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Introduction/Objective Homologous recombination deficiency (HRD) cancers have high levels of genetic instability, potentially being targets for platinum agents or poly-ADP ribose polymerase inhibitors. Tumor mutational burden (TMB), which is used to guide immunotherapy, is thought to be associated with HRD. This study aimed to evaluate the frequency of HRD and its correlation with other genomic parameters in melanoma. Methods/Case Report A total of 14 cases with the diagnosis of melanoma were found in the genomic database between March 1, 2021 to July 30, 2021. One case had an EWSR1-ATF1 translocation and was excluded. Copy number variations and absence of heterozygosity detection were analyzed by the NxClinical software (BioDiscovery, El Segundo, CA). HRD was scored by three DNA-based measures of genomic instability (loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale transitions (LST)). HRD-LOH is the number of LOH regions > 15 Mb and do not cross the centromere. HRD-TAI is the number of regions > 10 Mb with allelic imbalance that extend to one of the subtelomeres and do not cross the centromere. HRD-LST is the number of break points between regions > 10 Mb. A high HRD score and LOH percentage were defined as ≥ 42 and ≥ 16%, respectively. Results (if a Case Study enter NA) Of the 13 cases, 10 had a high TMB and 3 had a low TMB. A high HRD score was found in 3 cases; high LOH percentage was found in 4 cases. PDL-1 was expressed in 8 of the 11 cases tested. A high HRD score correlated with high LOH percentage by Pearson’s chi-squared test (p < 0.01). No significant association was found between TMB and HRD score or LOH percentage. Common alterations among cases with high TMB included mutations in NRAS (3/13; 23.1%), CDKN2A (2/13; 15.4%), BRAF (2/13; 15.4%), BRCA2 (2/13; 15.4%), RAF1 (2/13; 15.4%), RET (1/13; 7.7%), IDH1 (1/13; 7.7%), PALB2 (1/13; 7.7%), BRCA1 (1/13; 7.7%), ERBB2 (1/13; 7.7%), NF1 (1/13; 7.7%), MLH1 (1/13; 7.7%), ATM (1/13; 7.7%) and MET (1/13; 7.7%). One case had amplifications in CCND1, FGF 3/4/19 and MET. Among cases with low TMB, alterations included MYC amplification (1/3; 33.3%) and BRAF mutations (2/3; 66.6%). Conclusion In our study, HRD score is not associated with TMB status. There is a strong correlation between HRD score and LOH percentage, suggesting that LOH is a major component in the genomic scarring seen in HRD. HRD may be an independent biomarker of immunogenicity to guide immunotherapy.

BACKGROUND: Clonidine is a presynaptic alpha‐2‐adrenergic receptor agonist that has been used for many years to treat hypertension and other conditions, including chronic pain. Adverse events associated with systemic use of the drug have limited its application. Topical use of drugs has been gaining interest since the beginning of the century, as it may limit adverse events without loss of analgesic efficacy. Topical clonidine (TC) formulations have been investigated for almost 20 years in clinical trials. This is an update of the original Cochrane Review published in Issue 8, 2015. OBJECTIVES: The objective of this review was to assess the analgesic efficacy and safety of TC compared with placebo or other drugs in adults aged 18 years or above with chronic neuropathic pain. SEARCH METHODS: For this update we searched the Cochrane Register of Studies Online (CRSO), MEDLINE (Ovid), and Embase (Ovid) databases, and reference lists of retrieved papers and trial registries. We also contacted experts in the field. The most recent search was performed on 27 October 2021. SELECTION CRITERIA: We included randomised, double‐blind studies of at least two weeks' duration comparing TC versus placebo or other active treatment in adults with chronic neuropathic pain. DATA COLLECTION AND ANALYSIS: Two review authors independently screened references for eligibility, extracted data, and assessed risk of bias. Any discrepancies were resolved by discussion or by consulting a third review author if necessary. Where required, we contacted trial authors to request additional information. We presented pooled estimates for dichotomous outcomes as risk ratios (RRs) with 95% confidence intervals (CIs), and continuous outcomes as mean differences (MDs) with P values. We used Review Manager Web software to perform the meta‐analyses. We used a fixed‐effect model if we considered heterogeneity as not important; otherwise, we used a random‐effects model. The review primary outcomes were: participant‐reported pain relief of 50% or greater; participant‐reported pain relief of 30% or greater; much or very much improved on Patient Global Impression of Change scale (PGIC); and very much improved on PGIC. Secondary outcomes included withdrawals due to adverse events; participants experiencing at least one adverse event; and withdrawals due to lack of efficacy. All outcomes were measured at the longest follow‐up period. We assessed the certainty of evidence using GRADE and created two summary of findings tables. MAIN RESULTS: We included four studies in the review (two new in this update), with a total of 743 participants with painful diabetic neuropathy (PDN). TC (0.1% or 0.2%) was applied in gel form to the painful area two to three times daily. The double‐blind treatment phase of three studies lasted 8 weeks to 85 days and compared TC versus placebo. In the fourth study, the double‐blind treatment phase lasted 12 weeks and compared TC versus topical capsaicin. We assessed the studies as at unclear or high risk of bias for most domains; all studies were at unclear risk of bias for allocation concealment and blinding of outcome assessment; one study was at high risk of bias for blinding of participants and personnel; two studies were at high risk of attrition bias; and three studies were at high risk of bias due to notable funding concerns. We judged the certainty of evidence (GRADE) to be moderate to very low, downgrading for study limitations, imprecision of results, and publication bias. TC compared to placebo There was no evidence of a difference in number of participants with participant‐reported pain relief of 50% or greater during longest follow‐up period (12 weeks) between groups (risk ratio (RR) 1.21, 95% confidence interval (CI) 0.78 to 1.86; 179 participants; 1 study; low certainty evidence). However, the number of participants with participant‐reported pain relief of 30% or greater during longest follow‐up period (8 to 12 weeks) was higher in the TC group compared with placebo (RR 1.35, 95% CI 1.03 to 1.77; 344 participants; 2 studies, very low certainty evidence). The number needed to treat for an additional beneficial outcome (NNTB) for this comparison was 8.33 (95% CI 4.3 to 50.0). Also, there was no evidence of a difference between groups for the outcomes much or very much improved on the PGIC during longest follow‐up period (12 weeks) or very much improved on PGIC during the longest follow‐up period (12 weeks) (RR 1.06, 95% CI 0.76 to 1.49 and RR 1.82, 95% CI 0.89 to 3.72, respectively; 179 participants; 1 study; low certainty evidence). We observed no evidence of a difference between groups in withdrawals due to adverse events and withdrawals due to lack of efficacy during the longest follow‐up period (12 weeks) (RR 0.34, 95% CI 0.04 to 3.18 and RR 1.01, 95% CI 0.06 to 15.92, respectively; 179 participants; 1 study; low certainty evidence) and participants experiencing at least one adverse event during longest follow‐up period (12 weeks) (RR 0.65, 95% CI 0.14 to 3.05; 344 participants; 2 studies; low certainty evidence). TC compared to active comparator There was no evidence of a difference in the number of participants with participant‐reported pain relief of 50% or greater during longest follow‐up period (12 weeks) between groups (RR 1.41, 95% CI 0.99 to 2.0; 139 participants; 1 study; low certainty evidence). Other outcomes were not reported. AUTHORS' CONCLUSIONS: This is an update of a review published in 2015, for which our conclusions remain unchanged. Topical clonidine may provide some benefit to adults with painful diabetic neuropathy; however, the evidence is very uncertain. Additional trials are needed to assess TC in other neuropathic pain conditions and to determine whether it is possible to predict who or which groups of people will benefit from TC.

e17567 Background: Platinum-taxane chemotherapy and surgical debulking are the optimal treatment for patients with advanced ovarian cancer. While initial response rates are above 80%, tumor recurrence occurs in about 70 to 80% of patients. Cells with defects in homologous recombination repair (HRR) are susceptible to cell death induced by Poly (ADP-ribose) polymerase inhibitors (PARPi). These drugs are used to treat recurrent neoplasms that have BRCA1 or BRCA2 mutations or homologous recombination deficiency (HRD). Low tumor percentage in test samples, which is common in clinical practice, is often overlooked when addressing HRD tests. The goal of this study was to determine the optimal tumor content rate needed to detect HRD changes. Methods: A total of sixteen ovarian neoplasms were studied. These samples were sequenced using Illumina TSO500 NGS and interpreted using NxClinical software 6.1. In all cases, HRD scores were evaluated. A score of ≥42 was determined to be HR-deficient and a score < 42 was considered HR-proficient. We aimed to identify the optimal tumor percentage needed for detection of HRD alterations. HRD scores were calculated with tumor percentages of 70%, 60%, 40%, and 20%. Additionally, chemotherapy response scores (CRS) were available in 8 of 16 cases. We correlated the CRS with HRD scores. Results: In this project, visualization of a 523-gene cancer exome panel was shown to be 66.7% sensitive and 100% specific for detecting genomic scars (HRD score). 68.75% of cases showed low HRD score and 31.25% of cases showed a high HRD score. Next generation sequencing (NGS) results for most specimens are adequate with a tumor content rate of 70%. CRS1 cases were HR-proficient. For CRS2 and CRS3 we had mixed results. Conclusions: HRD correlates with platinum sensitivity in epithelial ovarian tumors, which has clinical significance as a predictor of sensitivity to PARPi. During treatment, tissue samples are obtained at different times points and sources, some at diagnosis/surgical debulking and some after neoadjuvant therapy. After neoadjuvant treatment, tumor volume is reduced. Cytology specimens are convenient for obtaining tumoral cells, but tumor volumes are usually small. Profiling tumors of low volume decrease the chances of detecting a patient’s eligibility for targeted maintenance. Our next steps will evaluate the performance of tissue microarrays using the Infinium CytoSNP-850K array compared to NGC cytogenomics at low tumor volumes.