Brain Metastasis Growth Kinetics: A Novel Prognosticator for Stereotactic Radiotherapy.

AIMS: The rate of size change in brain metastasis may have clinical implications on tumour biology and prognosis for patients who receive stereotactic radiotherapy (SRT). We analysed the prognostic value of brain metastasis size kinetics and propose a model for patients with brain metastases treated with linac-based SRT in predicting overall survival. MATERIALS AND METHODS: We analysed the patients receiving linac-based SRT between 2010 and 2020. Patient and oncological factors, including the changes in sizes of brain metastasis between the diagnostic and stereotactic magnetic resonance imaging, were collected. The associations between prognostic factors and overall survival were assessed using Cox regression with least absolute selection and shrinkage operator (LASSO) checked by 500 bootstrap replications. Our prognostic score was calculated by evaluating the most statistically significant factors. Patients were grouped and compared according to our proposed score, Score Index for Radiosurgery in Brain Metastases (SIR) and Basic Score for Brain Metastases (BS-BM). RESULTS: In total, 85 patients were included. We developed the prognostic model based on the most important predictors of overall survival: growth kinetics, i.e. percentage change in brain metastasis size per day between the diagnostic and stereotactic magnetic resonance imaging (hazard ratio per 1% increase, 1.32; 95% confidence interval 1.06-1.65), extracranial oligometastatic diseases (≤5 involvements) (hazard ratio 0.28; 95% confidence interval 0.16-0.52) and the presence of neurological symptoms (hazard ratio 2.99; 95% confidence interval 1.54-5.81). Patients with scores 0, 1, 2 and 3 had a median overall survival of 44.4 (95% confidence interval 9.6-not reached), 20.4 (95% confidence interval 15.6-40.8), 12.0 (95% confidence interval 7.2-22.8) and 2.4 (95% confidence interval 1.2-not reached) years, respectively. The optimism-corrected c-indices for our proposed model, SIR and BS-BM were 0.65, 0.58 and 0.54, respectively. CONCLUSIONS: Brain metastasis growth kinetics is a valuable metric for survival outcomes of SRT. Our model is useful in identifying patients with brain metastasis treated with SRT with different overall survival.

Cyanotoxin exposure and hepatocellular carcinoma.

Cyanobacteria are ubiquitous in aquatic and terrestrial environments worldwide and include a number of species producing tumor-promoting hepatotoxins. Human exposure to cyanobacteria and cyanotoxins primarily occurs though ingestion of contaminated drinking water and food sources. In a Northeast U.S. population, we recently reported an independent association of oral cyanobacteria with risk of hepatocellular carcinoma (HCC). In a cross-sectional study of 55 HCC patients in Hawaii, U.S.A., serum microcystin/nodularin (MC/NOD), cylindrospermopsin (CYN), and anabaenopeptin (AB) were measured by ELISA. In a subset of 16 patients, cyanotoxin levels were compared by tumor expression of over 700 genes analyzed via the Nanostring nCounter Fibrosis panel. MC/NOD, CYN, and AB were detected in all HCC patients. MC/NOD and CYN levels significantly varied by etiology with the highest levels in cases attributed to metabolic risk factors, specifically, hyperlipidemia, type 2 diabetes, and non-alcoholic fatty liver disease/non-alcoholic steatohepatitis. Cyanotoxin levels were significantly positively correlated with tumor expression of genes functioning in PPAR signaling and lipid metabolism. Our study provides novel albeit limited evidence that cyanotoxins may a role in the pathogenesis of HCC through the dysregulation of lipid metabolism and progression of hepatic steatosis.

Can Quantitative Measures of T790M Allelic Fraction Predict Survival Outcomes in Patients Receiving Osimertinib? Observations From an Early Access Programme.

AIMS: Multiple studies have shown conflicting results on the correlation between the EGFR T790M quantitative level and survival outcomes in osimertinib-treated patients. We sought to validate such correlations using data from an osimertinib early access programme (EAP) providing access for metastatic non-small cell lung cancer patients with limited treatment options. PATIENTS AND METHODS: This observational, multicentre, retrospective analysis included EAP participants who received osimertinib until disease progression, intolerable toxicities or death. Digital droplet polymerase chain reaction-based quantitative plasma genotyping was carried out upon disease progression and data were analysed to explore the relationships between T790M mutant allele fraction (MAF), T790M copy number, MAF ratio and post-osimertinib overall survival. Real-world treatment outcomes and safety were also evaluated. RESULTS: Data from 156 EAP participants were analysed (median follow-up 37.7 months). The median age was 62 years, 62.2% were women, 79.5% were never-smokers, 60.9% had Eastern Cooperative Oncology Group performance status 0/1. In patients with available plasma data (n = 114), T790M MAF (%) showed no significant relationships with overall survival (hazard ratio 1.02; 95% confidence interval 0.99-1.04) or time to treatment discontinuation (TTD) (hazard ratio 1.01; 95% confidence interval 0.98-1.04). Absolute T790M copy number and T790M to activating EGFR mutation MAF ratio also showed no prognostic value. The investigator-assessed response rate was 42.3% and the disease control rate was 85.5%. The median TTD was 15.8 (95% confidence interval 12.5-18.5) months and the median overall survival was 22.3 (95% confidence interval 18.6-26.1) months. CONCLUSION: T790M MAF did not correlate with TTD or overall survival in this EAP cohort but limitations should not be overlooked. Observed survival outcomes and the toxicity profile were consistent with data from other real-world series.

Real-world prevalence of programmed death ligand 1 expression in locally advanced or metastatic non-small-cell lung cancer: The global, multicenter EXPRESS study.

OBJECTIVES: Tumor programmed death ligand 1 (PD-L1) expression is associated with improved clinical benefit from immunotherapies targeting the PD-1 pathway. We conducted a global, multicenter, retrospective observational study to determine real-world prevalence of tumor PD-L1 expression in patients with NSCLC. MATERIALS AND METHODS: Patients ≥18 years with histologically confirmed stage IIIB/IV NSCLC and a tumor tissue block (≤5 years old) obtained before treatment were identified in 45 centers across 18 countries. Tumor samples from eligible patients were selected consecutively, when possible. PD-L1 expression was evaluated at each center using the PD-L1 IHC 22C3 pharmDx kit (Agilent, Santa Clara, CA, USA). RESULTS: Of 2617 patients who met inclusion criteria, 2368 (90%) had PD-L1 data; 530 (22%) patients had PD-L1 TPS ≥ 50%, 1232 (52%) had PD-L1 TPS ≥ 1%, and 1136 (48%) had PD-L1 TPS < 1%. The most common reason for not having PD-L1 data (n = 249) was insufficient tumor cells (<100) on the slide (n = 170 [6%]). Percentages of patients with PD-L1 TPS ≥ 50% and TPS ≥ 1%, respectively were: 22%/52% in Europe; 22%/53% in Asia Pacific; 21%/47% in the Americas, and 24%/55% in other countries. Prevalence of EGFR mutations (19%) and ALK alterations (3%) was consistent with prior reports from metastatic NSCLC studies. Among 1064 patients negative for both EGFR mutation and ALK alteration, the percentage with PD-L1 TPS ≥ 50% and TPS ≥ 1%, respectively, were 27% and 53%. CONCLUSIONS: This is the largest real-world study in advanced NSCLC to date evaluating PD-L1 tumor expression using the 22C3 pharmDx kit. Testing failure rate was low with local evaluation of PD-L1 TPS across a large number of centers. Prevalence of PD-L1 TPS ≥ 50% and TPS ≥ 1% among patients with stage IIIB/IV NSCLC was similar across geographic regions and broadly consistent with central testing results from clinical trial screening populations.

The Role of Radiotherapy in Epidermal Growth Factor Receptor Mutation-positive Patients with Oligoprogression: A Matched-cohort Analysis.

AIMS: Almost all patients with epidermal growth factor receptor (EGFR) mutations will develop resistance to first-line EGFR tyrosine kinase inhibitors (TKIs). The management of oligoprogression on EGFR TKI is controversial. Irradiating progressing tumours may potentially eradicate the resistant clone and allow continuation of EGFR TKI, but the clinical data remain sparse. We aimed to assess the effect of radiotherapy on survival outcomes in patients with oligoprogression in a matched-cohort study. MATERIALS AND METHODS: This was a retrospective matched-cohort study comparing patients with EGFR mutation-positive stage IV non-small cell lung cancer receiving radiotherapy versus chemotherapy for progression. Patients in the radiotherapy group received radiotherapy (mainly stereotactic ablative radiotherapy) for oligoprogression, whereas the chemotherapy group received only systemic chemotherapy upon progression. Key prognostic factors including gender, age, performance status, time to first progression and mutation subtypes were matched. RESULTS: Twenty-five patients with oligoprogression (radiotherapy group) were identified, and a matched chemotherapy group with the same number of patients was generated. The median duration of follow-up was 24.3 and 34 months for the radiotherapy and chemotherapy groups, respectively. The median overall survival of the radiotherapy group was significantly longer than the chemotherapy group, 28.2 versus 14.7 months (P = 0.026). The median progression-free survival (PFS) was 7.0 and 4.1 months after radiotherapy and chemotherapy, respectively (P = 0.0017). The use of radiotherapy was an independent predictive factor of overall survival and PFS in multivariate analysis. Only one patient had ≥grade 3 toxicity after radiotherapy. The frequency of secondary T790M mutation and subsequent Osimertinib exposure were similar in both groups. CONCLUSION: Radiotherapy may effectively extend EGFR TKI therapy for patients with oligoprogression on TKI. Improved PFS and overall survival were observed, although potential biases should not be overlooked. Further randomised studies are warranted.

Improving the emergency department management of post-chemotherapy sepsis in haematological malignancy patients.

OBJECTIVE: To review the result of the implementation of treatment protocol for post-chemotherapy sepsis in haematological malignancy patients. DESIGN: Case series with internal comparison. SETTING: Accident and Emergency Department, Queen Elizabeth Hospital, Hong Kong. PATIENTS: Febrile patients presenting to the Accident and Emergency Department with underlying haematological malignancy and receiving chemotherapy within 1 month of Accident and Emergency Department visit between June 2011 and July 2012. Similar cases between June 2010 and May 2011 served as historical referents. MAIN OUTCOME MEASURES: The compliance rate among emergency physicians, the door-to-antibiotic time before and after implementation of the protocol, and the impact of the protocol on Accident and Emergency Department and hospital service. RESULTS: A total of 69 patients were enrolled in the study. Of these, 50 were managed with the treatment protocol while 19 patients were historical referents. Acute myeloid leukaemia was the most commonly encountered malignancy. Overall, 88% of the patients presented with sepsis syndrome. The mean door-to-antibiotic time of those managed with the treatment protocol was 47 minutes versus 300 minutes in the referent group. Overall, 86% of patients in the treatment group met the target door-to-antibiotic time of less than 1 hour. The mean lengths of stay in the emergency department (76 minutes vs 105 minutes) and hospital (11 days vs 15 days) were shorter in those managed with the treatment protocol versus the historical referents. CONCLUSION: Implementation of the protocol can effectively shorten the door-to-antibiotic time to meet the international standard of care in neutropenic sepsis patients. The compliance rate was also high. We proved that effective implementation of the protocol is feasible in a busy emergency department through excellent teamwork between nurses, pharmacists, and emergency physicians.

Improvement in hepatic insulin sensitivity after Roux-en-Y gastric bypass in a rat model of obesity is partially mediated via hypothalamic insulin action.

AIMS/HYPOTHESIS: Roux-en-Y gastric bypass (RYGB) surgery, an effective treatment for morbid obesity, commonly leads to near complete resolution of type 2 diabetes. The underlying mechanisms, however, remain unclear and factors other than weight loss alone may be involved. METHODS: To determine whether increased hypothalamic insulin sensitivity after RYGB drives the rapid improvement in glucose metabolism, high-fat-fed rats received either an insulin receptor (IR) antisense vector or a control lentiviral vector that was microinjected into the ventromedial hypothalamus (VMH). Six weeks later, rats underwent RYGB or control gastrointestinal surgery. RESULTS: Four weeks after surgery, weight loss was comparable in RYGB and surgical controls. Nevertheless, only RYGB rats that received the control vector demonstrated both improved hepatic and peripheral insulin sensitivity. Insulin suppressed hepatic glucose production (HGP) by 50% (p < 0.05) with RYGB, whereas the effect of insulin on HGP was completely absent in VMH IR knockdown (IRkd) rats. By contrast, both RYGB groups displayed an identical twofold increase in insulin-stimulated peripheral glucose uptake. The animals that underwent control gastrointestinal surgery failed to show any improvement in either hepatic or peripheral insulin sensitivity; VMH IRkd did not influence the magnitude of insulin resistance. CONCLUSIONS/INTERPRETATION: Our findings demonstrate that RYGB surgery in high-fat-fed obese rats enhances hepatic and peripheral insulin sensitivity independently of weight loss. The improved hepatic, but not the peripheral, response to insulin is mediated centrally at the level of the VMH. These data provide direct evidence that the metabolic benefits of RYGB surgery are not simply a consequence of weight loss but likely in part involve the central nervous system.

Laparoscopic versus open repair for strangulated groin hernias: 188 cases over 4 years.

INTRODUCTION: Currently transabdominal pre-peritoneal and totally extraperitoneal repairs are the two standard laparoscopic approaches for groin hernia repair. However, they are still largely reserved for uncomplicated elective cases. To determine whether laparoscopic groin hernia repair can achieve similar results for acute strangulated hernias as laparoscopic cholecystectomy for acute cholecystitis, we analyzed and compared the results of emergency laparoscopic surgery and open repair for strangulated groin hernias performed by our team over the past 4 years. METHODS: This is a retrospective analysis of prospectively collected data. We analyzed the results of patients admitted between January 2007 and January 2011 who were diagnosed with acute strangulated groin hernia and underwent emergency open or laparoscopic hernia repair during the same admission. Patients' demographic details, mode of presentation, type of hernia, intraoperative findings, operative time, postoperative course and complications were compared. RESULTS: In total, 188 patients fulfilled the criteria for emergency surgical repair of strangulated groin hernias; 57 received laparoscopic and 131 received open repairs. The mean operative time was 79.82 ± 29.571 min and 80.75 ± 35.161 min, respectively. More laparotomies were performed in the open group (19 vs 0). The wound infection rate was significantly higher in the open group (12 vs 0). The mean hospital stay was shorter in the laparoscopic group (4.39 days vs 7.34 days). There was no mesh infection in either group. Recurrence occurred one case in the laparoscopic group and in three cases in the open group. CONCLUSIONS: Emergency laparoscopic repair for strangulated groin hernias is feasible and appears to have a lower morbidity relative to open repair. Further study should be performed to evaluate its full potential.

Single-incision transabdominal preperitoneal and totally extraperitoneal repair for inguinal hernia: early experience from a single center in Asia.

INTRODUCTION: Laparoscopic inguinal hernia repair is currently one of the most commonly performed minimally invasive surgical procedures. In recent years, single-incision operations have been developed to further reduce the invasiveness of the surgery. Herein, we report our early experience with single-incision laparoscopic inguinal hernia repair in Asia, with both the transabdominal preperitoneal (TAPP) and totally extraperitoneal (TEP) approaches. METHODS: This is a retrospective review of prospectively collected data on a cohort of consecutive patients with inguinal hernia who underwent single-incision laparoscopic inguinal hernia repair in a minimal access surgical center in Hong Kong between January 2010 and January 2011. RESULTS: Our cohort consists of 15 patients who underwent single-incision laparoscopic inguinal hernia; 13 were unilateral and two were bilateral hernias. The mean age was 59.8 years old (range, 28-74 years). The overall mean operative time was 59.53 min (range, 25-120 min). For unilateral hernia repair, the mean operative time was 56 min (range, 25-75 min) and 48.5 min (range, 41-55 min) for TAPP and TEP, respectively. In all cases single-incision laparoscopic hernia repair was successfully performed, no additional trocars were required, and there were no conversions to conventional laparoscopic or open inguinal hernia repair. All patients were discharged on the same day as the procedure. CONCLUSION: Single-incision laparoscopic inguinal hernia is feasible in both TEP and TAPP approaches. The procedure should be performed by laparoscopic surgeons with a high level of experience in single-incision surgery. Further randomized trials should be performed to evaluate the full potential and clinical application of single-incision TAPP and TEP.

A survey of prenatal first-trimester aneuploidy screening among Hong Kong specialist obstetricians.

OBJECTIVES: To determine the background, qualifications, and certification status of specialists currently performing first trimester screening in Hong Kong, the extent of their participation (and the laboratories they use) in quality assurance programmes, and their willingness to provide follow-up data for auditing purposes. DESIGN: Questionnaire survey. SETTING: Hong Kong. PARTICIPANTS: A survey was mailed to all registered Hong Kong specialist obstetricians. Results were reported using descriptive statistics. RESULTS: The response rate was 32% (106/331). Overall, 73% offered universal screening to all pregnant women. The majority (72%) most commonly performed first trimester screening for their patients. Sixty-six (62%) of the respondents performed nuchal translucency scanning; only 30 (45%) were accredited by a recognised body to perform such scans. Only 33% of the relevant laboratories used by specialists participated in external quality assurance programmes specific to Down's syndrome screening undertaken by a third party organisation. CONCLUSIONS: According to our data, first trimester screening has become one of the most common screening strategies for Down's syndrome in Hong Kong, but there is a need to assess the quality of such prenatal screening for aneuploidy to ensure its efficacy.

First-trimester fetal nasal bone length in an ethnic Chinese population.

OBJECTIVES: To determine reference ranges of fetal nasal bone length (NBL) in a Chinese population and to assess the value of NBL measurement in screening for chromosomal defects in the first trimester. METHODS: In this prospective study the fetal profile was examined and the fetal NBL and crown-rump length (CRL) were measured in Chinese women presenting with singleton pregnancies for first-trimester screening for aneuploidy between January 2004 and June 2007. Screening was performed on the basis of nuchal translucency (NT) measurement and maternal serum free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A levels. RESULTS: NBL was measured in 7543 fetuses, of which 7517 were euploid. The best fit equation for median NBL in euploid fetuses in relation to CRL was: NBL (mm) = 0.4593 + (0.0186 x CRL(mm)). The NBL for gestational age (GA, in days) was given by the equation NBL(mm) = 0.2392 + (0.0027 x GA). There was no correlation between log(10)(NBL multiples of the median (MoM)) and log(10)(NT MoM) in unaffected pregnancies (r = - 0.009; P = 0.43). Only two of the 11 cases with trisomy 21 had an NBL outside the 5(th) or 95(th) centiles of the reference range for euploid fetuses. CONCLUSION: Reference ranges for NBL in a Chinese population suitable for screening for aneuploidy between 11 and 13 + 6 weeks' gestation have been derived. The NBL in Chinese fetuses is similar to that of other ethnic groups. However, unlike the determination of presence vs. absence of the nasal bone, NBL measurement is unlikely to further improve screening for aneuploidy.

Stapled technique for acute thrombosed hemorrhoids: a randomized, controlled trial with long-term results.

PURPOSE: This study was designed to compare stapled vs. conventional hemorrhoidectomy for patients with acute thrombosed hemorrhoids. METHODS: Forty-one patients with acute thrombosed hemorrhoids were randomized into: 1) stapled hemorrhoidectomy (PPH group; n = 21), and 2) open hemorrhoidectomy (open group; n = 20). Emergency surgery was performed with perioperative data and complications were recorded. Patients were followed up by independent assessors to evaluate pain, recurrence, continence function, and satisfaction at regular intervals. RESULTS: The median follow-up for the PPH group and open group were 59 and 56 weeks, respectively. There was no significant difference in terms of the hospital stay, complication rate, and continence function; however, the mean pain intensity in the first postoperative week was significantly less in the PPH group (4.1 vs. 5.7, P = 0.02). Patients in the PPH group recovered significantly faster in terms of the time to become analgesic-free (4 vs. 8.5 days, P < 0.01), time to become pain-free (9 vs. 20.5 days, P = 0.01), resumption of work (7 vs. 12.5 days, P = 0.01), and time for complete wound healing (2 vs. 4 weeks, P < 0.01). On long-term follow-up, significantly fewer patients in the PPH group complained of recurrent symptoms (0 vs. 5, P = 0.02). The overall symptom improvement and patients' satisfaction were significantly better in the PPH group (90 vs. 80 percent, P = 0.03 and +3 vs. +2, P < 0.01 respectively). CONCLUSIONS: Stapled hemorrhoidectomy is safe and effective for acute thrombosed hemorrhoids. Similar to elective stapled procedure, emergency stapled excision has greater short-term benefits compared with conventional excision: diminished pain, faster recovery, and earlier return to work. Long-term results and satisfaction were excellent.

Lansoprazole reduces ulcer relapse after eradication of Helicobacter pylori in nonsteroidal anti-inflammatory drug users--a randomized trial.

AIM: To study whether prophylaxis with lansoprazole could prevent relapse of ulcers after eradication of Helicobacter pylori in patients with NSAID-related peptic ulcers. METHODS: Patients who presented with peptic ulcers and were found to be infected with H. pylori while receiving NSAIDs were recruited into the study. They received, twice daily, lansoprazole 30 mg, amoxicillin 1 g and clarithromycin 500 mg for 1 week, followed by lansoprazole 30 mg daily for 4 weeks. Patients with healed ulcers and H. pylori eradicated were given naproxen 750 mg daily, and randomly assigned to receive lansoprazole 30 mg daily or no treatment for 8 weeks. The primary endpoint was the cumulative recurrence of symptomatic and complicated ulcers. RESULTS: At the end of the 8-week treatment period, significantly fewer patients (1/22, 4.5%, 95% confidence interval [CI] 0-23) in the lansoprazole group compared with the group that received H. pylori eradication alone (9/21, 42.9%, 95% CI 22-66) developed recurrence of symptomatic and complicated ulcers (log rank test P=0.0025). CONCLUSIONS: Lansoprazole significantly reduced the cumulative relapse of symptomatic and complicated ulcers in patients requiring NSAIDs after eradication of H. pylori.

Diagnosing Kikuchi disease on fine needle aspiration biopsy: a retrospective study of 44 cases diagnosed by cytology and 8 by histopathology.

OBJECTIVE: To study the accuracy of fine needle aspiration (FNA) diagnosis of Kikuchi lymphadenitis (KL). STUDY DESIGN: Retrospective review of all cases of FNA biopsy of lymph nodes in which KL was diagnosed or suggested. False positive cases were studied. Cases of KL diagnosed by histopathology were examined for the false negative rate of FNA diagnosis. RESULTS: Forty-four cases of KL diagnosed or suggested by FNA were found. Five of eight cases were confirmed on lymph node excision. The false positive rate was 37.5%. One case was nonspecific reactive changes. Two cases were proven to be tuberculous lymphadenitis by culture. Eight cases of KL diagnosed by lymph node excisional biopsy had prior FNA. Four were diagnosed as or suspected to be KL. The false negative rate was 50%. CONCLUSION: The overall accuracy of FNA diagnosis of KL was 56.25%. Detailed study offalse positive cases and knowledge of other conditions suggested that overreliance on certain cytologic features and the morphologic erlap between KL and tuberculous lymphadenitis could have been the reasons for the inaccuracies.

Computed tomography 21 days after chemotherapy, three-dimensional estimates of metastatic volume and the need for surgery in patients with germ cell cancer.

OBJECTIVE: To assess whether the response visible on computed tomography (CT) 21 days after the first course of chemotherapy in patients with nonseminomatous germ cell tumour predicts the need for surgery and whether three-dimensional (3D) reconstruction adds to the diagnostic accuracy. PATIENTS AND METHODS: CT scans from 52 patients treated with cisplatin-based chemotherapy were assessed for tumour shrinkage by measuring the changes of a one-dimensional (1D) measurement of the maximum transverse diameter, and comparing CT scans before, 21 days after the first course and at the end of chemotherapy (1D method). In a subset of patients, using a special formula, the 1D-derived 2D and 3D shrinkage (2Dder and 3Dder) were compared with four other computed or calculated methods (1D, 2D, 3Dcalc, 3Dcomp). RESULTS: At day 21, in 32 of 52 patients (62%) there was < 50% tumour shrinkage using the 1D assessment; 21 of them (66%) needed surgery, compared with none of the 20 patients with > 50% tumour shrinkage by day 21 (chi2 = 22.83, P < 0.001). The 1D method showed significantly less shrinkage than all the other methods but when this was used to derive a 3D shrinkage, assuming the mass to be spherical (3Dder), it was not statistically different from that of 3Dcomp. CONCLUSIONS: The assessment of the response from 1D CT scan estimates 21 days after initiating chemotherapy identifies a subgroup of patients who have a high probability of needing surgery. Although expected to be more accurate, the 3Dcomp estimate of tumour shrinkage was no better than the 3Dder estimate.