Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

The evolution of lung cancer and impact of subclonal selection in TRACERx

Lung cancer is the leading cause of cancer-associated mortality worldwide. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource

The evolution of non-small cell lung cancer metastases in TRACERx

Metastatic disease is responsible for the majority of cancer-related deaths. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse

Genomic–transcriptomic evolution in lung cancer and metastasis

Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic–transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary–metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Device closure of patent ductus arteriosus in interrupted inferior vena cava

Introduction: A 3-year-old child, weighing 8 kg, presented with patent ductus arteriosus (PDA) and interrupted inferior vena cava (IVC). The patient underwent successful PDA device closure via transjugular route after failing attempt at femoral venous route. Case summary: PDA device closure was attempted via femoral venous route but could not be accomplished due to difficult curves to negotiate. Following this, PDA could be closed by device from jugular venous route with ease. Discussion: Interrupted IVC poses challenges for PDA device closure and various alternative routes are described like internal jugular, transhepatic, or femoral venous – azygous route. Our case describes difficulties associated with femoral venous route and advantages of jugular venous route in such cases. Conclusion: Internal jugular access is a safe and feasible method of PDA device closure in cases of interrupted IVC even in smaller children

Outcomes of primary repair of sternal cleft defects: Providing a “bony cover”

Background : Sternal clefts are rare congenital anterior chest wall defects created by a lack of midline thoracic fusion. Various surgical repairs have been proposed to provide protection to underlying viscera in these defects. Aim : This study aims to perform primary sternal cleft repair using techniques, leading to the provision of a complete bony cover and to assess their outcomes on follow-ups. Materials and Methods : During 2009–2020, seven patients were referred to our unit with sternal defects. Out of them, four infants with sternal clefts underwent primary repair using bilateral perichondrial flap creation of the sternal bars and sliding costal chondrotomy at our institute. In one of them with a wider defect, bilateral “intraperiosteal” sliding clavicular osteotomy was additionally performed to achieve tension-free closure. Results : Satisfactory surgical outcomes were achieved with an uneventful postoperative period. On follow-up, all four patients are thriving well and have a stable anterior chest wall. Those with follow-ups longer than 5 years showed evidence of bone formation. Conclusion : Bony cover to the heart can be provided in all varieties of sternal cleft defects using primary surgical repair early in infancy. The delay in surgical correction increases the complexity of the procedure and may require the use of prosthetic material which has its own disadvantages

Strategies to mitigate inflammation in management of complex congenital heart disease complicated by “multisystem inflammatory syndrome in children”

A 6-month-old boy, a case of Shone's complex, presented in decompensated state was found to have severe mitral stenosis along with multisystem inflammatory syndrome in children (MISC) warranting urgent surgical intervention. Various modalities including cytokine-adsorbing hemofilter were used to target inflammation. Postoperatively, the child recovered from low cardiac output accompanied by decrease in the levels of inflammatory markers, inopressors, and ventilatory requirements. Open heart surgery in itself is a proinflammatory process and is best avoided during the active inflammatory phase of MISC. In the rare and unavoidable circumstance exemplified by this index case, multipronged strategy targeting inflammation as described can be successfully implemented

A comparative randomised controlled parallel group study of efficacy and tolerability of labetalol versus methyldopa in the treatment of new onset hypertension during pregnancy. Int J Life Sci Pharma Res 2012;2:L23-31. DOI: 10.5455/2320-1770.ijrcog2013020

ABSTRACT Hypertensive disorders in pregnancy remain one of the major causes of maternal and perinatal mortality in developing as well as developed countries and can result in hospital admission, pre-eclampsia and possible premature delivery. Antihypertensive drugs are often used to lower blood pressure to prevent this progression to adverse outcomes for the mother and the fetus. Methyldopa has often been used as control while comparing the effects of different dugs. Labetalol has also been successfully used for treatment of hypertensive disorders in pregnancy. Hence, we wanted to compare the efficacy and tolerability of labetalol versus methyldopa in pregnancy induced hypertension (PIH) in an Indian population. We carried out a prospective randomised controlled parallel group study on 90 outpatients as well as inpatients of the antenatal ward of Obstetrics and Gynaecology department of our tertiary care teaching hospital. Pregnant patients (20-40 weeks gestational age) newly diagnosed with blood pressure of ≥140/90mmHg and single ton with vertex presentation were included in the study. All patients with a history of hypertension, diabetes, Rh iso-immunisation, depression, congestive heart failure, heart block or bronchial asthma, patients at risk of major obstetric complications -antepartum haemorrhage, malnutrition, twins and hydramnios during the current pregnancy and patients who had already received antihypertensive drugs were excluded. 45 patients each were randomised to either of the two treatment arms -oral methyldopa or oral/IV labetalol. Difference in BP measurements pre-and post-treatments (on 8 th day) were analysed by applying paired&apos;t&apos; test for the difference in pre-and post-treatment values. For inter group analysis, we applied chi-square test, using Epi Info statistical software version 3.3. A P-value &lt; 0.05 was regarded as significant with 95% confidence limits. Adverse events were documented and subjected to causality analysis by Naranjo&apos;s scale. There was no statistically significant difference in antihypertensive efficacy between the methyldopa and labetalol groups. Adverse drug reactions were possible to probable and occurred less with labetalol. However, despite equal efficacy and better tolerability, effect on fetal and maternal outcomes determines whether labetalol is better than methyldopa in PIH