Brief Report: Risk of Recurrent Interstitial Lung Disease From Osimertinib Versus Erlotinib Rechallenge After Symptomatic Osimertinib-Induced Interstitial Lung Disease.

Introduction: Interstitial lung disease (ILD) is the most frequent cause of drug-related mortality from EGFR tyrosine kinase inhibitors (TKIs). Yet, for patients with symptomatic osimertinib-induced ILD, the risk of recurrent ILD associated with EGFR TKI rechallenge, either with osimertinib or another TKI, such as erlotinib, is unclear. Methods: Retrospective study of 913 patients who received osimertinib treatment for EGFR mutation-positive NSCLC. Clinical characteristics, ILD treatment history, and subsequent anticancer therapy of patients with symptomatic osimertinib-induced ILD were collated. The primary end point was to compare the incidence of recurrent ILD with osimertinib versus erlotinib rechallenge. Results: Of 913 patients, 35 (3.8%) had symptomatic osimertinib-induced ILD, of which 12 (34%), 15 (43%), and eight (23%) had grade 2, 3 to 4, and 5 ILD, respectively. On ILD recovery, 17 patients had EGFR TKI rechallenge with eight received osimertinib and nine received erlotinib. The risk of recurrent ILD was higher with osimertinib rechallenge than erlotinib (p = 0.0498). Of eight, five (63%) developed recurrent ILD on osimertinib rechallenge, including three patients with fatal outcomes. In contrast, only one of nine patients (11%) treated with erlotinib had recurrent ILD. Median time to second ILD occurrence was 4.7 (range 0.7-12) weeks. Median time-to-treatment failure of patients with erlotinib rechallenge was 13.2 months (95% confidence interval: 8.6-15.0). Conclusions: The risk of recurrent ILD was considerably higher with osimertinib rechallenge than erlotinib. Osimertinib rechallenge should be avoided, whereas erlotinib may be considered in patients with symptomatic osimertinib-induced ILD.

The prevalence of gastroesophageal reflux disease and laryngopharyngeal reflux in patients with dysphagia after radiotherapy for nasopharyngeal carcinoma.

BACKGROUND: The prevalence of gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR) in post-irradiated patients with nasopharyngeal carcinoma (NPC) is unknown. MATERIALS AND METHODS: In a cross-sectional study, 31 NPC and 12 control patients completed questionnaires for GERD/LPR before esophageal manometry and 24-h pH monitoring. The DeMeester score and reflux finding score (RFS) were used to define GERD and LPR, respectively. Risk factors were identified. RESULTS: 51.6% of NPC and 8.3% of control patients, and 77.4% of NPC and 33% of control patients, were GERD-positive and LPR-positive, respectively. The GERD/LPR questionnaire failed to identify either condition in patients with NPC. No parameter differences in esophageal manometry or pneumonia incidence were noted between GERD/LPR-positive and GERD/LPR-negative patients. Post radiotherapy duration, high BMI, lack of chemotherapy, and dysphagia were positive risk factors for GERD/LPR. CONCLUSIONS: A high prevalence of GERD/LPR in patients with post-irradiated NPC exists, but reflux symptoms are inadequate for diagnosis.

Quality of life and swallowing outcomes after early proactive swallowing rehabilitation by either transcutaneous neuromuscular electrical stimulation or exercise-based swallowing training in patients with nasopharyngeal carcinoma after radiotherapy.

Background: Exercise-based swallowing training (EBST) and transcutaneous neuromuscular electrical stimulation (TNMES) are common modalities used to treat late dysphagia after radiotherapy for nasopharyngeal carcinoma (NPC). We aimed to investigate and compare the efficacies of EBST and TNMES as proactive treatments administered early after radiotherapy. Methods: Patients with early post-radiotherapy NPC (n = 120) underwent either TNMES or EBST. Flexible endoscopic evaluation of swallowing (FEES), quality of life (QOL), and swallowing function questionnaires were completed before the intervention as well as immediately, 6, and 12 months after the intervention. Outcome measures included the scores for the swallowing function score (SFS), penetration and aspiration scale (PAS), dynamic imaging grade of swallowing toxicity (DIGEST), functional oral intake scale (FOIS), swallowing performance status scale (SPSS), pharyngeal motor impairment (PMI), pharyngeal function impairment (PFI), and functional assessment after cancer therapy-nasopharyngeal (FACT-NP) questionnaire. Results: Three months after radiotherapy, 31 and 34 patients underwent TNMES and EBST, respectively, and completed swallowing assessments at all four assessment timepoints. All patients showed post-radiotherapy impairments in the SFS, PAS, DIGEST, PMI, and PFI. Compared with the EBST group, the TNMES group showed significant improvements in the PFI and PMI scores, with small-to-medium effect sizes. Additionally, compared with the EBST group, the TNMES group demonstrated a trend toward slightly better improvements in the PAS, DIGEST, FOIS, and SPSS scores immediately and 6 months after the intervention. The SFS scores improved from baseline in both groups; however, the TNMES group showed an earlier improvement. Finally, the TNMES group showed better QOL according to the FACT-NP than the EBST group. Conclusion: Proactive TMNES and EBST are safe and feasible modalities for improving swallowing in patients with NPC when administered early after radiotherapy. Although TNMES showed better results than EBST, these results should be interpreted with caution given the study limitations. Level of evidence: 1B.

Consensus Statements on Precision Oncology in the China Greater Bay Area.

BACKGROUND: Next-generation sequencing comprehensive genomic panels (NGS CGPs) have enabled the delivery of tailor-made therapeutic approaches to improve survival outcomes in patients with cancer. Within the China Greater Bay Area (GBA), territorial differences in clinical practices and health care systems and strengthening collaboration warrant a regional consensus to consolidate the development and integration of precision oncology (PO). Therefore, the Precision Oncology Working Group (POWG) formulated standardized principles for the clinical application of molecular profiling, interpretation of genomic alterations, and alignment of actionable mutations with sequence-directed therapy to deliver clinical services of excellence and evidence-based care to patients with cancer in the China GBA. METHODS: Thirty experts used a modified Delphi method. The evidence extracted to support the statements was graded according to the GRADE system and reported according to the Revised Standards for Quality Improvement Reporting Excellence guidelines, version 2.0. RESULTS: The POWG reached consensus in six key statements: harmonization of reporting and quality assurance of NGS; molecular tumor board and clinical decision support systems for PO; education and training; research and real-world data collection, patient engagement, regulations, and financial reimbursement of PO treatment strategies; and clinical recommendations and implementation of PO in clinical practice. CONCLUSION: POWG consensus statements standardize the clinical application of NGS CGPs, streamline the interpretation of clinically significant genomic alterations, and align actionable mutations with sequence-directed therapies. The POWG consensus statements may harmonize the utility and delivery of PO in China's GBA.

Placement technique impacts gastrostomy tube-related complications amongst head and neck cancer patients.

OBJECTIVES: Percutaneous endoscopic gastrostomy (PEG) placement is essential for the provision of enteral nutrition in select head and neck cancer (HNC) patients. Minimally invasive tube placement is facilitated through one of two techniques, push or pull, but there have been conflicting results regarding safety profiles of these procedures. The objectives of this study were to determine the association of PEG insertion technique with gastrostomy tube complications, including stomal metastases. METHODS: A multi-institutional retrospective cohort study of patients with HNC undergoing PEG insertion by either the pull (gastroscope assisted) or push (fluoroscopy assisted) technique was performed. Tube-related complications included infection, dislodgement, deterioration, leak, and other. Adjusted analysis was performed via a multivariable logistic regression model. RESULTS: 1,575 patients were included across three institutions. Tube-related complications occurred in 36% of patients, the most common being peristomal leak (13%) and infection (16%). The push technique (OR 2.66, 95% CI: 1.42-4.97), and the presence of T4 disease (OR 4.62, 95% CI: 1.58-13.51), were associated with a greater risk of developing any tube-related complication. Infection rates were similar between pull and push cohorts. All detected stoma metastases occurred with the pull technique, with an overall prevalence of 0.32% amongst the cohort. CONCLUSIONS: The push technique is associated with a greater risk of developing any tube-related complication, but the rate of stomal metastases may be higher with the pull technique. There is potential for quality improvement measures to improve tube-related complications associated with either technique.

Esterified Hyaluronic Acid Placed in the Middle Ear Does Not Improve Outcomes in Cholesteatoma Surgery.

BACKGROUND: The aim of this article is to assess the efficacy of esterified hyaluronic acid as a barrier to formation of adhesions and improvement of tympanomastoid ventilation. METHODS: A prospective cohort analysis was performed at a tertiary referral centre. 126 ears were analysed in children with cholesteatoma. Esterified hyaluronic acid was placed on the promontory of 63 ears at primary canal wall intact surgery for cholesteatoma. No esterified hyaluronic acid was used in 63 control ears. Cholesteatoma recurrence, histopathological analysis of scar tissue following second-stage procedure, and middle ear pressure were the main outcome measures. RESULTS: At 5 years, esterified hyaluronic acid (7%) and non-esterified hyaluronic acid (10%) did not differ in cholesteatoma recurrence (Kaplan- Meier log rank analysis, P=.52). Esterified hyaluronic acid (n=11) and non-esterified hyaluronic acid (n=2) ears formed scar at the site of packing material (n=11) (Fisher's exact test, P=.04). Foamy histiocytes/macrophages were found in esterified hyaluronic acid (n=15) and non-esterified hyaluronic acid ears (n=1) (Fisher's exact test, P-125 daPa) in 44% (14/32) esterified hyaluronic acid ears and 42% (15/36) non-esterified hyaluronic acid ears (P=1.0, Fisher's exact test). CONCLUSIONS: We have discontinued the use of esterified hyaluronic acid in cholesteatoma surgery due to lack of detectable benefit. Esterified hyaluronic acid in the middle ear neither reduces cholesteatoma recurrence nor appears to improve the ventilation of the middle ear. Furthermore, esterified hyaluronic acid alters the inflammatory process within the middle ear, the significance of which remains unclear.

Local ablative radiotherapy on oligo-progression while continued on epidermal growth factor receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer patients: A longer cohort.

BACKGROUND: The effect of adding local ablative radiotherapy on oligo-progression while continuing EGFR-TKIs in advanced non-small cell Lung cancer (NSCLC) patients is to be determined. METHODS: Outcomes of patients with stage IV NSCLC harboring EGFR-activating mutations having ≤5 sites of oligo-progression while on EGFR-TKIs and given one to eight fractions of local ablative radiotherapy (LAR) were reviewed from 2012 to 2019. The time of starting first-line EGFR-TKIs to LAR is defined as progression-free survival 1 (PFS1; > one line of prior treatment allowed). The primary endpoint was PFS from LAR to further progression that led to stop of EGFR-TKIs (PFS2). The secondary endpoint was overall survival from LAR (OS). Factors affecting PFS2 and OS were analyzed with Cox regression. RESULTS: There were total 55 eligible patients. The median follow-up time was 13.3 months. Majority (89%) had sensitive mutations (exon 19 deletion and exon 21 L858R mutation). Total number of lesions treated were 75, including lung (n = 45), bone (n = 15), cervical lymph node (n = 1), adrenal (n = 1), and brain (n = 13). The median PFS2 was 6.9 months. The median OS was 25.1 months. On multivariable analysis, it was found that EGFR mutation type (exon 19 deletion / exon 21 L858R mutation vs. other rarer mutations), time from diagnosis to LAR within 70 days, and fewer lines of prior TKIs (1 or 2 vs. 3) had favorable effect on PFS2 (p = 0.006/0.00003; 0.046; 0.001/0.005, respectively). CONCLUSION: LAR is a noninvasive and effective modality in treatment of oligo-progressive diseases for patients with EGFR mutations positive NSCLC while on EGFR-TKIs.

Otolaryngology needs among an adult homeless population: a prospective study.

BACKGROUND: Homeless individuals frequently experience poor access to healthcare, delayed clinical presentation, and higher disease burden. Providing subspecialty otolaryngology care to this population can be challenging. We previously reported on the prevalence of hearing impairment in Toronto's homeless community. As a secondary objective of this study, we sought to define otolaryngology specific need for this population. METHODS: One hundred adult homeless individuals were recruited across ten homeless shelters in Toronto, Canada using a stratified random sampling technique. An audiometric evaluation and head and neck physical examination were performed by an audiologist and otolaryngology resident, respectively. Basic demographic and clinical information was captured through verbal administration of a survey. Descriptive statistics were used to estimate frequency of otolaryngology specific diseases for this population. RESULTS: Of the 132 individuals who were initially approached to participant, 100 (76%) agreed. There were 64 males, with median age of 46 years (IQR 37-58 years). The median life duration of homelessness was 24 months (IQR 6-72 months). Participants had a wide range of medical comorbidities, with the most common being current tobacco smoking (67%), depression (36%), alcohol abuse (32%), and other substance abuse (32%). There were 22 patients with otolaryngology needs as demonstrated by one or more abnormal findings on head and neck examination. The most common finding was nasal fracture with significant nasal obstruction (6%). Eleven patients required referral to a staff otolaryngologist based on concerning or suspicious findings, including two head and neck masses, 6 were later seen in follow-up. CONCLUSION: There were substantial otolaryngology needs amongst a homeless population within a universal healthcare system. Future research should focus on further elucidating head and neck related issues in this population and expanding the role of the otolaryngologist in providing care to homeless individuals.

Feedback Frequency in Competence by Design: A Quality Improvement Initiative.

BACKGROUND: Otolaryngology-head and neck surgery is in the first wave of residency training programs in Canada to adopt Competence by Design (CBD), a model of competency-based medical education. CBD is built on frequent, low-stakes assessments and requires an increase in the number of feedback interactions. The University of Toronto otolaryngology-head and neck surgery residents piloted the CBD model but were completing only 1 assessment every 4 weeks, which was insufficient to support CBD. OBJECTIVE: This project aimed to increase assessment completion to once per resident per week using quality improvement methodology. METHODS: Stakeholder engagement activities had residents and faculty characterize barriers to assessment completion. Brief electronic assessment forms were completed by faculty on residents' personal mobile devices in face-to-face encounters, and the number completed per resident was tracked for 10 months during the 2016-2017 pilot year. Response to the intervention was analyzed using statistical process control charts. RESULTS: The first bundled intervention-a rule set dictating which clinical instance should be assessed, combined with a weekly reminder implemented for 10 weeks-was unsuccessful in increasing the frequency of assessments. The second intervention was a leaderboard, designed on an audit-and-feedback system, which sent weekly comparison e-mails of each resident's completion rate to all residents and the program director. The leaderboard demonstrated significant improvement from baseline over 10 weeks, increasing the assessment completion rate from 0.22 to 2.87 assessments per resident per week. CONCLUSIONS: A resident-designed audit-and-feedback leaderboard system improved the frequency of CBD assessment completion.

Association Between Serum Folate Level and Toxicity of Capecitabine During Treatment for Colorectal Cancer.

BACKGROUND: Folate level was proposed to be a predictor for fluoropyrimidine-related toxicity. We conducted a prospective study to determine the association between serum and red-cell folate and capecitabine-related toxicity in patients with colorectal cancers. MATERIALS AND METHODS: Eligibility criteria included diagnosis of colorectal cancers; eligible patients who were scheduled to undergo capecitabine monotherapy or capecitabine-oxaliplatin (CAPOX) for adjuvant or palliative purposes. Exclusion criteria included concomitant radiotherapy or chemotherapy other than capecitabine or CAPOX and creatinine clearance <30 mL/min. Fasting serum and red-cell folate were measured prior to chemotherapy. Capecitabine was administered at 2,500 mg/m2 per day (monotherapy) or 2,000 mg/m2 per day (CAPOX) for 14 days every 3 weeks. The toxicity of the first four cycles was documented by clinical investigators who were blinded to folate levels. RESULTS: A total of 144 patients were recruited, of whom 126 were eligible; 40 patients had capecitabine alone, and 86 patients received CAPOX. The rates of grade 2 and grade 3 toxicity were 63.5% and 14.3%, respectively. Nausea and vomiting were the most common grade ≥2 adverse event (47.7%), followed by hand-foot syndrome (25.4%), diarrhea (23.1%), and neutropenia (22.3%). Combination with oxaliplatin (odds ratio [OR], 2.77; p = .043) and serum folate (OR, 10.33; p = .002) were independent predictors of grade ≥2 toxicity. Red-cell folate was not predictive of toxicity. For every 10 nmol/L increment in serum folate, the risk of grade ≥2 toxicity increased by 9%. CONCLUSION: Serum folate level, but not red-cell folate, was associated with higher rate of grade ≥2 toxicity during capecitabine-based treatment. Excessive folate intake may be avoided before and during capecitabine-based chemotherapy. IMPLICATIONS FOR PRACTICE: This is the first prospective study to evaluate the association between serum folate level and capecitabine-related toxicity in patients with colon cancers. It shows that higher serum folate level is associated with increased risks of moderate to severe toxicity during capecitabine-based treatment. Excessive folate intake should be avoided before and during capecitabine-based chemotherapy.

Adverse events across generations of bone-modifying agents in patients with solid tumor cancers reported in Phase III randomized trials.

AIMS: The objective of this study is to compare adverse events experienced among different bone-modifying agents. METHODS: A literature search was conducted to identify Phase III bisphosphonate and bone-modifying agent trials reporting adverse effects. Thirty-seven adverse events of interest were identified for six different treatment options. Weighted linear regression modeling was performed on the adverse event proportions with treatment groups, normalized through applying natural log transformations. RESULTS: There were significant differences in adverse events of vomiting (p = 0.045) and osteonecrosis of the jaw (p = 0.017), and combined item events of nausea/vomiting (p = 0.048), hematological and lymphatic system toxicities (p = 0.020), and any respiratory system problem (p = 0.023) between bone-modifying agent and placebo trials. The significant toxicities were observed even after adjusting for the two confounding factors of age and primary cancer site. CONCLUSION: While adverse effects are consistently experienced more frequently in patients receiving bone-modifying agents when compared with placebos, we find that the majority of individual side effects are not significantly more frequent in patients receiving bone-modifying agents compared with placebo.

'Who', 'when' and 'how' in re-irradiation of recurrent painful bone metastases.

Re-irradiation of painful bony metastases is increasingly performed since patients are receiving better systemic treatments and having longer life expectancy, and may also be due to the increase use of initial single fraction radiotherapy. However, randomized control trial on the efficacy of re-irradiation is lacking. A recent meta-analysis concluded with a 58% response rate for pain relief by re-irradiation of symptomatic bone metastases. In this review, the effectiveness of re-irradiation in terms of clinical and economical aspects, and clinical questions on who, when, and how to re-irradiate would be discussed. A brief review of other treatment options and comparison with re-irradiation of bone metastases would be performed.

A population-based study of juvenile disc degeneration and its association with overweight and obesity, low back pain, and diminished functional status.

BACKGROUND: Little is known regarding juvenile disc degeneration in individuals with normal spinal alignment. Consequently, the purpose of this study was to assess the prevalence, determinants, and clinical relevance associated with juvenile disc degeneration of the lumbar spine in individuals without spinal deformities. METHODS: A cross-sectional assessment of disc degeneration in juveniles was performed as part of a population-based study of 1989 Southern Chinese volunteers. Adolescents and young adults from thirteen to twenty years of age were defined as "juveniles." Juvenile subjects with no spinal deformity (n = 83) were stratified into two groups, those with and those without juvenile disc degeneration. Sagittal T2-weighted magnetic resonance images (MRI) were evaluated for the presence and extent of disc degeneration as well as other spinal findings. Demographics were assessed and clinical profiles were collected with use of standardized questionnaires. RESULTS: Juvenile disc degeneration was present in 35% (twenty-nine) of the juveniles without spinal deformity. Disc bulging or extrusion (p < 0.001), high-intensity zones on MRI (p = 0.040), and greater weight (p < 0.001) and height (p = 0.002) were significantly more prevalent in subjects with juvenile disc degeneration. Adjusted multivariate logistic regression modeling demonstrated that Asian-modified body-mass index (BMI) values in the overweight or obese range had a significant association with juvenile disc degeneration (odds ratio = 14.19; 95% confidence interval = 1.44 to 140.40; p = 0.023). Overweight and obese individuals had greater severity of disc degeneration than underweight and normal-weight individuals (p = 0.036). Furthermore, individuals with juvenile disc degeneration had an increased prevalence of low back pain and/or sciatica (p = 0.002), greater low back pain intensity (p < 0.001), diminished social functioning (p = 0.049), and greater physical disability (p < 0.05) than individuals without disc degeneration. The p value of <0.05 for physical disability represents both the physical function (p = 0.006) and the physical component (p = 0.032) of the SF-36. CONCLUSIONS: This study demonstrated that the presence of juvenile disc degeneration was strongly associated with overweight and obesity, low back pain, increased low back pain intensity, and diminished physical and social functioning. Furthermore, an elevated BMI was significantly associated with increased severity of disc degeneration. This study has public health implications regarding overweight and obesity and the development of lumbar disc disease.