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Candidate mechanisms of acquired resistance to first-line osimertinib in EGFR-mutated advanced non-small cell lung cancer
Get PDFOsimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits EGFR-TKI-sensitizing and EGFR T790M resistance mutations. In the Phase III FLAURA study (NCT02296125), first-line osimertinib improved outcomes vs comparator EGFR-TKIs in EGFRm advanced non-small cell lung cancer. This analysis identifies acquired resistance mechanisms to first-line osimertinib. Next-generation sequencing assesses circulating-tumor DNA from paired plasma samples (baseline and disease progression/treatment discontinuation) in patients with baseline EGFRm. No EGFR T790M-mediated acquired resistance are observed; most frequent resistance mechanisms are MET amplification (n = 17; 16%) and EGFR C797S mutations (n = 7; 6%). Future research investigating non-genetic acquired resistance mechanisms is warranted. © 2023. The Author(s).ope
Trastuzumab plus FOLFOX for HER2-positive biliary tract cancer refractory to gemcitabine and cisplatin: a multi-institutional phase 2 trial of the Korean Cancer Study Group (KCSG-HB19-14)
No full textBackground: HER2 overexpression or amplification, which is present in 15% of all cases of biliary tract cancer, has been identified as a druggable molecular target by genomic profiling. In the phase 3 ABC-06 trial, the folinic acid, fluorouracil, and oxaliplatin (FOLFOX) regimen showed a survival benefit compared with active symptom control as second-line therapy for biliary tract cancer. We aimed to evaluate the clinical activity of FOLFOX plus anti-HER2 antibody trastuzumab as a second-line or third-line treatment for HER2-positive biliary tract cancer.
Methods: This study was an investigator-initiated, open-label, non-randomised, single-arm, multi institutional, phase 2 trial in participants aged 19 years or older with HER2-positive (defined as immunohistochemistry 3+ or immunohistochemistry 2+ and in-situ hybridisation positive or ERBB2 gene copy number ≥6·0 by next-generation sequencing) biliary tract cancer (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer) who progressed on chemotherapy containing gemcitabine and cisplatin (with one or two previous chemotherapy lines permitted). In cycle one, patients received intravenous trastuzumab-pkrb at 6 mg/kg on day 1, and FOLFOX (consisting of intravenous oxaliplatin [85 mg/m2], intravenous leucovorin [200 mg/m2], and fluorouracil [400 mg/m2 bolus] all on day 1, and fluorouracil [2400 mg/m2 infusion] on days 1-2. In cycle two onwards, participants were administered intravenous trastuzumab-pkrb at 4 mg/kg and FOLFOX, every 2 weeks, until unacceptable toxic effects or disease progression. The primary endpoint of the study was objective response rate based on RECIST version 1.1, assessed in the participants who completed at least one study cycle. The response rate threshold for a positive objective response rate was 25%. This trial is registered with ClinicalTrials.gov (NCT04722133) and is ongoing.
Findings: 34 participants were enrolled between June 26, 2020, and Sept 1, 2021. At the time of data cutoff on May 1, 2022, median follow-up was 13·0 months (IQR 11·0-16·9), with three participants remaining on treatment. Ten patients had a partial response and 17 had stable disease; the overall response rate was 29·4% (95% CI 16·7-46·3) and the disease control rate was 79·4% (95% CI 62·9-89·9). Median progression-free survival was 5·1 months (95% CI 3·6-6·7); median overall survival was 10·7 (95%CI 7·9-not reached). The most common treatment-related grade 3 or 4 adverse events were neutropenia (ten [29%] participants with grade 3 and nine [26%] with grade 4), grade 3 anaemia (five [15%] participants), and grade 3 peripheral sensory neuropathy (four [12%] participants). There were no treatment-related cardiac toxic effects or deaths. The overall health assessment (EuroQoL-VAS) score did not change significantly throughout the treatment. Sensory and motor neuropathy symptoms as assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy twenty-item scale questionnaire did not change significantly over time.
Interpretation: For HER2-positive biliary tract cancer, second-line or third-line trastuzumab biosimilar plus FOLFOX exhibited promising activity with acceptable toxicity, warranting further investigation.
Funding: Boryung Pharmaceutical, Celltrion, National Research Foundation of Korea, National R&D Program for Cancer Control through the National Cancer Center, Yonsei University College of Medicine.
Copyright © 2022 Elsevier Ltd. All rights reserved.restrictio
Pre- and Immediate Post-Kasai Portoenterostomy Shear Wave Elastography for Predicting Hepatic Fibrosis and Native Liver Outcomes in Patients With Biliary Atresia
Get PDFObjective: To evaluate the feasibility of ultrasound shear wave elastography (SWE) for predicting hepatic fibrosis and native liver outcomes in patients with biliary atresia.
Materials and Methods: This prospective study included 33 consecutive patients with biliary atresia (median age, 8 weeks [interquartile range, 6–10 weeks]; male:female ratio, 15:18) from Severance Children’s Hospital between May 2019 and February 2022. Preoperative (within 1 week from surgery) and immediate postoperative (on postoperative days [PODs] 3, 5, and 7) ultrasonographic findings were obtained and analyzed, including the SWE of the liver and spleen. Hepatic fibrosis, according to the METAVIR score at the time of Kasai portoenterostomy and native liver outcomes during postsurgical follow-up, were compared and correlated with imaging and laboratory findings. Poor outcomes were defined as intractable cholangitis or liver transplantation. The diagnostic performance of SWE in predicting METAVIR F3–F4 and poor hepatic outcomes was analyzed using receiver operating characteristic (ROC) analyses.
Results: All patients were analyzed without exclusion. Perioperative advanced hepatic fibrosis (F3–F4) was associated with older age and higher preoperative direct bilirubin and SWE values in the liver and spleen. Preoperative liver SWE showed a ROC area of 0.806 and 63.6% (7/11) sensitivity and 86.4% (19/22) specificity at a cutoff of 17.5 kPa for diagnosing F3–F4. The poor outcome group included five patients with intractable cholangitis and three undergoing liver transplantation who showed high postoperative liver SWE values. Liver SWE on PODs 3–7 showed ROC areas of 0.783–0.891 for predicting poor outcomes, and a cutoff value of 10.3 kPa for SWE on POD 3 had 100% (8/8) sensitivity and 73.9% (17/23) specificity.
Conclusion: Preoperative liver SWE can predict advanced hepatic fibrosis, and immediate postoperative liver SWE can predict poor native liver outcomes in patients with biliary atresia.ope
Parotid gland evaluation of menopausal women with xerostomia using the iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL-IQ) method of MRI: a pilot study
No full textOBJECTIVES: This study aimed to analyze the quantitative fat fraction (FF) of the parotid gland in menopausal females with xerostomia using the iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL-IQ) method.
METHODS: A total 138 parotid glands of 69 menopausal females were enrolled in our study and participants were divided into normal group and xerostomia group. The xerostomia group was divided into those with or without Sjögren's syndrome. Participants underwent IDEAL-IQ sequences of MRI and the stimulated salivary flow test (s-SFR). The unpaired t-test was used to compare the FFs between the normal and xerostomia groups and between the subgroups with and without Sjögren's syndrome. The correlation between FF and s-SFR was analyzed by Pearson's correlation.
RESULTS: Excellent intra- and interobserver agreement during the measurement of FFs by IDEAL-IQ method (ICC>0.99, respectively). FF value in the xerostomia group was statistically significantly higher than the value in the normal group (p 0.05). Within the xerostomia group, FF value correlated negatively with s-SFR (p < 0.08).
CONCLUSIONS: The FF of the parotid gland was higher in the xerostomia group than in the normal group and FF value and s-SFR showed a negative correlation. Analyses of the FF using IDEAL-IQ in menopausal females can be helpful for the quantitative diagnosis of xerostomia.restrictio
Artificial intelligence assistance for women who had spot compression view: reducing recall rates for digital mammography
No full textBackground: Mammography yields inevitable recall for indeterminate findings that need to be confirmed with additional views.
Purpose: To explore whether the artificial intelligence (AI) algorithm for mammography can reduce false-positive recall in patients who undergo the spot compression view.
Material and Methods: From January to December 2017, 236 breasts from 225 women who underwent the spot compression view due to focal asymmetry, mass, or architectural distortion on standard digital mammography were included.
Three readers who were blinded to the study purpose, patient information, previous mammograms, following spot compression views, and any clinical or pathologic reports retrospectively reviewed 236 standard mammograms and determined the necessity of patient recall and the probability of malignancy per breast, first without and then with AI assistance. The performances of AI and the readers were evaluated with the recall rate, area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and accuracy.
Results: Among 236 examinations, 8 (3.4%) were cancers and 228 (96.6%) were benign. The recall rates of all three readers significantly decreased with AI assistance (P < 0.05). The reader-averaged recall rates significantly decreased with AI assistance regardless of breast composition (fatty breasts: 32.7% to 24.1%m P =0.002; dense breasts: 33.6% to 21.2%, P < 0.001). The reader-averaged AUC increased with AI assistance and was comparable to that of standalone AI (0.835 vs. 0.895; P =0.234). The reader-averaged specificity (71.2% to 79.8%, P < 0.001) and accuracy (71.3% to 79.7%, P<0.001) significantly improved with AI assistance.
Conclusion: AI assistance significantly reduced false-positive recall without compromising cancer detection in women with focal asymmetry, mass, or architectural distortion on standard digital mammography regardless of mammographic breast density.restrictio
Genotypic Profile and Clinical Characteristics of CRX-Associated Retinopathy in Koreans
Get PDFThis study aimed to investigate the clinical characteristics of Korean patients with retinal dystrophy associated with pathogenic variants of cone rod homeobox-containing gene (CRX). We retrospectively enrolled Korean patients with CRX-associated retinal dystrophy (CRX-RD) who visited two tertiary referral hospitals. Pathogenic variants were identified using targeted panel sequencing or whole-exome sequencing. We analyzed clinical features and phenotypic spectra according to genotype. Eleven patients with CRX-RD were included in this study. Six patients with cone-rod dystrophy (CORD), two with macular dystrophy (MD), two with Leber congenital amaurosis (LCA), and one with retinitis pigmentosa (RP) were included. One patient (9.1%) had autosomal recessive inheritance, and the other ten patients (90.9%) had autosomal dominant inheritance. Six patients (54.5%) were male, and the mean age of symptom onset was 27.0 ± 17.9 years. At the first presentation, the mean age was 39.4 ± 20.6 years, and best-corrected visual acuity (BCVA) (logMAR) was 0.76 ± 0.90 in the better eye. Negative electroretinography (ERG) was observed in seven (63.6%) patients. Nine pathogenic variants were identified, including two novel variants, c.101-1G>A and c.898T>C:p.(*300Glnext*118). Taken together with the variants reported in prior studies, all variants within the homeodomain are missense variants, whereas most variants downstream of the homeodomain are truncating variants (88%). The clinical features of pathogenic variants within the homeodomain are either CORD or MD with bull's eye maculopathy, whereas variants downstream of the homeodomain cause more diverse phenotypes, with CORD and MD in 36%, LCA in 40%, and RP in 24%. This is the first case series in Korea to investigate the CRX-RD genotype-phenotype correlation. Pathogenic variants downstream of the homeodomain of the CRX gene are present as RP, LCA, and CORD, whereas pathogenic variants within the homeodomain are mainly present as CORD or MD with bull's eye maculopathy. This trend was similar to previous genotype-phenotype analyses of CRX-RD. Further molecular biologic research on this correlation is required.ope
Primary Localized Cutaneous Nodular Amyloidosis on Scalp Successfully Treated with Excision
Get PDFPrimary localized cutaneous nodular amyloidosis (PLCNA) is the rarest form of cutaneous amyloidosis, characterized by nodular deposits of light chain amyloids in the dermis and subcutaneous tissue, without apparent systemic involvement. One or several nodules are preferably located on the extremities, trunk, or face. The most useful stain for detecting amyloid fibrils is Congo red, which, when combined with polarized light, makes amyloid proteins appear apple-green under a microscope. Immunohistochemical staining can help identify the exact type of amyloid proteins. Although the exact etiology of PLCNA is unclear, removal of nodules by shaving or surgical excision has shown good results. To the best of our knowledge, only seven cases of PLCNA have yet been reported in the Korean literature. In three of these cases, the patients had lesions on the scalp. Herein, we present a case of a 34-year-old male with PLCNA on the scalp with all the results of immunohistochemical evaluation.ope
Various Applications of Purse-String Suture and Its Cosmetic Outcome in Cutaneous Surgical Defects
Get PDFBackground: Purse-string suture is a simple technique to reduce wound size and to achieve complete or partial closure of skin defects.
Objective: To classify situations in which purse-string sutures can be utilized and to assess the long-term size reduction and cosmetic outcome of the final scar.
Methods: Patients (93 from Severance hospital and 12 from Gangnam Severance hospital) in whom purse-string sutures were used between January 2015 and December 2019 were retrospectively reviewed. Wound site, final reconstruction method, repair duration, final wound size, and Vancouver scar scale were assessed.
Results: A total of 105 patients were reviewed. Lesions were located on the trunk (48 [45.7%]), limbs (32 [30.5%]), and face (25 [23.8%]). Mean ratio of wound length/primary defect length was 0.79±0.30. Multilayered purse-string suture showed the shortest duration from excision to final repair (p<0.001) and most effectively minimized the scar size (scar to defect size ratio 0.67±0.23, p=0.002). The average Vancouver scar scale measured at the latest followup visit at least 6 months postoperatively was 1.62, and the risk of hypertrophic scarring was 8.6%. There was no significant difference in the Vancouver scar scale and the risk of hypertrophic scarring between the different surgical method groups.
Conclusion: Purse-string sutures can be utilized in many stages of reconstruction to effectively reduce scar size without compromising the final cosmetic outcome. Copyright © The Korean Dermatological Association and The Korean Society for Investigative Dermatology.ope
Mixed neuroendocrine-non-neuroendocrine carcinoma (MiNEN) in gallbladder with liver metastasis of neuroendocrine carcinoma component: a case report
Get PDFMixed neuroendocrine-non-neuroendocrine neoplasms of the gallbladder are rare with a lack of established standardized therapeutic strategies. We report a case of gallbladder mixed neuroendocrine-non-neuroendocrine neoplasm with liver metastasis of neuroendocrine carcinoma. A patient who underwent radical cholecystectomy for gallbladder adenocarcinoma was detected with increasing liver mass, and hepatectomy was performed. Pathological report revealed neuroendocrine carcinoma. To find primary origin, pathological review of the old specimen from previous cholecystectomy with a slightly different perspective was conducted, where the neuroendocrine component was positively dyed. In conclusion, though it might be impossible to review every pathological result in cases with ambiguous findings, reviewing the previous specimen can be a useful option in diagnosis.
Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2023.ope
Evaluating motion of pancreatic tumors and anatomical surrogates using cine MRI in 0.35T MRgRT under free breathing conditions
Get PDFTreatment tolerability is a significant limitation to pancreatic cancer treatment with radiotherapy due to proximity to highly radiosensitive organs and respiratory motion necessitating expanded target margins. Further, pancreatic tumors are difficult to visualize on conventional radiotherapy systems. Surrogates are often used to locate the tumor but are often inconsistent and do not provide strong positional relations throughout the respiratory cycle. This work utilizes a retrospective dataset of 45 pancreatic cancer patients treated on an MR-Linac system with cine MRI acquired for real-time target tracking. We investigated intra-fraction motion of tumors and two abdominal surrogates, leading to prediction models between the tumor and surrogate. Patient specific motion evaluation and prediction models were generated from 225 cine MRI series acquired during treatment. Tumor contours were used to evaluate the pancreatic tumor motion. Linear regression and principal component analysis (PCA) based models were used to predict tumor position from the anterior-posterior (AP) motion of the abdominal surface, the superior-inferior (SI) motion of the diaphragm, or a combination. Models were evaluated using mean squared error (MSE) and mean absolute error (MAE). Contour analysis showed the average pancreatic tumor motion range was 7.4 ± 2.7 mm and 14.9 ± 5.8 mm in the AP and SI directions, respectively. The PCA model had MSE of 1.4 mm2 and 0.6 mm2 , for the SI and AP directions, respectively, with both surrogates as inputs for the models. When only the abdomen surrogate was used, MSE was 1.3 mm2 and 0.4 mm2 in the SI and AP directions, while it was 0.4 mm2 and 1.3 mm2 when only the diaphragm surrogate was used. We evaluated intra-fraction pancreatic tumor motion and demonstrated prediction models between the tumor and surrogate. The models calculated the pancreatic tumor position from diaphragm, abdominal, or both contours within standard pancreatic cancer target margin, and the process could be applied to other disease sites in the abdominothoracic cavity.ope