Associations between KIR/KIR-ligand genotypes and clinical outcome for patients with advanced solid tumors receiving BEMPEG plus nivolumab combination therapy in the PIVOT-02 trial.

Bempegaldesleukin (BEMPEG), a CD122-preferential IL2 pathway agonist, has been shown to induce proliferation and activation of NK cells. NK activation is dependent on the balance of inhibitory and excitatory signals transmitted by NK receptors, including Fc-gamma receptors (FCγRs) and killer immunoglobulin-like receptors (KIRs) along with their KIR-ligands. The repertoire of KIRs/KIR-ligands an individual inherits and the single-nucleotide polymorphisms (SNPs) of FCγRs can influence NK function and affect responses to immunotherapies. In this retrospective analysis of the single-arm PIVOT-02 trial, 200 patients with advanced solid tumors were genotyped for KIR/KIR-ligand gene status and FCγR SNP status and evaluated for associations with clinical outcome. Patients with inhibitory KIR2DL2 and its ligand (HLA-C1) observed significantly greater tumor shrinkage (TS, median change -13.0 vs. 0%) and increased PFS (5.5 vs. 3.3 months) and a trend toward improved OR (31.2 vs. 19.5%) compared to patients with the complementary genotype. Furthermore, patients with KIR2DL2 and its ligand together with inhibitory KIR3DL1 and its ligand (HLA-Bw4) had improved OR (36.5 vs. 19.6%), greater TS (median change -16.1 vs. 0%), and a trend toward prolonged PFS (8.4 vs. 3.6 months) as compared to patients with the complementary genotype. FCγR polymorphisms did not influence OR/PFS/TS.These data show that clinical response to BEMPEG plus nivolumab treatment in the PIVOT-02 trial may be associated with the repertoire of KIR/KIR-ligands an individual inherits. Further investigation and validation of these results may enable KIR/KIR-ligand genotyping to be utilized prospectively for identifying patients likely to benefit from certain cancer immunotherapy regimens.

Ventral hernia repair using bioresorbable poly-4-hydroxybutyrate mesh in clean and contaminated surgical fields: a systematic review and meta-analysis.

PURPOSE: Use of biologic or synthetic mesh in hernia repair shifts is based on evolving evidence. Poly-4-hydroxybutyrate (P4HB) biosynthetic mesh is a potential alternative to biologic and synthetic mesh in ventral hernia repair (VHR). This meta-analysis assesses the efficacy of P4HB mesh in clean and contaminated surgical settings. METHODS: Two authors searched literature on PubMed, reviewing titles and abstracts of all articles to determine inclusion eligibility. Post-operative data were compared via transformation method to convert the proportion of patients with the outcome of interest into a suitable quantity for random-effects synthesis using STATA software. RESULTS: Initial search yielded 287 citations. Six studies were included and categorized on whether hernia repairs were conducted in clean (CDC class I) or contaminated cases (CDC class II-IV). The pooled proportion of surgical site infection (SSI), surgical site occurrence (SSO), hernia recurrence, total surgical complications, and reoperation were calculated in 391 clean and 81 contaminated cases. For clean vs. contaminated cases, the following pooled proportions were noted: SSI (2% (CI 0-7%) vs 9% (CI 0-025) (p = 0.03), SSO: 14% (CI 5-25%) vs 35% (CI 22-50%) (p = 0.006), hernia recurrence (8% (CI 1-19%) vs 4% (CI 0-12%) (p = 0.769); surgical complications (17% (CI 6-32%) vs 50% (CI 27-72%) (p = 0.009). Reoperation data were available in 298 clean cases across four studies: 5% (CI 0-15%). CONCLUSIONS: P4HB biosynthetic mesh may be more effective than previously thought, particularly in clean wounds. P4HB may also be superior to biologic mesh when compared to clinical trial data. Further research is necessary for more direct comparison.

Value of adding second-trimester uterine artery Doppler to patient characteristics in identification of nulliparous women at increased risk for pre-eclampsia: an individual patient data meta-analysis.

OBJECTIVE: To investigate the value of adding second-trimester uterine artery Doppler ultrasound to patient characteristics in the identification of nulliparous women at risk for pre-eclampsia. METHODS: For this individual patient data meta-analysis, studies published between January 1995 and December 2009 were identified in MEDLINE and EMBASE. Studies were eligible in which Doppler assessment of the uterine arteries had been performed among pregnant women and in which gestational age at ultrasound, Doppler ultrasound findings and data on the occurrence of pre-eclampsia were available. We invited corresponding authors to share their original datasets. Data were included of nulliparous women who had had a second-trimester uterine artery Doppler ultrasound examination. Shared data were checked for consistency, recoded to acquire uniformity and merged into a single dataset. We constructed random intercept logistic regression models for each of the patient and Doppler characteristics in isolation and for combinations. We compared goodness of fit, discrimination and calibration. RESULTS: We analyzed eight datasets, reporting on 6708 nulliparous women, of whom 302 (4.5%) developed pre-eclampsia. Doppler findings included higher, lower and mean pulsatility index (PI) and resistance index (RI) and any or bilateral notching. Of these, the best predictors were combinations of mean PI or RI and bilateral notching, with areas under the receiver-operating characteristics curve (AUC) of 0.75 (95% confidence interval (CI), 0.56-0.95) and 0.70 (95% CI, 0.66-0.74), respectively. Addition of Doppler findings to the patient characteristics blood pressure or body mass index (BMI) significantly improved discrimination. A model with blood pressure, PI and bilateral notching had an AUC of 0.85 (95% CI, 0.67-1.00). CONCLUSIONS: The addition of Doppler characteristics of mean PI or RI and bilateral notching to patient characteristics of blood pressure or BMI improves the identification of nulliparous women at risk for pre-eclampsia.

Shared trauma, resilience, and growth: A roadmap toward transcultural conceptualization.

Objective: Countless communities worldwide are exposed directly and subsequently to the effects of massive-scale collective stressors, from natural disasters to human-caused. In contexts of collective adversity, health care providers who are also members of these communities share and interdependently affect the range of responses their patients have. We aim to conceptualize this spectrum, termed shared trauma, shared resilience, and shared growth. Method: In this metasynthesis, we review the literature on these underacknowledged dynamics globally. We include prior conceptualizations of direct and indirect trauma, collective trauma, cultural context, and the COVID-19 pandemic toward clearer conceptualization of shared mental health in global collective stressor contexts. Results: Most trauma and resilience research focuses on prevailing concepts and measures with questionable cross-cultural applicability. These works usually center on acute, highly distressing threats to physical safety at the individual level. The scarce literature on shared trauma describes it as a rare phenomenon, entailing conflicting messages of narrative accounts within contexts of few cultures with medium to high degrees of individualism. There has been little consideration of other non-Western and indigenous communities with more collectivist values and collective trauma histories. There is limited understanding of these concepts as they pertain to the vast majority of cultures. As a result, shared trauma, resilience, and growth have been poorly conceptualized, differentiated, or empirically researched. Conclusions: We propose uniquely inclusive models of shared trauma, resilience, and growth. These models reflect the cumulative effects and interplay of direct to indirect, acute to chronic, individual to collective, and historic to transgenerational factors influenced by cultural context. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Racial and ethnic disparities in women's mental health: a narrative synthesis of systematic reviews and meta-analyses of the US-based samples.

Over 2 decades of research indicate the significance of racial or ethnic disparities in mental illness in the United States. However, minoritized racial or ethnic groups tend to report overall lower prevalence rates of psychiatric disorders than White adults, although this varies depending on gender and race or ethnicity. We conducted a rigorous and systematic narrative synthesis on the differences in the prevalence rates and symptoms that differ across racial or ethnic women in depression, anxiety, eating disorders, and premenstrual syndrome or premenstrual dysphoric disorder. Seven systematic reviews and meta-analyses that examined racial/ethnic differences in depression and eating disorders were included. No review that examined racial/ethnic differences in anxiety or premenstrual syndrome or premenstrual dysphoric disorder met inclusion criteria. Methodological quality of the reviews, which was determined by the Assessment of Multiple Systematic Reviews criteria, revealed that the results of 5 reviews were rated as critically low confidence, one review was rated as low confidence, and one review was rated as high confidence. Findings were inconsistent across systematic reviews and meta-analyses because of the methodological differences in the original studies. Overall, racially or ethnically minoritized women generally report lower prevalence rates in depressive and eating disorders than the White women; however, they exhibit different or greater symptom presentation that could influence prevalence estimates depending on the diagnostic criteria followed. Methodological considerations are provided to strengthen the literature on racial or ethnic mental health disparities in women.

Intraspecific diversity of Edwardsiella ictaluri isolates from diseased freshwater catfish, Pangasianodon hypophthalmus (Sauvage), cultured in the Mekong Delta, Vietnam.

A molecular epidemiology study was conducted on 90 Edwardsiella ictaluri isolates recovered from diseased farmed freshwater catfish, Pangasianodon hypophthalmus, cultured in the Mekong Delta, Vietnam. Thirteen isolates of E. ictaluri derived from diseased channel catfish, Ictalurus punctatus, cultured in the USA were included for comparison. All the E.ictaluri isolates tested were found to be biochemically indistinguishable. A repetitive (rep)-PCR using the single (GTG)(5) primer was shown to possess limited discriminatory power, yielding two similar DNA profiles categorized as (GTG)(5) -PCR group 1 or 2 among the Vietnam isolates and (GTG)(5) -PCR group 1 within the USA isolates. Macrorestriction analysis identified 14 and 22 unique pulsotypes by XbaI and SpeI, respectively, among a subset of 59 E. ictaluri isolates. Numerical analysis of the combined macrorestriction profiles revealed three main groups: a distinct cluster formed exclusively of the USA isolates, and a major and minor cluster with outliers contained the Vietnam isolates. Antibiotic susceptibility and plasmid profiling supported the existence of the three groups. The results indicate that macrorestriction analysis may be regarded as a suitable typing method among the E. ictaluri species of limited intraspecific diversity. Furthermore, the findings suggest that E. ictaluri originating from Vietnam may constitute a distinct genetic group.

Expression of Smad4, E-cadherin and beta-catenin in advanced colorectal cancer: a retrospective study.

PURPOSE: To correlate the expression of E-cadherin and beta-catenin with alterations of expression of Smad4 in advanced colorectal cancer (CRC). METHODS: Tissue specimens from 75 colorectal cancer cases (Dukes stage C and D) were tested for Smad4, E-cadherin and beta-catenin by the Avidin-Biotin immunoperoxidase method. The results were correlated with patients' clinicopathological parameters. RESULTS: Smad4 expression was lost or reduced in roughly 1 out of every 3 Dukes C and D CRCs. Association of Smad4 expression with other clinicopathological parameters was not noted. Association of expression of E-cadherin with other clinicopathological parameters was not noted, apart from tumor location. Expression of beta-catenin was not associated with clinicopathological parameters. Lack of expression of Smad4 was associated with lack of expression of both E-cadherin (<0.000) and beta-catenin (p<0.000). As regards the relation between E-cadherin and beta-catenin, the expression of each seemed to parallel the expression of the other (p<0.000). Beta-catenin was overexpressed in 68.5% of the specimens studied. CONCLUSION: Clinically advanced CRC is associated with a reduced or complete lack of expression of Smad4. Ecadherin and beta-catenin are expressed in parallel with each other and also with Smad4. This tumor suppressor role of Smad4 by affecting both E-cadherin and beta-catenin may indicate a novel pathway for metastatic tumor via cellular reshaping. The precise underlined mechanism(s) and the clinical significance of these findings remain to be determined.

The value of expression of EGFR, telomerase and topoisomerase IIα in malignant effusion smears before and after chemotherapy.

PURPOSE: To evaluate the significance of expression of epidermal growth factor receptor (EGFR), telomerase and topoisomerase IIα (topo IIα) in cells of malignant effusions of patients under chemotherapy. METHODS: We studied the expression of EGFR, telomerase and topo IIα in malignant effusion smears of 95 cancer patients before and after chemotherapy. Immunocytochemical and in situ hybridization techniques were applied. RESULTS: Positive expression before chemotherapy of telomerase, topo IIα and EGFR was found in 64.2, 63.2 and 69.5% of the cases, respectively; the expression of these markers following chemotherapy was 43.6, 28.2 and 53.8%, respectively. The stronger prognostic factor affecting survival before chemotherapy was telomerase (p=0.0002), whereas after chemotherapy the strongest factor was EGFR (p<0.0001). A positivity for all three markers following chemotherapy was associated with shorter survival compared with positivity for only 1 or 2 markers (p<0.0001) or with a negative expression. CONCLUSION: It seems that expression of EGFR, telomerase and topo IIα in malignant effusion smears is adversely affecting prognosis and survival.

The influence of anesthesia type on perioperative maternal glycemic-stress response during elective cesarean section: A prospective cohort study.

BACKGROUND: It has been known that the type of anesthesia can affect the stress response to surgery in form of hyperglycemia. This study aims to evaluate and compare the influence of general anesthesia (GA) and spinal anesthesia (SA) on pregnant women who are scheduled to undergo cesarean section (CS) and to understand the impact of obstetrical factors on the maternal hyperglycemic-stress response during CS. METHODS: Prospectively, we identified, assessed and followed those pregnant women who were scheduled to undergo elective CS surgery. The included group comprises any women who was scheduled to undergo an elective CS. The preoperative and postoperative blood glucose levels were measured and compared between both groups (GA and SA groups). RESULTS: The study included 302 patients who satisfied the inclusion and exclusion criteria of the study. GA was more commonly utilized in cesarean sections (56.6%) compared with SA (43.4%). The average gestational age at time of delivery was 37.4 weeks. The post-operative readings were significantly higher in the GA group with a mean sugar level of 110.1 mg/dL and a mean sugar level in the SA group of 87.7 mg/dL (P = 0.00). After performing multiple regression analysis, it was revealed that the type of anesthesia is the most independent factor affecting the postoperative sugar level. CONCLUSION: GA causes higher blood glucose concentrations than SA, which indicates that the impact of GA on hormonal stress response and metabolic hemostasis is greater than in SA.

The significance of baroreflex sensitivity in hypertensive subjects with stroke.

The relationship between baroreflex sensitivity expressed in ms/mm Hg (BRS) or in Hz/mm Hg (BRSf) in hypertensives with stroke in comparison with a group of stroke-free patients was evaluated. Twenty-six patients (aged 66+/-10 years, 11 females/ 15 males) with a history of the first ever ischemic stroke (6 months and more after stroke onset), which was neuroradiologically confirmed, were studied. These were compared to 30 hypertensive patients without history of any cardiovascular event, being of similar age and sex. BRS and BRSf were determined by the sequence and spectral methods (five-minute non-invasive beat-to-beat recording of blood pressure and inter-beat interval, controlled breathing at a frequency of 0.1 Hz). A significant negative correlation between spontaneous BRS and blood pressure (BP) represented by the grade of hypertension was present (r = -0.52, p<0.001). Differences between hypertensives with and without stroke were detected in BRS obtained by the spectral method (BRS spect p=0.0237, BRSf spect p=0.0285) or BRS obtained by sequence method (BRS seq p=0.0532, BRSf seq p=0.0273). The greatest decline in BRS values was in hypertensive stroke patients with metabolic syndrome, who had BRS values below 3 ms/mm Hg. We found out that BRS and BRSf were more impaired in stroke patients with essential hypertension even 6 months and more after stroke onset than in stroke-free hypertensive patients. This finding was independent of age-dependent decrease of BRS. Examination of baroreflex sensitivity as a marker of autonomic dysfunction along with global cardiovascular risk stratification of individuals seems to be a method for identifying patients at high residual cardiovascular risk.

A snapshot of Ischemic stroke risk factors, sub-types, and its epidemiology: Cohort study.

The burden of stroke can be substantially studied by establishing the functional consequences of stroke and its predictors on the population, economy and to guide rehabilitation efforts. This study aims to determine the subtypes, risk factors, and epidemiology of stroke in Jordan. Methods: A retrospective cohort study design was carried out to determine the risk factors and subtypes of stroke during 2017-2018. The study sample included 176 ischemic stroke patients of the King Abdullah University Hospital. Data was collected through medical records, which was then statistically analysed through frequencies and percentages. Results: Total 176 cases were identified out of which 101 (57.38%) were males and 75 (42.61%) were females and male to female ratio was 1.9:1. Hypertension was the commonest risk factor identified (50.56%), followed by diabetes mellitus (19.88%), hyperlipidaemia (15.34%), coronary artery disease (6.25%), atrial fibrillation (4.54%), and past history of stroke (1.13%). Risk factors such as hypertension (p = 0.007), diabetes (p = 0.000), coronary artery disease (p = 0.000) were significantly associated with subtypes of ischemic strokes. Conclusion: The study concludes that mean age of men was higher as compared to women in small vessel occlusion. The risk of ischemic stroke in patients with dyslipidaemia, diabetes mellitus, and hypertension was higher in middle-aged and old patients.

Successful Anesthetic Management in Cesarean Section for Pregnant Woman with COVID-19.

BACKGROUND The current COVID-19 pandemic highlights the importance of the mindful use of financial and human resources. Preventing infections and preserving resources and manpower are crucial in healthcare. It is important to ensure the ability of surgeons and specialized interventionalists to function through the pandemic. Until now, no justified protocol has been reported for the anesthetic management in cesarean section (CS). CASE REPORT A 29-year-old pregnant woman, G2P1 at 37+4 weeks of gestation, was referred to our center on March 28, 2020, after she had tested positive for COVID-19. She was stable and the CS was planned after she reached term. Through spinal anesthesia, CS was conducted. The anesthesia team was protected with full personal protection equipment. The operation was carried out smoothly without complication. A female neonate was delivered and was tested to be negative for COVID-19. No medical staff cross-infection was reported. CONCLUSIONS Special precautions should be considered when pregnant women are undergoing CS. Spinal anesthesia is preferred over general anesthesia.

Successful and Complete Recovery of the Ulnar Nerve After Eight Years of Chronic Injury Through Local Steroid Injections: A Case Report.

Peripheral neuropathy is a common neurodegenerative disease, with vastness of inducers and causalities. The acquired form peripheral neuropathy can be caused by traumatic injuries caused by nerve lacerations or compressions. Such injuries are usually followed by Wallerian degeneration, and inflammatory reaction. We present a case of a 33-year-old female with a chronic loss of the ulnar nerve function for 8 years after traumatic laceration. After that, she regained the functions of ulnar nerve after nerve stimulation by peri-ulnar nerve injection of methylprednisolone and lidocaine. The theory behind using steroids is related to the fact that the immune system could induce a secondary injury that interferes with the recovery. Many studies have shown effectiveness in using steroids alone or when combined with other substances on nerve regeneration in animal models. We believe that this is the first report of nerve recovery using local steroidal injections after a traumatic injury.

Spinal versus General Anesthesia for Patients with Parkinson's Disease.

BACKGROUND: Anesthesiologists prefer using general anesthesia (GA) in Parkinson's disease (PD). However, GA may mask neurological symptoms in the intraoperative period and exacerbate them postoperatively. Furthermore, the anesthetics used in GA have clear interactions with the drugs used to control PD. On the other hand, drugs used in spinal anesthesia (SA) might be safer for patients with PD. The aim of this study is to evaluate the effect of SA and GA in patients with PD who underwent hip fracture repairs. METHODS: Retrospectively, we identified those patients with PD who were admitted due to hip joint fracture. The following information were obtained: demographics, preoperative assessment information of the patients, type of anesthesia, and types of fractures and orthopedic procedures. In addition, intraoperative and postoperative complications were studied. The patients were divided based on the type of anesthesia received and were compared. RESULTS: Ten (8 males) patients with PD who underwent hip fracture surgery included in the study. Six patients received SA and 4 patients received GA. The mean age was 73.2 years. The preoperative assessment was not significant for all patients. Postoperatively, within the inpatient period, 3 out of 4 patients received GA developed complications (two atelectasis and urinary tract infection) while no patient developed complication from the SA group. Postoperative outpatient complications within one-month included 3 out of 4 cases in the GA group and only one complication in the SA group. The mean hospitalization period was 9 days for patients received GA and 5.8 days for patients received SA. CONCLUSION: This study reported less perioperative complications in the SA. Accordingly, further investigations and rp-randomized controlled trials evaluating various anesthetic techniques or drugs are needed.

Rituximab as a single agent in the management of adult patients with haemophilia A and inhibitors: marked reduction in inhibitor level and clinical improvement in bleeding but failure to eradicate the inhibitor.

Management of patients with severe haemophilia A who develop inhibitors is difficult and expensive. Standard treatment of this complication is immune tolerance induction (ITI) therapy, but is successful in only 60-80% of the patients. Failure of ITI results in a higher risk of morbidity and mortality. We used rituximab, an anti-CD20 antibody, in three patients with severe haemophilia A and inhibitors. Two patients with high-titre inhibitors had marked reduction in the inhibitor level; the third patient with low-titre inhibitor had a disappearance of the inhibitor. All patients improved clinically, with fewer bleeding episodes and a better quality of life. Inhibitor level increased with time in these patients, but the clinical benefit continued in two patients with high-titre inhibitors initially, after a follow-up of 48 and 22 months. One of the patients with concomitant human immunodeficiency virus (HIV) infection and a very low CD4 lymphocyte count developed severe truncal herpes zoster after the third weekly dose of rituximab. Caution is required in such patients, and we recommend avoiding rituximab use in HIV-infected patients with very low CD4 lymphocyte count. In conclusion, rituximab is useful in reducing the inhibitor level with clinical benefit in patients with severe haemophilia A and inhibitors, but it cannot eradicate the inhibitors for long periods with the currently used protocol of up to five doses.

Superficial parotidectomy under local anaesthesia.

The modern tendency of surgery is to perform a constantly rising number of operations under local anaesthesia. Superficial parotidectomy under local anaesthesia has not been widely attempted. However only few reports show that this kind of procedure could be feasible. If this is the case, standard assessment of benign parotid tumors will change radically.

Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.

Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti-programmed cell death 1 protein (PD-1) immunotherapy (n = 112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus nonresponders. Analysis of patient fecal microbiome samples (n = 43, 30 responders, 13 nonresponders) showed significantly higher alpha diversity (P < 0.01) and relative abundance of bacteria of the Ruminococcaceae family (P < 0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in responders, including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.

DNA demethylation induces SALL4 gene re-expression in subgroups of hepatocellular carcinoma associated with Hepatitis B or C virus infection.

Sal-like protein 4 (SALL4), an embryonic stem cell transcriptional regulator, is re-expressed by an unknown mechanism in poor prognosis hepatocellular carcinoma (HCC), often associated with chronic hepatitis B virus (HBV) infection. Herein, we investigated the mechanism of SALL4 re-expression in HBV-related HCCs. We performed bisulfite sequencing PCR of genomic DNA isolated from HBV-related HCCs and HBV replicating cells, and examined DNA methylation of a CpG island located downstream from SALL4 transcriptional start site (TSS). HBV-related HCCs expressing increased SALL4 exhibited demethylation of specific CpG sites downstream of SALL4 TSS. Similarly, SALL4 re-expression and demethylation of these CpGs was observed in HBV replicating cells. SALL4 is also re-expressed in poor prognosis HCCs of other etiologies. Indeed, increased SALL4 expression in hepatitis C virus-related HCCs correlated with demethylation of these CpG sites. To understand how CpG demethylation downstream of SALL4 TSS regulates SALL4 transcription, we quantified by chromatin immunoprecipitation (ChIP) assays RNA polymerase II occupancy of SALL4 gene, as a function of HBV replication. In absence of HBV replication, RNA polymerase II associated with SALL4 exon1. By contrast, in HBV replicating cells RNA polymerase II occupancy of all SALL4 exons increased, suggesting CpG demethylation downstream from SALL4 TSS influences SALL4 transcriptional elongation. Intriguingly, demethylated CpGs downstream from SALL4 TSS are within binding sites of octamer-binding transcription factor 4 (OCT4) and signal transducer and activator of transcription3 (STAT3). ChIP assays confirmed occupancy of these sites by OCT4 and STAT3 in HBV replicating cells, and sequential ChIP assays demonstrated co-occupancy with chromatin remodeling BRG1/Brahma-associated factors. BRG1 knockdown reduced SALL4 expression, whereas BRG1 overexpression increased SALL4 transcription in HBV replicating cells. We conclude demethylation of CpGs located within OCT4 and STAT3 cis-acting elements, downstream of SALL4 TSS, enables OCT4 and STAT3 binding, recruitment of BRG1, and enhanced RNA polymerase II elongation and SALL4 transcription.

Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.

Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs' therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy.

Mutations in exons 6 and 7 of TP53 gene correlate positively with serum tumor necrosis factor alpha independent of microsatellite instability in BAT26 gene in Egyptian patients with endometrial carcinoma.

UNLABELLED: Abnormalities in the TP53 gene are the most frequent genetic alterations in human cancers. The role and mechanism of TP53 mutations have been well studied in many types of human cancer. Similarly, the presence of microsatellite instability (MSI) in the DNA mismatch repair system (hMSH2) may provide evidence of faulty DNA mismatch repair. One of the most important locations of MSI is the BAT26 gene. In addition, deranged serum cytokines, especially elevated levels of the tumor necrosis factor (TNF) alpha, have been found in many gynecological conditions. AIMS: The current study aimed at evaluating mutations in exons 6 and 7 of TP53 and the presence of microsatellite instability in BAT26 of the hMSH2 system in Egyptian patients with endometrial carcinoma. The study also evaluated whether there was a correlation between any of these genetic mutations/instability and the tissue expression of estrogen and progesterone receptors and the serum TNF-alpha level. PATIENTS AND METHODS: The current study included 2 groups: a control group comprising 20 healthy women aged 52.21 +/- 5.80 years attending the clinic for routine checkups and 40 patients with endometrial cancer aged 55.30 +/- 6.21 years. Mutations in TP53 and BAT26 were evaluated using polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP) and automated sequencing while serum TNF-alpha was measured using an ELISA technique. Estrogen and progesterone receptor expression in biopsy tissue was evaluated using immunohistochemical staining. RESULTS: Seven of the 40 patients (17.5%) were positive for TP53 gene alterations in exon 6, while 9 patients (22.5%) were positive for TP53 alterations in exon 7. Cases positive for TP53 mutations had higher tumor stages. Ten patients (25%) showed MSI in BAT26. Nearly all patients with mutations in BAT26 had a strong family history for endometrial cancer (chi2=13.33, p<0.05). There was no positive correlation between the presence of MSI in the BAT26 gene and mutations in the TP53 gene or high serum TNF-alpha levels. Cases positive for TP53 mutations had a significantly higher level of TNF-alpha than cases negative for TP53 mutations (p<0.05). Cases showing mutations in exon 6 or 7 of TP53 showed a significantly higher intensity of immunohistochemical staining for estrogen and progesterone receptor expression in biopsy tissue than cases negative for mutations. (chi2=8.11, p<0.05). CONCLUSION: Our results suggest that the development of endometrial carcinoma is probably mediated through a multi-step carcinogenesis pathway and mutation of TP53 does not necessarily result from the presence of microsatellite instability in BAT26. The high serum TNF-alpha levels detected in our patients may represent an immunological antitumor response that was particularly evident in cases positive for TP53 mutations.