0.02) and tumour growth pattern (p=0.04). Postoperative RT was less effective in the infiltrative than in non-infiltrative pattern of STSs. CONCLUSION: Postoperative RT does not influence local recurrence outcomes in infiltrative STSs.

Streptococcal Toxic Shock Syndrome Induced by Group A Streptococcus with the emm28 Genotype That Developed after a Uterine Cancer Test.

A 69-year-old woman without pre-existing disease visited our hospital due to general malaise, diarrhea, and arthralgia 3 days after a uterine cancer test. We diagnosed her with sepsis of unknown focus and started treatment immediately, but she died 20 hours after the first visit due to multi-organ failure and septic shock. Later, group A streptococcus was detected from the blood culture, and streptococcal toxic shock syndrome (STSS) was diagnosed. The strain had the emm28 genotype and a mutation in csrR with increased NADase activity. These virulence factors were considered to be related to STSS development in this patient.

Performance of the Pandemic Medical Early Warning Score (PMEWS), Simple Triage Scoring System (STSS) and Confusion, Uremia, Respiratory rate, Blood pressure and age ≥ 65 (CURB-65) score among patients with COVID-19 pneumonia in an emergency department triage setting: a retrospective study

ABSTRACT BACKGROUND: Healthcare institutions are confronted with large numbers of patient admissions during large-scale or long-term public health emergencies like pandemics. Appropriate and effective triage is needed for effective resource use. OBJECTIVES: To evaluate the effectiveness of the Pandemic Medical Early Warning Score (PMEWS), Simple Triage Scoring System (STSS) and Confusion, Uremia, Respiratory rate, Blood pressure and age ≥ 65 years (CURB-65) score in an emergency department (ED) triage setting. DESIGN AND SETTING: Retrospective study in the ED of a tertiary-care university hospital in Düzce, Turkey. METHODS: PMEWS, STSS and CURB-65 scores of patients diagnosed with COVID-19 pneumonia were calculated. Thirty-day mortality, intensive care unit (ICU) admission, mechanical ventilation (MV) need and outcomes were recorded. The predictive accuracy of the scores was assessed using receiver operating characteristic curve analysis. RESULTS: One hundred patients with COVID-19 pneumonia were included. The 30-day mortality was 6%. PMEWS, STSS and CURB-65 showed high performance for predicting 30-day mortality (area under the curve: 0.968, 0.962 and 0.942, respectively). Age > 65 years, respiratory rate > 20/minute, oxygen saturation (SpO2) < 90% and ED length of stay > 4 hours showed associations with 30-day mortality (P < 0.05). CONCLUSIONS: CURB-65, STSS and PMEWS scores are useful for predicting mortality, ICU admission and MV need among patients diagnosed with COVID-19 pneumonia. Advanced age, increased respiratory rate, low SpO2 and prolonged ED length of stay may increase mortality. Further studies are needed for developing the triage scoring systems, to ensure effective long-term use of healthcare service capacity during pandemics.

Acquisition of genetic mutations in Group A Streptococci at infection site and subsequent systemic dissemination of the mutants with lethal mutations in a streptococcal toxic shock syndrome mouse model.

Streptococcal toxic shock syndrome (STSS) is caused mainly by Streptococcus pyogenes (Group A Streptococci, GAS), and it has a fatality rate of 25%. Mutations in CsrRS and RopB, which suppress the transcription of many virulence factors, were recently found in clinical isolates from STSS patients, but it is not fully understood when and where GAS acquires the mutations in the host. To resolve this question, we used our mouse model of human STSS to recover GAS strains from injections sites, spleens and blood of moribund mice with STSS-like symptoms, and analyzed the sequence of the covR/covS genes and ropB gene that encode CsrRS and RopB. Fifteen out of twenty mice that were inoculated transdermally into muscles with GAS organisms became moribund with STSS-like symptoms after more than 20 days after inoculation. We found that all the disseminated GAS strains recovered from the blood and spleens of the moribund mice had mutations in either the covR genes or the covS genes. The mutation sites in the GAS strains recovered from the blood and spleen were identical in each mouse, whereas the strains recovered from the muscles included a mix of disseminated strains, other mutant strains, and the parent strain. The mutant strains killed mice significantly earlier than the parent strain. Our data indicated that GAS organisms remained at the injection site, and various mutants appeared there, among which the strain that acquires the mutation in the covR/S gene is expected to overexpress various virulence factors simultaneously and cause systemic infection such as STSS.

Validity, Reliability, and Factor Structure of the Secondary Traumatic Stress Scale-French Version.

Secondary traumatic stress (STS) is a syndrome including intrusion, avoidance, and arousal due to indirect trauma exposure (e.g., by caring for traumatized patients in a professional context or transgenerational transmission of trauma in familial or cultural systems). Bride et al. (1) developed the Secondary Traumatic Stress Scale (STSS), designed to measure these reactions of helping professionals who have experienced traumatic stress through their work with their traumatized clients. This study aimed to validate the French version of the STSS (STSS-F) by evaluating factorial and criterion validity. Furthermore, its reliability and other psychometric properties were evaluated. Two-hundred-and-twenty midwives at two university hospitals in the French-speaking part of Switzerland completed an anonymous online survey. Midwives were chosen as study population because STS represents a serious professional risk in this population. In a series of confirmatory factor analyses and exploratory structural equation modeling (ESEM), a model with two correlated ESEM factors (i.e., intrusion, avoidance-arousal) provided the best model fit, thus establishing factorial validity. Differential associations of the STSS-F total score to general distress and posttraumatic stress and the utility of the STSS-F total score to account for variance in core dimensions of burnout beyond general distress, posttraumatic stress, perceived stress, occupational reward, and efforts supported the criterion validity of the STSS-F. The full STSS-F and its subscales showed acceptable to good levels of reliability. Limitations include the relatively small and homogeneous sample and the lack of tests of factorial invariance of the STSS-F and the original STSS. In conclusion, the present study provides evidence for the reliability and validity of the STSS-F. It makes the SSTS accessible to French speaking research contexts.

Soft tissue sarcomas: new opportunity of treatment with PARP inhibitors?

BACKGROUND: Poly(ADP-ribose) polymerases (PARP) are a large family of enzymes involved in several cellular processes, including DNA single-strand break repair via the base-excision repair pathway. PARP inhibitors exert antitumor activity by both catalytic PARP inhibition and PARP-DNA trapping, moreover PARP inhibition represents a potential synthetic lethal approach against cancers with specific DNA-repair defects. Soft tissue sarcoma (STSs) are a heterogeneous group of mesenchymal tumors with locally destructive growth, high risk of recurrence and distant metastasis. OBJECTIVES: The purpuse of this review is to provide an overview of the main preclinical and clinical data on use of PARPi in STSs and of effect and safety of combination of PARPi with irradiation. RESULTS: Due to numerous genomic alterations in STSs, the DNA damage response pathway can offer an interesting target for biologic therapy. Preclinical and clinical studies showed promising results, with the most robust evidences of PARPi efficacy obtained on Ewing sarcoma bearing EWS-FLI1 or EWS-ERG genomic fusions. The activity of PARP inhibitors resulted potentiated by chemotherapy and radiation. Although mechanisms of synergisms are not completely known, combination of radiation therapy and PARP inhibitors exerts antitumor effect by accumulation of unrepaired DNA damage, arrest in G2/M, activity both on oxic and hypoxic cells, reoxygenation by effect on vessels and promotion of senescence. Early trials have shown a good tolerance profile. CONCLUSIONS: The use of PARP inhibitors in advanced stage STSs, alone or combined in multimodal treatments, is of great interest and warrants further investigations.