INTEGRATE IIa Phase III Study: Regorafenib for Refractory Advanced Gastric Cancer.

PURPOSE: Treatment options for refractory advanced gastric and esophagogastric junction cancer (AGOC) are limited. Regorafenib, an oral multikinase inhibitor, prolonged progression-free survival (PFS) versus placebo in the INTEGRATE I phase II trial. INTEGRATE IIa was designed to examine whether regorafenib improved overall survival (OS). METHODS: A double-blind placebo-controlled phase III trial compared regorafenib and best supportive care (BSC) versus placebo and BSC for participants with confirmed evaluable metastatic/advanced AGOC who failed ≥two prior therapies on a 2:1 random assignment, stratified by tumor location, geographic region (Asia v rest of world), and prior vascular endothelial growth factor inhibitors. The primary end point was OS. Treatment efficacy on OS was first tested in the pooled INTEGRATE I + INTEGRATE IIa cohort and, if significant, then in the INTEGRATE IIa cohort. Secondary end points were PFS, objective response rate, safety, and quality of life (QoL). RESULTS: INTEGRATE IIa enrolled 251 participants: 157 from Asia and 94 from rest of world and 169 received regorafenib and 82 received placebo. No significant heterogeneity was observed between INTEGRATE I and INTEGRATE IIa studies on OS. Pooled OS analysis hazard ratio (HR) was 0.70 (95% CI, 0.56 to 0.87; P = .001; 361 events). INTEGRATE IIa alone OS HR was 0.68 (95% CI, 0.52 to 0.90; P = .006; 238 events), the median OS was 4.5 months versus 4.0 months, and 12-month survival rates were 19% and 6%, for regorafenib versus placebo, respectively. After a preplanned adjustment for multiplicity, there were no statistically significant differences across regions or other prespecified subgroups. Regorafenib improved PFS (HR, 0.53 [95% CI, 0.40 to 0.70]; P < .0001) and delayed deterioration in global QoL (HR, 0.68 [95% CI, 0.52 to 0.89]; P = .0043). The toxicity profile was consistent with that of previous reports. CONCLUSION: Regorafenib improves survival compared with placebo in refractory AGOC.

Natural History and Clinicopathological Associations of TRPC6-Associated Podocytopathy.

BACKGROUND: Understanding the genetic basis of human diseases has become integral to drug development and precision medicine. Recent advancements have enabled the identification of molecular pathways driving diseases, leading to targeted treatment strategies. The increasing investment in rare diseases by the biotech industry underscores the importance of genetic evidence in drug discovery and approval processes. Here we studied a monogenic Mendelian kidney disease, TRPC6-associated podocytopathy (TRPC6-AP), to present its natural history, genetic spectrum, and clinicopathological associations in a large cohort of patients with causal variants in TRPC6, in order to help define the specific features of disease and further facilitate drug development and clinical trials design. METHODS: the study involved 64 individuals from 39 families with TRPC6 causal missense variants. Clinical data, including age of onset, laboratory results, response to treatment, kidney biopsy findings, and genetic information, were collected from multiple centers nationally and internationally. Exome or targeted sequencing was performed and variant classification was based on strict criteria. Structural and functional analyses of TRPC6 variants were conducted to understand their impact on protein function. In depth re-analysis of light and electron microscopy specimens for 9 available kidney biopsies was conducted to identify pathological features and correlates of TRPC6-AP. RESULTS: Large-scale sequencing data did not support causality for TRPC6 protein-truncating variants. We identified 21 unique TRPC6 missense variants, clustering in three distinct regions of the protein, and with different effects on TRPC6 3D protein structure. Kidney biopsy analysis revealed FSGS patterns of injury in most cases, along with distinctive podocyte features including diffuse foot process effacement and swollen cell bodies. The majority of patients presented in adolescence or early adulthood but with ample variation (average 22, SD ± 14 years), with frequent progression to kidney failure but with variability in time between presentation and ESKD. CONCLUSIONS: This study provides insights into the genetic spectrum, clinicopathological associations, and natural history of TRPC6-AP.

Lymphatic mapping in second primary or recurrent oral cavity cancer with prior neck treatment: A case series and scoping review.

OBJECTIVES: Lymphatic mapping is an established technique to map drainage patterns in oral cancer. Its utility in patients who have undergone prior radiation or neck dissection is not well studied. METHODS: Patients presenting to a single tertiary cancer center between 2021-2023 for a recurrent/second oral cancer that underwent lymphatic mapping were considered. All patients had a history of a head and neck cancer treated with either radiation or neck dissection. We further conducted a scoping review in MEDLINE, Embase, and Web of Science of lymphatic mapping in oral cancer patients with previous neck treatment. RESULTS: In our single center review, a total of 11 patients were included. 73 % received prior radiotherapy and 55 % underwent prior neck dissections for a head and neck cancer. Lymphoscintigraphy-directed neck dissections identified sentinel nodes in 9/11 patients, with only one patient who had positive sentinel node disease. There were no reports of regional recurrence at a median of 10 months follow-up. Our scoping review of 980 studies identified 151 additional patients who underwent sentinel node biopsy for a second oral cancer after previous neck treatment. Overall, the negative predictive value of lymphatic mapping in all studies was 96.7 %. CONCLUSION: Lymphatic mapping is feasible in secondary or recurrent oral cavity cancers even in patients with prior radiation or surgical management of the neck. The literature to date demonstrates a negative predictive value of âˆ¼ 97 % for sentinel node mapping and warrants further consideration in the management of salvage oral cancer.

Smoking and alcohol by HPV status in head and neck cancer: a Mendelian randomization study.

HPV-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) are recognized as distinct entities. There remains uncertainty surrounding the causal effects of smoking and alcohol on the development of these two cancer types. Here we perform multivariable Mendelian randomization (MR) to evaluate the causal effects of smoking and alcohol on the risk of HPV-positive and HPV-negative HNSCC in 3431 cases and 3469 controls. Lifetime smoking exposure, as measured by the Comprehensive Smoking Index (CSI), is associated with increased risk of both HPV-negative HNSCC (OR = 3.03, 95%CI:1.75-5.24, P = 7.00E-05) and HPV-positive HNSCC (OR = 2.73, 95%CI:1.39-5.36, P = 0.003). Drinks Per Week is also linked with increased risk of both HPV-negative HNSCC (OR = 7.72, 95%CI:3.63-16.4, P = 1.00E-07) and HPV-positive HNSCC (OR = 2.66, 95%CI:1.06-6.68, P = 0.038). Smoking and alcohol independently increase the risk of both HPV-positive and HPV-negative HNSCC. These findings have important implications for understanding the modifying risk factors between HNSCC subtypes.

Radiotherapy Versus Transoral Robotic Surgery for Oropharyngeal Squamous Cell Carcinoma: Final Results of the ORATOR Randomized Trial.

Radiotherapy (RT) and transoral robotic surgery (TORS) are both curative-intent treatment options for oropharyngeal squamous cell carcinoma (OPSCC). Herein, we report the final outcomes of the ORATOR trial comparing these modalities, 5 years after enrollment completion. We randomly assigned 68 patients with T1-2N0-2 OPSCC to RT (with chemotherapy if node-positive) versus TORS plus neck dissection (± adjuvant RT/chemoradiation). The primary end point was swallowing quality of life (QOL) assessed with the MD Anderson Dysphagia Inventory (MDADI). Secondary end points included overall and progression-free survival (OS, PFS), adverse events (AEs), and other QOL metrics. The primary end point has been previously reported (Nichols 2019). In this report, the median follow-up was 5.1 years (IQR, 5.0-5.3 years). MDADI total scores converged by 5 years and were not significantly different across the follow-up period (P = .11). EORTC QLQ-C30 and H&N35 scores demonstrated differing profiles, including worse dry mouth in the RT arm (P = .032) and worse pain in the TORS arm (P = .002). Grade 2-5 AE rates did not differ between arms (91% [n = 31] v 97% [n = 33] respectively, P = .61), with more neutropenia and hearing loss in the RT arm, and more dysphagia and other pain in the TORS arm based on grades 2-5 (all P < .05). There were no differences in OS or PFS. In conclusion, toxicity and QOL profiles differ in some domains between RT and TORS, but oncologic outcomes were excellent in both arms. Choice of treatment should remain a shared decision between the patient and their providers.

Do germline genetic variants influence surgical outcomes in drug-resistant epilepsy?

OBJECTIVE: We retrospectively explored patients with drug-resistant epilepsy (DRE) who previously underwent presurgical evaluation to identify correlations between surgical outcomes and pathogenic variants in epilepsy genes. METHODS: Through an international collaboration, we evaluated adult DRE patients who were screened for surgical candidacy. Patients with pathogenic (P) or likely pathogenic (LP) germline variants in genes relevant to their epilepsy were included, regardless of whether the genetic diagnosis was made before or after the presurgical evaluation. Patients were divided into two groups: resective surgery (RS) and non-resective surgery candidates (NRSC), with the latter group further divided into: palliative surgery (vagus nerve stimulation, deep brain stimulation, responsive neurostimulation or corpus callosotomy) and no surgery. We compared surgical candidacy evaluations and postsurgical outcomes in patients with different genetic abnormalities. RESULTS: We identified 142 patients with P/LP variants. After presurgical evaluation, 36 patients underwent RS, while 106 patients were NRSC. Patients with variants in ion channel and synaptic transmission genes were more common in the NRSC group (48 %), compared with the RS group (14 %) (p<0.001). Most patients in the RS group had tuberous sclerosis complex. Almost half (17/36, 47 %) in the RS group had Engel class I or II outcomes. Patients with channelopathies were less likely to undergo a surgical procedure than patients with mTORopathies, but when deemed suitable for resection had better surgical outcomes (71 % versus 41 % with Engel I/II). Within the NRSC group, 40 underwent palliative surgery, with 26/40 (65 %) having ≥50 % seizure reduction after mean follow-up of 11 years. Favourable palliative surgery outcomes were observed across a diverse range of genetic epilepsies. SIGNIFICANCE: Genomic findings, including a channelopathy diagnosis, should not preclude presurgical evaluation or epilepsy surgery, and appropriately selected cases may have good surgical outcomes. Prospective registries of patients with monogenic epilepsies who undergo epilepsy surgery can provide additional insights on outcomes.

Persistent Autonomic and Immunologic Abnormalities in Neurologic Post-Acute Sequelae of SARS-CoV2 Infection.

OBJECTIVES: After acute coronavirus disease-2019 (COVID-19), people often experience fatigue, "brain fog," or other central neurologic symptoms (neuro-post-acute SARS-CoV2, or "Neuro-PASC"). In this observational study we evaluated whether abnormalities noted on initial evaluation persist after at least another year. METHODS: Neuro-PASC research participants who had undergone comprehensive inpatient testing at the NIH Clinical Center returned after at least 1 year for follow-up assessments including symptoms rating scales, MRI, lumbar puncture for tests of the CSF, physiologic recordings during the Valsalva maneuver and head-up tilting (with serial plasma catechols and cardiac Doppler ultrasound during the tilting), blood volume measurement, skin biopsies to examine sympathetic innervation, and blood sampling for neuroendocrine and immunologic measures. RESULTS: 7 patients with Neuro-PASC (6 women, age range 42-63 years) underwent follow-up testing. 71% of initially abnormal test results remained abnormal at follow-up, including the pattern of CSF and serum oligoclonal bands, CSF indices of central catecholamine deficiency, baroreflex-cardiovagal dysfunction, the occurrence of tilt-evoked sudden hypotension, white matter hyperintensities on MRI, and adaptive responses in CSF. DISCUSSION: In Neuro-PASC most of the autonomic and immunologic abnormalities found initially are still present after more than a year.

Validity of Patient-Reported Outcome Measures in Evaluating Nerve Damage Following Chemotherapy.

Importance: Chemotherapy-induced peripheral neuropathy (CIPN) is a substantial adverse effect of anticancer treatments. As such, the assessment of CIPN remains critically important in both research and clinic settings. Objective: To compare the validity of various patient-reported outcome measures (PROMs) with neurophysiological and sensory functional measures as the optimal method of CIPN assessment. Design, Setting, and Participants: This cohort study evaluated participants treated with neurotoxic chemotherapy across 2 cohorts using a dual-study design. Participants commencing treatment were assessed prospectively at beginning of neurotoxic treatment, midtreatment, and at the end of treatment. Participants who completed treatment up to 5 years prior were assessed cross-sectionally and completed a single assessment time point. Participants were recruited from oncology centers in Australia from August 2015 to November 2022. Data analysis occurred from February to November 2023. Exposures: Neurotoxic cancer treatment including taxanes, platinums, vinca-alkaloids, proteasome inhibitors, and thalidomide. Main Outcomes and Measures: CIPN was assessed via PROMs (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC-CIPN20], Functional Assessment of Cancer Therapy/Gynecological Cancer Group Neurotoxicity Questionnaire (FACT/GOG-Ntx), and the patient-reported outcomes version of the Common Terminology Criteria for Adverse Events [PRO-CTCAE]), neurological and neurophysiological assessment (Total Neuropathy Score and sural and tibial compound nerve amplitudes), and sensory measures (Grating orientation, Von Frey monofilament, and 2-point discrimination tasks). Core measurement properties of CIPN outcome measures were evaluated. Convergent and known-groups validity was assessed cross-sectionally following treatment completion, and responsiveness was evaluated prospectively during treatment. Neurological, neurophysiological, and sensory outcome measure scores were compared between those who reported high and low levels of CIPN symptoms using linear regressions. Results: A total of 1033 participants (median [IQR] age, 61 [50-59] years; 676 female [65.4%]) were recruited to this study, incorporating 1623 assessments. PROMs demonstrated best ability to accurately assess CIPN (convergent validity), especially the PRO-CTCAE composite score (r = 0.85; P < .001) and EORTC-CIPN20 (r = 0.79; P < .001). PROMS also demonstrated the best ability to discriminate between CIPN severity (known-groups validity) and to detect changes at onset of CIPN development (responsiveness), especially for EORTC-CIPN20 (d = 0.67; 95% CI, 0.52-0.83), FACT/GOG-Ntx (d = 0.65; 95% CI, 0.49-0.81) and the PRO-CTCAE (d = 0.83; 95% CI, 0.64-1.02). Other measures did not achieve threshold for convergent validity (α < 0.7). Neurophysiological and sensory measures did not demonstrate acceptable responsiveness. In regression models, neurological, neurophysiological, and sensory outcome measures were significantly impaired in participants who reported high levels of CIPN symptoms compared with those who reported low levels of CIPN symptoms. Conclusions and Relevance: In this cohort study of 1033 cancer patients, PROMs were the only measures to satisfy all 3 core measurement property criteria (convergent validity, known-groups validity, and responsiveness). These findings suggest that adoption of PROMs in clinical practice can equip clinicians with valuable information in assessing CIPN morbidity.

Vertical Partial Laryngectomy With Temporoparietal Free-Flap Reconstruction for Recurrent Laryngeal Cancer: Long-Term Study.

Objective: Treatment options for recurrent early glottic carcinoma's include conservative and radical surgical options. These options offer similar survival benefits with different impacts of patient's quality of life. We previously present our experience with vertical partial laryngectomy (VPL) and showed high locoregional control rates with high-quality voice results and normal swallowing. Study Design: A long-term retrospective review. Setting: Tertiary Care Center. Methods: We analyzed all patients underwent VPL between the years 1995 to 2018. Long-term oncologic and functional outcomes were collected. Results: A total of 40 patients were included. The majority of whom were male (n = 38, 95%) with a mean age of 64.9 years (SD ± 9.5). With a median follow up time of 12 years (range 0-24), 9 patients (22.5%) had disease recurrence; the majority of whom (8 patients), had local recurrence and all were salvaged with total laryngectomy. Eight patients (20%) developed second primaries in the head and neck region with a median time to diagnosis of 77 months (range 8-227 months). Ten-years overall survival, disease specific survival, and local disease-free survival were 80%, 90%, and 80%, respectively. Five patients had postoperative laryngeal dysfunction with a total 10-years laryngectomy free survival of 70%. Conclusion: VPL has a sustainable oncologic outcome with a high long-term laryngectomy free survival rate. This entity is an acceptable conservative salvage option for selected postradiated recurrent laryngeal squamous cell carcinoma patients.

Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 300,000 people worldwide. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms continue to develop, such as antisense oligonucleotides, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation. METHODS: Building on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger multi-ethnic cohort of 6,970 ALS patients, 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS. RESULTS: A gene based collapsing model showed significant associations with SOD1, TARDBP, and TBK1 (OR = 19.18, p = 3.67 × 10-39; OR = 4.73, p = 2 × 10-10; OR = 2.3, p = 7.49 × 10-9, respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 (p = 4.88 × 10-7), was protective for ALS in this model. An intolerant domain-based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR = 10.08, p = 3.62 × 10-16). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 (p = 8.38 × 10-6). CONCLUSIONS: In a large multi-ethnic cohort of 6,970 ALS patients, collapsing analyses validated known ALS genes and identified a novel potentially protective gene, ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2.

A multi-institutional feasibility lead-in trial of lymphatic mapping with SPECT-CT for evaluating contralateral disease in lateralized oropharynx cancer using 99m-technetium sulfur colloid.

BACKGROUND: Lymphatic mapping with SPECT-CT has been demonstrated to accurately define lymphatic drainage patterns in oropharyngeal cancer but there has yet to be a study demonstrating its feasibility across multiple institutions. METHODS: Twelve adult patients with lateralized oropharyngeal carcinoma (T1-T3) who were planned for definitive or adjuvant radiotherapy without contralateral nodal disease underwent injection of 99-m technetium sulfur colloid followed by static planar lymphoscintigraphy to verify tracer migration, and SPECT-CT acquired at 30 ± 15 min (optional) and 3 h (±1 h) (mandatory time-point). RESULTS: All 12 patients completed the study with 7/12 patients having the injections performed under local anesthetic and 5 patients requiring general anesthetic. There were no tracer migration failures and there were no serious adverse events or complications encountered. Four out of 12 patients (33%) showed contralateral drainage patterns. CONCLUSIONS: Lymphatic mapping with SPECT-CT of lateralized oropharyngeal squamous cell carcinoma can be performed safely across multiple institutions.

Clinical Predictors of Cisplatin Chemoradiation-Induced Ototoxicity in HPV-Positive Oropharyngeal Squamous Cell Carcinoma: A Case-Control Study.

BACKGROUND: Cisplatin-based chemoradiation is a standard treatment for many patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC), an etiologically distinct subset of head and neck cancer. Although associated with good long-term survival, clinical risk factors for ototoxicity have been understudied in this population. This study aimed to evaluate clinical predictors associated with ototoxicity in HPV-positive OPSCC patients treated with cisplatin chemoradiation. METHODS: This retrospective case-control study included 201 adult patients (>18 years) with histologically confirmed HPV-positive OPSCC who received cisplatin chemoradiation as their primary treatment from 2001 and 2019 at a single tertiary cancer center. Ototoxicity was determined using baseline and follow-up audiometry and the Common Terminology Criteria for Adverse Events v5.0 grading criteria (Grade ≥2). Multivariable logistic regression [adjusted odds ratio (aOR)] identified significant predictors that increased the odds of ototoxicity. RESULTS: A total of 201 patients [165 males; median (IQR) age, 57 (11) years] were included in the study. The incidence of ototoxicity in the worst ear was 56.2%, with the greatest hearing loss occurring at high frequencies (4-8 kHz), resulting in a loss of 12.5 dB at 4 to 6 kHz and 20 dB at 6 to 8 kHz. High-dose cisplatin administration compared to weekly administration [aOR 4.93 (95% CI: 1.84-14.99), P = .003], a higher mean cochlear radiation dose [aOR 1.58 (95% CI: 1.12-2.30), P = .01], smoking history [aOR 2.89 (95% CI: 1.51-5.63), P = .001], and a 10 year increase in age [aOR 2.07 (95% CI: 1.25-3.52), P = .006] were each independently associated with increased odds of ototoxicity. CONCLUSIONS: Clinical predictors of ototoxicity in HPV-positive OPSCC patients treated with cisplatin-based chemoradiation include the use of a high-dose cisplatin regimen, higher cochlear radiation doses, a history of smoking, and older age. With the rising incidence of this malignancy in Western countries and overall improved survivorship, our research motivates future studies into risk stratification and earlier interventions to mitigate and reduce the risk of ototoxicity.

Ultrasound Imaging in Active Surveillance of Small, Low-Risk Papillary Thyroid Cancer.

The recent surge in the incidence of small papillary thyroid cancers (PTCs) has been linked to the widespread use of ultrasonography, thereby prompting concerns regarding overdiagnosis. Active surveillance (AS) has emerged as a less invasive alternative management strategy for low-risk PTCs, especially for PTCs measuring ≤1 cm in maximal diameter. Recent studies report low disease progression rates of low-risk PTCs ≤1 cm under AS. Ongoing research is currently exploring the feasibility of AS for larger PTCs (<20 mm). AS protocols include meticulous ultrasound assessment, emphasis on standardized techniques, and a multidisciplinary approach; they involve monitoring the nodules for size, growth, potential extrathyroidal extension, proximity to the trachea and recurrent laryngeal nerve, and potential cervical nodal metastases. The criteria for progression, often defined as an increase in the maximum diameter of the PTC, warrant a review of precision and ongoing examinations. Challenges exist regarding the reliability of volume measurements for defining PTC disease progression. Although ultrasonography plays a pivotal role, challenges in assessing progression and minor extrathyroidal extension underscore the importance of a multidisciplinary approach in disease management. This comprehensive overview highlights the evolving landscape of AS for PTCs, emphasizing the need for standardized protocols, meticulous assessments, and ongoing research to inform decision-making.

A Comparison of Transoral Versus Transcervical Surgical Approaches to Retropharyngeal Lymphadenectomy: A Scoping Review.

IMPORTANCE: A gap in knowledge exists concerning the functional outcomes and complications when comparing various surgical approaches for retropharyngeal lymph node (RPLN) metastases. OBJECTIVE: To explore perioperative outcomes, functional outcomes, and complications associated in the treatment of RPLN metastases. DESIGN: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping Reviews (PRISMA-ScR) protocol was used to conduct a scoping review of the PubMed and Scopus databases. REVIEW METHODS: We systematically searched 2 databases from inception to January 2023 for articles examining the treatment approaches and postoperative outcomes in the retropharyngeal space. We included English records about surgical approaches, complications, functional outcomes for patients >18 years old with retropharyngeal lymphadenopathy. RESULTS: One-hundred ninety-nine articles were identified, of which 17 were included in the analysis. Three studies assessed RPLN dissection in the postradiation setting. We identified limited knowledge about functional outcomes and complications following surgery for retropharyngeal lymphadenopathy. Overall, acute postoperative dysphagia was documented in 35/170 patients (20.5%). However, the assessment of dysphagia was limited, and not described in the majority of studies. The overall rate of postoperative neuropathy and hematoma were 4.1% and 4.7%, respectively. No postoperative hematomas were documented in the transcervical approach. CONCLUSION: Our findings underscore the need for further research on postoperative outcomes following RPLN dissection. We recommend further studies focusing on objective swallow assessments and long-term outcomes of either surgical approaches.

Cerebrospinal fluid concentration gradients of catechols in synucleinopathies.

The synucleinopathies Parkinson disease (PD), multiple system atrophy (MSA), and the Lewy body form of pure autonomic failure (PAF) entail intra-cytoplasmic deposition of the protein alpha-synuclein and pathogenic catecholaminergic neurodegeneration. Cerebrospinal fluid (CSF) levels of catecholamines and their metabolites are thought to provide a "neurochemical window" on central catecholaminergic innervation and can identify specific intra-neuronal dysfunctions in synucleinopathies. We asked whether there are CSF concentration gradients for catechols such as 3,4-dihydroxyphenylacetic acid (DOPAC), the main neuronal metabolite of dopamine, and if so whether the gradients influence neurochemical differences among synucleinopathies. In a retrospective cohort study, we reviewed data about concentrations of catechols in the first, sixth, and twelfth 1-mL aliquots from 33 PD, 28 MSA, and 15 PAF patients and 41 controls. There were concentration gradients for DOPAC, dopamine, norepinephrine, and 3,4-dihydroxyphenylglycol (the main neuronal metabolite of norepinephrine) and gradients in the opposite direction for 5-S-cysteinyldopa and 5-S-cysteinyldopamine. In all 3 aliquots, CSF DOPAC was low in PD and MSA compared with controls (p < 0.0001 each) and normal in PAF. Synucleinopathies differ in CSF catechols regardless of concentration gradients. Concentration gradients for 5-S-cysteinyl derivatives in opposite directions from the parent catechols may provide biomarkers of spontaneous oxidation in the CSF space.

Radiology-Pathology Concordance and Prognostication of Nodal Features in pN+ Oral Cavity Cancer.

BACKGROUND AND PURPOSE: The aims of our study are to evaluate the diagnostic performance and prognostic value of radiological lymph node (LN) characteristics in pN+ oral cavity squamous carcinoma (OSCC). MATERIALS AND METHODS: pN+ OSCC treated between 2012 and 2020 were included. Preoperative imaging was reviewed by a single radiologist blinded to pathologic findings for the following nodal features: imaging-positive LN (iN+), laterality and total number, and image-identified extranodal extension (iENE). The sensitivity of iN+ for pN+ was calculated. The diagnostic performance of other nodal features was evaluated in the iN+ subgroup. The association of radiologic nodal features with overall survival (OS) was evaluated. Inter-rater kappa for radiologic nodal features was assessed in 100 randomly selected cases. RESULTS: Of 406 pN+ OSCC, 288 were iN+. The sensitivity of iN+ for pN+ was 71% overall, and improved to 89% for pN+ LN >1.5 cm. Within iN+, sensitivity/specificity for LN size (>3 cm), total LN number (>4), and ENE were 0.44/0.95, 0.57/0.84, and 0.27/0.96, respectively. Sensitivity of iENE was higher in the subset, with major (>2 mm) versus minor (≤2 mm) pENE (43% vs. 13%, p = 0.001). Reduced OS was observed in iN+ versus iN- (p = 0.006), iENE+ versus iENE- (p = 0.004), LN size >3 versus ≤3 cm (p < 0.001), and higher LN number (p < 0.001). Inter-rater kappa for iN+, laterality, total LN number, and presence of iENE were 0.71, 0.57, 0.78, and 0.69, respectively. CONCLUSION: Our study shows that despite modest sensitivity of most radiological nodal features, the specificity of image-identified nodal features is high and their prognostic values are retained in pN+ OSCC. LEVEL OF EVIDENCE: Level 3 (retrospective review comparing cases and controls) Laryngoscope, 2024.

Changes in New Patient Consultations During the COVID-19 Pandemic at a Canadian Comprehensive Cancer Center.

BACKGROUND: The impact of COVID-19 pandemic-related disruptions on cancer services is emerging. We evaluated the impact of the first 2 years of the pandemic on new patient consultations for all cancers at a comprehensive cancer center within a publicly funded health care system and assessed whether there was evidence of stage shift. METHODS: We performed a retrospective study using the Princess Margaret Cancer Registry. New consultations with medical, radiation, or surgical oncology were categorized by year and quarter. Logistic regression was used to assess the effect of period before and during the COVID-19 pandemic on cancer stage at consultation, adjusting for age, sex, and diagnosis location (our hospital network vs elsewhere). RESULTS: In all, 53,759 new patient consultations occurred from January 1, 2018, to June 30, 2022. After the pandemic was declared, there was a decrease in all types of consultations by 43.3% in the second quarter of 2020, and referral volumes did not recover during the first year. There was no evidence of stage shift for all cancer types during the later quarters of the pandemic for the overall population. CONCLUSIONS: New patient consultations decreased across cancer stages, referral type, and most disease sites at our tertiary cancer center. We did not observe evidence of stage shift in this population. Further research is needed to determine whether this reflects the resilience of our health care system in maintaining cancer services or a delay in the presentation of advanced cancer cases. These data are important for shaping future cancer care delivery and recovery strategies.

A pathophysiological biomarker combination separates Lewy body from non-Lewy body neurogenic orthostatic hypotension ​.

PURPOSE: Neurogenic orthostatic hypotension (nOH) results from deficient reflexive delivery of norepinephrine to cardiovascular receptors in response to decreased cardiac venous return. Lewy body (LB) forms of nOH are characterized by low 18F-dopamine-derived radioactivity (a measure of cardiac noradrenergic deficiency), olfactory dysfunction by the University of Pennsylvania Smell Identification Test (UPSIT), and increased deposition of alpha-synuclein (α-syn) in dermal sympathetic noradrenergic nerves by the α-syn-tyrosine hydroxylase (TH) colocalization index. This observational, cross-sectional study explored whether combinations of these biomarkers specifically identify LB forms of nOH. METHODS: Clinical laboratory data were reviewed from patients referred for evaluation at the National Institutes of Health for chronic autonomic failure between 2011 and 2023. The cutoff value for low myocardial 18F-dopamine-derived radioactivity was 6000 nCi-kg/cc-mCi, for olfactory dysfunction an UPSIT score ≤ 28, and for an increased α-syn-TH colocalization index ≥ 1.57. RESULTS: A total of 44 patients (31 LB, 13 non-LB nOH) had data for all three biomarkers. Compared to the non-LB group, the LB nOH group had low myocardial 18F-dopamine-derived radioactivity, low UPSIT scores, and high α-syn-TH colocalization indexes (p < 0.0001 each). Combining the three biomarkers completely separated the groups. Cluster analysis identified two distinct groups (p < 0.0001) independently of the clinical diagnosis, with one cluster corresponding exactly to LB nOH. CONCLUSION: LB forms of nOH feature cardiac noradrenergic deficiency, olfactory dysfunction, and increased α-syn-TH colocalization in skin biopsies. Combining the data for these variables efficiently separates LB from non-LB nOH. Independently of the clinical diagnosis, this biomarker triad identifies a pathophysiologically distinct cluster of nOH patients.

Nodal Metastases in Stage 3 Head and Neck Melanoma: Patterns of Metastases and Patterns of Failure.

OBJECTIVE: Stage 3 patients with clinically positive nodal metastasis are treated with therapeutic neck dissection and adjuvant systemic therapy. The aim of our study was to examined the predictability of pre-operative CT as a nodal drainage assessment tool. METHODS: Retrospective review of all patients with clinically positive head and neck cutaneous melanoma between 2010 and 2019. Clinical disease was diagnosed as radiological suspicious, biopsy-proven node. A pre-operative CT evaluation for nodal metastasis was compared to pathology report. RESULTS: A total of 53 patients were included. Forty patients (75.5%) were males with a mean age of 59 (SD 15.52). The majority of patients (26.4%) had an unknown primary site. The most common sites for primary were the cheek in eight patients (15.1%) followed by forehead (9.4%) and lateral neck (9.4%). Preoperative CT predicted nodal disease in 84.6% of cases. The primary region that mainly failed from the previously described clinical prediction was the upper anterior neck with 83.3% parotid involvement. A total of 10 patients (18.9%) were diagnosis with non-clinical nodes on pathology with a median non-clinical node of 1 (range 1-2). Of them, 9 (90%) were in the same clinical levels detected by CT. Pre-operative CT was associated with a neck level accuracy of 98.1%. CONCLUSION: Stage 3 head and neck melanoma with clinically positive nodal metastasis that are eligible for an adjuvant systemic treatment, may benefit from a highly selective neck dissection according to their pre-operative imaging studies. This should be further evaluated in a large-scale clinical trial. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:4292-4297, 2024.