Revisiting “Meniere’s Disease” as “Cervicogenic Endolymphatic Hydrops” and Other Vestibular and Cervicogenic Vertigo as “Spectrum of Same Disease”: A Novel Concept

Vertigo and dizziness are one of the commonest and least understood symptom. Vestibular vertigo of Meniere’s disease and Benign Paroxysmal positional vertigo (BPPV) and cervicogenic dizziness are classified as separate entities. Cervicogenic dizziness is not considered the domain of Otolaryngologists, as it is mainly related to neck proprioceptors. Headache and neck pain, have been found to be associated with both Meniere’s disease and BPPV, so is cervicogenic dizziness. The present study was undertaken to study the association between cervical signs and symptoms in patients with Vestibular Vertigo of Meniere''s disease, Benign Paroxysmal Positional Vertigo and cervicogenic dizziness. 132 patients complaining of vertigo and diagnosed with Meniere’s disease, BPPV or cervicogenic dizziness were examined for symptoms and signs related to neck, shoulder and muscle tightness and asymmetry. Most of the patients of Meniere’s Disease (80% for unilateral and 88.23% for bilateral), Benign Paroxysmal Positional Vertigo (75%for right sided BPPV, 66.67% for left sided BPPV) and cervicogenic dizziness (90%) had associated symptoms of neck pain or headache, and were found to be positive for neck tightness and/or asymmetry of shoulder. Headache was more common in patients with Meniere’s Disease. Vestibular Dizziness of Meniere’s Disease, Benign Paroxysmal Positional Vertigo and Cervicogenic Dizziness may be spectrum of the same disease with underlying myofascial problems. Meniere’s Disease of Idiopathic or primary type needs to be revisited as Cervicogenic Hydrops.     

Clinicopathologic and protein markers distinguishing the “polymerase epsilon exonuclease” from the “copy number low” subtype of endometrial cancer

ObjectiveThe need to perform genetic sequencing to diagnose the polymerase epsilon exonuclease (POLE) subtype of endometrial cancer (EC) hinders the adoption of molecular classification. We investigated clinicopathologic and protein markers that distinguish the POLE from the copy number (CN)-low subtype in EC.MethodsNinety-one samples (15 POLE, 76 CN-low) were selected from The Cancer Genome Atlas EC dataset. Clinicopathologic and normalized reverse phase protein array expression data were analyzed for associations with the subtypes. A logistic model including selected markers was constructed by stepwise selection using area under the curve (AUC) from 5-fold cross-validation (CV). The selected markers were validated using immunohistochemistry (IHC) in a separate cohort.ResultsBody mass index (BMI) and tumor grade were significantly associated with the POLE subtype. With BMI and tumor grade as covariates, 5 proteins were associated with the EC subtypes. The stepwise selection method identified BMI, cyclin B1, caspase 8, and X-box binding protein 1 (XBP1) as markers distinguishing the POLE from the CN-low subtype. The mean of CV AUC, sensitivity, specificity, and balanced accuracy of the selected model were 0.97, 0.91, 0.87, and 0.89, respectively. IHC validation showed that cyclin B1 expression was significantly higher in the POLE than in the CN-low subtype and receiver operating characteristic curve of cyclin B1 expression in IHC revealed AUC of 0.683.ConclusionBMI and expression of cyclin B1, caspase 8, and XBP1 are candidate markers distinguishing the POLE from the CN-low subtype. Cyclin B1 IHC may replace POLE sequencing in molecular classification of EC.     

Surrogacy Beyond Prognosis: The Importance of “Trial-Level” Surrogacy

Many candidate surrogate endpoints are currently assessed using a 2-level statistical approach, which consists in checking whether (1) the potential surrogate is associated with the final endpoint in individual patients and (2) the effect of treatment on the surrogate can be used to reliably predict the effect of treatment on the final endpoint. In some situations, condition (1) is fulfilled but condition (2) is not. We use concepts of causal inference to explain this apparently paradoxical situation, illustrating this review with 2 contrasting examples in operable breast cancer: the example of pathological complete response (pCR) and that of disease-free survival (DFS). In a previous meta-analysis, pCR has been shown to be a strong and independent prognostic factor for event-free survival (EFS) and overall survival (OS) after neoadjuvant treatment of operable breast cancer. Yet, in randomized trials, the effects of experimental treatments on pCR have not translated into predictable effects on EFS or OS, making pCR an “individual-level” surrogate, but not a “trial-level” surrogate. In contrast, DFS has been shown to be an acceptable surrogate for OS at both the individual and trial levels in early, HER2-positive breast cancer. The distinction between the prognostic and predictive roles of a tentative surrogate, not always made in the literature, avoids unnecessary confusion and allows better understanding of what it takes to validate a surrogate endpoint that is truly able to replace a final endpoint.

Many candidate surrogate endpoints are currently assessed using a two-level statistical approach. This article explores tentative surrogates versus actual outcomes, focusing on the “surrogate paradox”.

Implications for PracticeThe distinction between the prognostic and predictive roles of a tentative surrogate, not always made in the literature, avoids unnecessary confusion and allows better understanding of what it takes to validate a surrogate endpoint that is truly able to replace a final endpoint.     

Correction to “Novel long non-coding RNA LINC02532 promotes gastric cancer cell proliferation,migration, and invasion in vitro”

We have replaced the misapplied images and the revised Figure 3 is provided.     

Opportunities and challenges for the development of “core outcome sets” in neuro-oncology

Core Outcome Sets (COS) define minimum outcomes to be measured and reported in clinical effectiveness trials for a particular health condition/health area. Despite recognition as critical to clinical research design for other health areas, none have been developed for neuro-oncology. COS development projects should carefully consider: scope (how the COS should be used), stakeholders involved in development (including patients as both research partners and participants), and consensus methodologies used (typically a Delphi survey and consensus meeting), as well as dissemination plans. Developing COS for neuro-oncology is potentially challenging due to extensive tumor subclassification (including molecular stratification), different symptoms related to anatomical tumor location, and variation in treatment options. Development of a COS specific to tumor subtype, in a specific location, for a particular intervention may be too narrow and would be unlikely to be used. Equally, a COS that is applicable across a wider area of neuro-oncology may be too broad and therefore lack specificity. This review describes why and how a COS may be developed, and discusses challenges for their development, specific to neuro-oncology. The COS under development are briefly described, including: adult glioma, incidental/untreated meningioma, meningioma requiring intervention, and adverse events from surgical intervention for pediatric brain tumors.     

Towards precision oncology in angiosarcomas using next generation “omic” technologies

Angiosarcomas are a group of aggressive tumors of vascular origin. Although thought to be a rare cancer constituting just 1–2% of all soft tissue sarcomas, recent observations suggest that angiosarcomas are more common amongst Asian populations as compared to the West, suggesting the possibility of distinct genetic or environmental triggers influencing its pathogenesis. Advances in genomic sequencing efforts have led to the discovery of ultraviolet mutation signatures and high tumor mutation burden as common features of angiosarcoma of the head and neck. In addition, multi-omic analyses integrated with clinical data identified 3 subtypes characterized by distinctive etiological and biological phenotypes, with potential implications on precision therapy. The systemic and local immune milieu, as well as the presence of “giant” tumor cells, was also recently demonstrated to influence clinical behavior and patient outcomes, further highlighting complexities of this disease. Improvements in next generation “omic”-based technologies are expected to improve our understanding of angiosarcoma and guide the development of precision oncology in this rare cancer.     

The Mandible Sparing “POSC Technique” for Management of Middle and Posterior Third Tongue Cancers

Cancer of the tongue forms more than 50% of oral cavity cancers. Generally, patients come with locally advanced tongue cancer. The treatment for this cancer is multi-modality. For resectable cancer, multiple surgical approaches are described in the literature. Mandibulotomy for resection of the middle and posterior third oral cancer is a well-established technique but it has its attended morbidity. We present our results of a new surgical technique, called the Peroral and submandibular cervical surgical approach wherein tongue cancer of middle third and posterior third is resected without mandibulotomy. The advantages of this technique are that the complications of malunion or non-union of bone are avoided, no chances of osteoradionecrosis or osteomyelitis, no need of periosteal elevation or damage, the malignancy is removed with wide margin with minimal blood loss, there is no scar on face or chin, morbidity of surgery is minimal. Also, the technique is easily reproducible.     

Factors Associated with “Survivor Identity” in Men with Breast Cancer

Cancer patients vary in their comfort with the label “survivor”. Here, we explore how comfortable males with breast cancer (BC) are about accepting the label cancer “survivor”. Separate univariate logistic regressions were performed to assess whether time since diagnosis, age, treatment status, and cancer stage were associated with comfort with the “survivor” label. Of the 70 males treated for BC who participated in the study, 58% moderately-to-strongly liked the term “survivor”, 26% were neutral, and 16% moderately-to-strongly disliked the term. Of the factors we explored, only a longer time since diagnosis was significantly associated with the men endorsing a survivor identity (OR = 1.02, p = 0.05). We discuss how our findings compare with literature reports on the comfort with the label “survivor” for women with BC and men with prostate cancer. Unlike males with prostate cancer, males with BC identify as “survivors” in line with women with BC. This suggests that survivor identity is more influenced by disease type and treatments received than with sex/gender identities.     

“We’re on a Merry-Go-Round”: Reflections of Patients and Carers after Completing Treatment for Sarcoma

Sarcoma is a rare cancer that has a significant impact on patients’ and carers’ quality of life. Despite this, there has been a paucity of research exploring the diverse experiences of patients and carers following sarcoma treatment. The aim of this study was to explore patients’ and carers’ reflections on life after treatment for sarcoma. A qualitative research design with a social constructionist epistemology was used. Participants included patients previously treated for sarcoma (n = 21) and family carers of patients treated for sarcoma (n = 16). Participants completed semi-structured interviews which were analysed using thematic analysis. Three primary themes were identified: “This journey is never going to be over”, “But what happens when I am better?”, and finding a silver lining. Participants represented sarcoma as having a long-term, and sometimes indefinite, threat on their life that they had limited control over. Conclusions: This study highlight the heterogeneous and ongoing needs of sarcoma survivors and their families. Patients and carers strove to translate their experiences in a meaningful way, such as by improving outcomes for other people affected by sarcoma. Parental carers in particular attempted to protect the patient from the ongoing stress of managing the disease.     

Molecularly profiled trials: toward a framework of actions for the “nil actionables”

The sequencing of tumour or blood samples is increasingly used to stratify patients into clinical trials of molecularly targeted agents, and this approach has frequently demonstrated clinical benefit for those who are deemed eligible. But what of those who have no clear and evident molecular driver? What of those deemed to have “nil actionable” mutations? How might we deliver better therapeutic opportunities for those left behind in the clamour toward stratified therapeutics? And what significant learnings lie hidden in the data we amass but do not interrogate and understand? This Perspective article suggests a holistic approach to the future treatment of such patients, and sets a framework through which significant additional patient benefit might be achieved. In order to deliver upon this framework, it encourages and invites the clinical community to engage more enthusiastically and share learnings with colleagues in the early drug discovery community, in order to deliver a step change in patient care.Subject terms: Drug development, Target identification, Drug development