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

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease

The decomposition of starch grains in soils: implications for archaeological residue analyses

Recent research involving starch grains recovered from archaeological contexts has highlighted the need for a review of the mechanisms and consequences of starch degradation specifically relevant to archaeology. This paper presents a review of the plant physiological and soil biochemical literature pertinent to the archaeological investigation of starch grains found as residues on artefacts and in archaeological sediments. Preservative and destructive factors affecting starch survival, including enzymes, clays, metals and soil properties, as well as differential degradation of starches of varying sizes and amylose content, were considered. The synthesis and character of chloroplast-formed 'transitory' starch grains, and the differentiation of these from 'storage' starches formed in tubers and seeds were also addressed. Findings of the review include the higher susceptibility of small starch grains to biotic degradation, and that protective mechanisms are provided to starch by both soil aggregates and artefact surfaces. These findings suggest that current reasoning which equates higher numbers of starch grains on an artefact than in associated sediments with the use of the artefact for processing starchy plants needs to be reconsidered. It is argued that an increased understanding of starch decomposition processes is necessary to accurately reconstruct both archaeological activities involving starchy plants and environmental change investigated through starch analysis. (C) 2004 Elsevier Ltd. All rights reserved

MEDULLOBLASTOMA

BACKGROUND: LMD in children with recurrent medulloblastoma and other PNETs carries a poor prognosis and novel therapies are urgently needed to improve disease control. Somatostatin receptor-2 (SSR-2)is overexpressed in medulloblastoma and other central PNETs and can serve as a target for radionuclide tagged somatostatin analogues like 177Lu-DOTA-TATE that has shown considerable efficacy in adults with SSR-2 positive neuro-endocrine tumors. As a preliminary step prior to testing this agent in children with LMD, we performed an efficacy study of i.t. 177Lu-DOTA-TATE in athymic rats bearing LMD from MBL. METHODS: The subarachnoid space was accessed through the animal's cervical spine and a catheter was threaded along the dorsal aspect of spinal cord to the lumbar region and injected with 1 x 107 D341 human MBL cells and treatment initiated 3 days later. Groups of 10 animals received a single i.t. dose of 2, 3, or 5 mCi of 177Lu- DOTA-TATE or saline control. Animals were followed 300 days for survival. RESULTS: Treatment with 2 mCi resulted in an increase in median survival of 58.3% compared with saline control (p < 0.001). Treatment with 5.0 mCi of 177Lu-DOTA-TATE increased median survival by 75.0% compared with the saline control group while a single dose of 3.0 mCi 177Lu-DOTA-TATE increased median survival compared with saline controls by 519.4%. Long-term survivors were seen in 0 of 10 animals treated with saline, 4 of 11 treated with 3 mCi, and 3 of 12 treated with 5.0 mCi. CONCLUSION: Intrathecal 177Lu- DOTA TATE is efficacious in controlling LMD from medulloblastoma in athymic rats. A phase I trial of this agent is being planned in children with LMD from recurrent MBL and other CNS PNETs. INTRODUCTION: Medulloblastoma/PNET is the most common malignant brain tumor in children. For children older than 3 years, the treatment of high risk group includes surgery, craniospinal (CSI) radiation therapy (30-36 Gy) plus local boost radiotherapy (54-56 Gy) and adjuvant chemotherapy, such as cisplatinum, carboplatin, lomustine, cyclophosphamide, and vincristine. The results have demonstrated 5-year overall survival (OS) of 40-60%. This study aimed to evaluate the outcomes of high risk medulloblastoma/PNET patients who were treated with radiation and adjuvant chemotherapy. METHODS: Patients were diagnosed with high risk medulloblastoma/PNET according to the histopathology, medulloblastoma risk classification by an evidence of metastasis or the residual tumor more than 1.5 cm2 and evidence of residual tumor after surgery in PNET. Treatment protocol was CSI RT 36 Gy with local boost at tumor 54-56 Gy. Two to four weeks after RT, patients received 8 courses of chemotherapy consisting of cyclophosphamide 800 mg/m2, day 1-3 and vincristine 2 mg/m2, week 1-3, alternated with carboplatin 200 mg/m2, day 1-3 and etoposide 150 mg/m2, day 1-3. RESULTS: Total of 25 patients, male: female of 2.6:1 and mean ± SD for age of 9.7± 3.0 years, were enrolled. The 5-year progression free survival and OS were 41.6± 11.7% and 61.5± 12.9%,respectively. The age and sex did not determine the difference in outcomes. The hematotoxic side effect, according to the National Cancer Institute's Common Terminology Criteria, were grade 4 leucopenia 60%, grade 4 neutropenia 60%, grade 4 anemia 20%, grade 4 thrombocytopenia 16%, grade 3 leucopenia 20%, grade 3 neutropenia 20%, grade 3 anemia 40%, and grade 3 thrombocytopenia 36%. Febrile neutropenia was found in 11 patients (44%). CONCLUSION: The present study demonstrated the similar outcomes of high risk medulloblastoma/PNET with the previous studies. Although, the grade 3 and 4 hematologic toxicity was high, no treatment related death was found. OBJECTIVE: Recent investigations revealed an association between transcriptional subtypes and morphological features in medulloblastoma. Since both characteristics are of prognostic significance, a precise correlation between them should be well established. Therefore we re-examined paediatric nodular medulloblastoma tumours for correlation with molecular subtypes of disease. METHODS: Paediatric patients with previously diagnosed desmoplastic/nodular (D/N) or medulloblastoma with extensive nodularity (MBEN) histopathology were re-analysed by two neuropathologists. In addition to H&E-stained slides, reticulin preparations were simultaneously analysed from the same FFPE blocks. For identification of transcriptional subtypes of tumours immunohistopathological analyses were performed using a panel of representative antibodies. MYCC amplification was detected by FISH. RESULTS: Altogether 28 tumours with original MBEN or D/N diagnosis where molecular subtypes could be determined were identified. All tumours with MBEN histology belonged to SHH group and displayed distinctive reticulin-positive internodular reaction. However, only ∼60% of tumours with original D/N diagnosis were reticulin-positive. They belonged to SHH type, were mainly infantile and patients are still alive. Among reticulin-negative tumours only two were of the SHH type and were subsequently reclassified as classic and anaplastic tumours with pseudonodules. Importantly, all remaining reticulin-negative tumours with a presence of nodules in H&E staining belonged to the non-WNT,SHH type. Therefore the original diagnosis was again reclassified as classic or anaplastic tumours with pseudonodules. Patients from this group were only males, with median age 14 years old, one had MYCC amplification and two of them died because of disease. Therefore, non-WNT,SHH tumours did not display typical desmoplastic/nodular histology accompanied by reticulin positive reaction as opposite to truly D/N tumours being typical for SHH molecular group (p < 0.001). CONCLUSION: Reticulin staining is necessary to distinguish two different biologically and clinically group of nodular tumours which appear morphologically similar under H&E staining alone. BACKGROUND: In the PNET4 European randomised controlled trial, children with standard risk medulloblastoma were allocated to HFRT or to STRT. All received maintenance chemotherapy. Event-free survival was similar between the two treatment arms. HFRT was associated with worse growth and better questionnaire-based executive function 6.1 years post-diagnosis, especially in children aged <8 years at diagnosis (Kennedy et al., IJROBP, 2014). Therefore the aim of this study was to compare cognitive outcomes between treatment arms. METHODS: Neuropsychological data was collected prospectively in 137 patients from Germany, France, Italy and Sweden. Using results of the Wechsler Intelligence Scales, Kaufman Assessment Battery for Children, and Raven's progressive matrices, we generated: Full scale IQ (FSIQ), Verbal IQ (VIQ), Performance IQ (PIQ), working memory index (WMI) and speed of processing index (PSI). RESULTS: Among the 137 participants, [n = 71 HFRT, n = 66 STRT, 63.5% males; mean (SD, range) age at diagnosis 9.3 years (3.2, 4 to 17.6), 40.9% aged <8 years at diagnosis; age at assessment 15.6 years (3.7, 8.3 to 25). Mean (SD, range) FSIQ in all participants was 88 (19, 40-137); mean intergroup difference [95% CIs] (3.88, [-2.66 to 10.41], p = .24). No difference was found in children aged > 8 years at diagnosis. In children aged <8 at diagnosis, VIQ was significantly higher in children receiving HFRT compared to STRT; a similar trend was found for PSI but not for PIQ,WMI and FSIQ (mean inter-group differences [95% CIs]): VIQ 12.02 [2.37 to 21.67], p = 0.02; PIQ (2.73 [-7.89 to 13.35], p > .10); WMI (5.20 [-2.07 to 12.47], p > .10), PSI (10.91 [-1.54 to 23.36], p = .08; FSIQ (5.28 [-4.23 to 14.79], p > .10). CONCLUSION: HFRT was associated with higher verbal IQ in children aged <8 years at diagnosis, consistent with the previous report using questionnaire-based data. Effect sizes were small, albeit with 10 point inter-group differences within their 95% CIs. Preoperative chemotherapy is often used in pediatric oncology to treat metastatic disease and facilitate the surgery of the primary tumor, but not for brain tumors. A first pilot study showed in 2004 the feasibility and effectiveness of preoperative chemotherapy in treating high-risk medulloblastomas. Seventy-one patients were treated for a metastatic medulloblastoma between 2002 and 2010 at Gustave Roussy. Two strategies were compared in intention to treat. Forty-two children were operated at the time of the diagnosis (group A) and the 29 others children were treated with 2 courses of carboplatin and etoposide (group B) after histological diagnosis (biopsy) and before a delayed surgery. Children of group A received the two courses of carboplatin and etoposide afterwards. The rest of the protocol (high-dose chemotherapy and cranio-spinal irradiation) was similar in the both groups. Complete neuropsychological testing, including intelligence quotient measurements, was scheduled before surgery, before radiotherapy and every year thereafter. MRI performed after neo-adjuvant chemotherapy showed an objective response in 24 patients (83%) and a stable disease in 4 patients (14%). Complete excision rate was significantly higher in group B (100% versus 64%, p = 0.00248) without any difference in postoperative complication rate. Medulloblastoma cells could still be evidenced despite preoperative chemotherapy. The median Total Intelligence Quotient (TIQ) was 81 and 90 in group A and B respectively (p = 0.02543). This difference was even more significant in young children (77 vs 91 points for groupe A and B, respectively). Hydrocephalus and brain radiotherapy dose were not associated with TIQ. Neo-adjuvant chemotherapy had no negative impact on local disease control (79 versus 83%). Event-free survival and overall survival at 3 years were 54 versus 62% and 58 versus 68% respectively (p = NS). Neo-adjuvant chemotherapy in metastatic medulloblastoma is safe and could have a positive impact on neuropsychological outcome and completeness of surgery. BACKGROUND: We prospectively evaluated histopathological findings and molecular variables, which have shown to impact prognosis of medulloblastoma patients, for outcome prediction in homogenously treated metastatic medulloblastoma patients. METHODS: One hundred twenty-three patients aged 4-21 years, diagnosed from 2001 to 2007, received systemic induction chemotherapy and intraventricular methotrexate, followed by hyperfractionated radiotherapy, and maintenance chemotherapy. From 86 patients paraffin material was available for immunohistochemical analysis to determine the activation status of the wingless (WNT) pathway, by immunostaining for β-catenin and sequencing of CTNNB1. In 81 of those 86 patients, material was available for gene amplification assessment of MYCC and MYCN by multiplex ligation-dependent probe amplification. RESULTS: Tumors with nuclear β-catenin immunopositivity showed excellent outcome (n = 4, all classic histology, 3 / 4 with CTNNB1 mutation; 5-year event-free (EFS) and overall survival (OS): 100%) compared to patients with tumors lacking nuclear β-catenin staining (n = 82; 5-year rates: 63% and 72%, respectively; p = 0.134 for EFS, p = 0.213 for OS). Patients with tumors characterized by MYC amplification (n = 5; MYCC, n = 2; MYCN, n = 3; all classic histology despite one case with MYCC amplification showing large cell histology) had poor outcome (20% for EFS and OS, respectively) when compared to patients with non-MYCC/MYCN amplified tumors (n = 76; 5-year EFS and OS: 65% and 75%, respectively; p = 0.011 for EFS, p < 0.001 for OS). Based on histopathological and molecular findings, we identified three risk groups: Favorable- (β-catenin nucleopositive and/or desmoplastic histology (n = 7; one death of disease), n = 11; 5-year EFS and OS 89 ± 11%), poor- (MYCC/MYCN amplification and/or anaplastic or large cell histology, n = 6; 5-year EFS and OS 33 ± 19%), and intermediate-risk group (n = 64; 5-year EFS and OS 61 ± 7%, and 72 ± 6%, respectively; p = 0.020 for EFS, and p = 0.002 for OS). CONCLUSION: Histopathological subtyping together with molecular features (WNT pathway and MYCC/MYCN amplification status) differentiate three risk groups in homogenously treated metastatic medulloblastoma patients. Supported by Deutsche Kinderkrebsstiftung. BACKGROUND: A number of different second neoplasms have been reported in patients with neuroblastoma including brain tumors. None of these second cancers have occurred with sufficient frequency to indicate a specific relationship between neuroblastoma and any other neoplasm except in rare cancer syndromes. OBJECTIVE: We report a case of medulloblastoma in a child 5 months after successful treatment of metastatic neuroblastoma. DESIGN AND METHOD: A MEDLINE search was conducted for queries including “Children”, “medulloblastoma” and ‘neuroblastoma”. Relevant papers were selected for literature review. RESULT: A 10 months old female presented with 2-month history of right eye proptosis. CT scan of the abdomen showed a right adrenal mass with liver metastasis. Brain MRI revealed disease at the right orbital fossa extends to middle cranial fossa with no intracranial disease. Pathology of the right adrenal mass confirmed neuroblastoma with non amplified N myc. The patient was classified as intermediate risk disease and started on chemotherapy consisted of vincristine, cyclophosphamide, cisplatin, dacarbazine, ifosphamide and Adriamycin followed by 5 cycles of Accutane. Surveillance MIBG revealed no evidence of residual disease. Five months later, she had a new onset of trouble walking. CT and MRI of the brain showed a mass in the right cerebellar hemisphere with hydrocephalus. Complete Surgical resection of the mass was done and pathology revealed anaplastic medullobastoma. The patient initiated chemoradiation treatment for medulloblastoma. Her treatment was stopped because of disseminated fungal infection. She is currently receiving metronomic therapy with cyclophosphamide and topotecan and has been clinically stable. Molecular genetic tests are pending for familial cancer syndromes. CONCLUSION: We report a case of metachronous medullobastoma after treatment of metastatic neuroblastoma in a two year-old child. The occurrence of metachronous neoplasms is rare and challenging to treat. Cancer familial syndromes like neurofibromatosis type 1 and Simpson-Golabi-Behmel syndrome need to be excluded. Group 3 medulloblastoma with elevated c-MYC has the worst prognoses of the four molecular subgroups. To generate a genetically defined model of this disease, we transformed human fetal cerebellar stem cells with MYC along with hTERT, dominant negative p53 and constitutively active AKT. The resulting xenografts showed morphological similarities to large cell/anaplastic medulloblastoma, leptomeningeal and spinal dissemination, and had a gene expression profile closely aligned with Group 3 primary tumors. Because MYC over-expression leads to increased glutamine metabolism and glutamine addiction in other cancers, we hypothesized that MYC-driven MB would exhibit increased glutamine metabolism and be sensitive inhibitors of glutamine metabolism. In both our human stem cell derived and established medulloblastoma cell lines, MYC expression positively correlates with increased expression of glutaminolytic enzymes. Inhibition of glutamine metabolism was achieved using two glutamine analogs, acivicin and 6-diazo-5-L-norleucine (DON). In our human stem cell models, MYC-transformed cells experienced a significant decrease in proliferation and an increase in apoptosis after acivicin treatment (p < 0.005), while SV40-transformed cells were unaffected. Both compounds also significantly decreased growth and increased apoptosis of the high-MYC MB cell lines D425Med and D283Med. In xenograft experiments using D283Med, fewer mice receiving acivicin developed flank tumors, and the resulting tumors were significantly smaller (80.9 mm3 treated vs 273.8 mm3 untreated). Glutaminase knockdown using short hairpins also significantly decreased growth of D425Med and D283Med. In summary, we present a novel human cerebellar stem cell based model of Group 3 medulloblastoma, and data suggesting that glutamine metabolism may be a therapeutic target in MYC-driven MB