Nivolumab plus ipilimumab combination therapy in patients with advanced hepatocellular carcinoma previously treated with sorafenib: 5-year results from CheckMate 040.

BACKGROUND: Nivolumab plus ipilimumab demonstrated promising clinical activity and durable responses in sorafenib-treated patients with advanced hepatocellular carcinoma (HCC) in the CheckMate 040 study at 30.7-month median follow-up. Here, we present 5-year results from this cohort. PATIENTS AND METHODS: Patients were randomized 1 : 1 : 1 to arm A [nivolumab 1 mg/kg plus ipilimumab 3 mg/kg Q3W (four doses)] or arm B [nivolumab 3 mg/kg plus ipilimumab 1 mg/kg Q3W (four doses)], each followed by nivolumab 240 mg Q2W, or arm C (nivolumab 3 mg/kg Q2W plus ipilimumab 1 mg/kg Q6W). The primary objectives were safety, tolerability, investigator-assessed objective response rate (ORR), and duration of response (DOR) per RECIST version 1.1. RESULTS: A total of 148 patients were randomized across treatment arms. At 60-month minimum follow-up (62.6-month median follow-up), the ORR was 34% (n = 17), 27% (n = 13), and 29% (n = 14) in arms A, B, and C, respectively. The median DOR was 51.2 months [95% confidence interval (CI) 12.6 months-not estimable (NE)], 15.2 months (95% CI 7.1 months-NE), and 21.7 months (95% CI 4.2 months-NE), respectively. The median overall survival (OS) was 22.2 months (34/50; 95% CI 9.4-54.8 months) in arm A, 12.5 months (38/49; 95% CI 7.6-16.4 months) in arm B, and 12.7 months (40/49; 95% CI 7.4-30.5 months) in arm C; 60-month OS rates were 29%, 19%, and 21%, respectively. In an exploratory analysis of OS by response (6-month landmark), the median OS was meaningfully longer for responders versus nonresponders for all arms. No new safety signals were identified with longer follow-up. There were no new discontinuations due to immune-mediated adverse events since the primary analysis. CONCLUSIONS: Consistent with the primary analysis, the arm A regimen of nivolumab plus ipilimumab continued to demonstrate clinically meaningful responses and long-term survival benefit, with no new safety signals in patients with advanced HCC following sorafenib treatment, further supporting its use as a second-line treatment in these patients.

Nivolumab in sorafenib-naive and sorafenib-experienced patients with advanced hepatocellular carcinoma: 5-year follow-up from CheckMate 040.

BACKGROUND: Patients with advanced hepatocellular carcinoma (aHCC) have a poor prognosis and high mortality. Nivolumab monotherapy demonstrated clinical benefit with an acceptable safety profile in patients with aHCC in the CheckMate 040 study. Five-year follow-up of the sorafenib-naive and sorafenib-experienced groups of CheckMate 040 is presented here. PATIENTS AND METHODS: Patients received nivolumab monotherapy at dose levels of 0.1-10.0 mg/kg (dose-escalation phase) or 3 mg/kg (dose-expansion phase) every 2 weeks until disease progression or unacceptable toxicity. Primary endpoints were safety and tolerability (dose escalation), and objective response rate (ORR) by blinded independent central review (BICR) and by investigator as per RECIST version 1.1 (dose expansion). RESULTS: Eighty sorafenib-naive and 154 sorafenib-experienced patients were treated. Minimum follow-up in both groups was 60 months. ORR as per BICR was 20% [95% confidence interval (CI) 12% to 30%] and 14% (95% CI 9% to 21%) in the sorafenib-naive and sorafenib-experienced groups, respectively. Responses occurred regardless of HCC etiology or baseline tumor cell programmed death-ligand 1 (PD-L1) expression levels. Median overall survival (OS) was 26.6 months (95% CI 16.6-30.6 months) and 15.1 months (95% CI 13.0-18.2 months) in sorafenib-naive and sorafenib-experienced patients, respectively. The 3-year OS rates were 28% in the sorafenib-naive and 20% in the sorafenib-experienced groups; 5-year OS rates were 14% and 12%, respectively. No new safety signals were identified; grade 3/4 treatment-related adverse events were observed in 33% and 21% of patients in the sorafenib-naive and sorafenib-experienced groups, respectively. Biomarker analyses showed that baseline PD-L1 expression ≥1% was associated with higher ORR and longer OS compared with PD-L1 <1%. In the sorafenib-naive group, patients with OS ≥3 years exhibited higher baseline CD8 T-cell density compared with those with OS <1 year. CONCLUSION: With 5 years of follow-up, nivolumab monotherapy continued to provide durable clinical benefit with manageable safety in sorafenib-naive and sorafenib-experienced patients with aHCC.

The P Value Problem in Otolaryngology: Shifting to Effect Sizes and Confidence Intervals.

There is a lack of reporting effect sizes and confidence intervals in the current biomedical literature. The objective of this article is to present a discussion of the recent paradigm shift encouraging the use of reporting effect sizes and confidence intervals. Although P values help to inform us about whether an effect exists due to chance, effect sizes inform us about the magnitude of the effect (clinical significance), and confidence intervals inform us about the range of plausible estimates for the general population mean (precision). Reporting effect sizes and confidence intervals is a necessary addition to the biomedical literature, and these concepts are reviewed in this article.

Incidence, characteristics and course of narrow phenotype paediatric bipolar I disorder in the British Isles.

OBJECTIVE: To estimate the surveillance incidence of first-time diagnosis of narrow phenotype bipolar I disorder (NPBDI) in young people under 16 years by consultants in child and adolescent psychiatry (CCAP) in the British Isles and describe symptoms, comorbidity, associated factors, management strategies and clinical outcomes at 1-year follow-up. METHOD: Active prospective surveillance epidemiology was utilised to ask 730 CCAP to report cases of NPBDI using the child and adolescent psychiatry surveillance system. RESULTS: Of the 151 cases of NPBDI reported, 33 (age range 10-15.11 years) met the DSM-IV analytical case definition with 60% having had previously undiagnosed mood episodes. The minimum 12-month incidence of NPBDI in the British Isles was 0.59/100 000 (95% CI 0.41-0.84). Irritability was reported in 72% cases and comorbid conditions in 51.5% cases with 48.5% cases requiring admission to hospital. Relapses occurred in 56.67% cases during the 1-year follow-up. CONCLUSIONS: These rates suggest that the first-time diagnosis of NPBDI in young people <16 years of age by CCAP in the British Isles is infrequent; however, the rates of relapse and admission to hospital warrant close monitoring.

Guide to Academic Research Career Development.

OBJECTIVES/HYPOTHESIS: Development of an academic career easily follows a clinical course for which there are multiple role models; however, development of an academic research career involves few role models, and rarely do instructional guides reach out to the new faculty. The purpose of this article is to present the cumulative experiences of previously and currently funded authors to serve as a guide to young as well as older faculty for developing their research careers. STUDY DESIGN: Cumulative experiences of research-dedicated faculty. METHODS: This article is the result of lessons learned from developing a Triological Society National Physician-Scientist Program and Network, as well as the cumulative experiences of the authors. RESULTS: Table I illustrates key elements in developing a serious research career. Table II records the career courses of five surgeon-scientists, highlighting the continued theme focus with theme-specific publications and progressive grants. These cumulative experiences have face validity but have not been objectively tested. The value added is a composite of 50 years of experiences from authors committed to research career development for themselves and others. CONCLUSION: Crucial elements in developing a research career are a desire for and commitment to high-quality research, a focus on an overall theme of progressive hypothesis-driven investigations, research guidance, a willingness to spend the time required, and an ability to learn from and withstand failure. LEVEL OF EVIDENCE: 5.

Practical guide to understanding clinical research compliance.

Noncompliance with federal regulations, as monitored through institutional review boards for the ethical conduct of clinical research, can occur, even to seasoned investigators. The cause of this noncompliance can be that an investigator is overloaded, does not know the regulations, or does not take the time to pay attention to the details. Sometimes it happens just because of inevitable human error that can befall us all at any time. The authors begin by citing the inherent differences between clinical practice and clinical research. This is followed by an illustration of common noncompliance errors, with examples, followed by general and specific concepts and methods to minimize noncompliance events. The objective of this article is to condense the myriad details involved in conducting clinical research into a set of manageable recommendations that can be recalled easily before and during the research. The material supporting these recommendations comes from years of institutional review board work at several institutions and consultation with experienced principal investigators and their research coordinators.

Practical guide to understanding Comparative Effectiveness Research (CER).

"Comparative effectiveness research" (CER) is not a new concept; however, recently it has been popularized as a method to develop scientifically sound actionable data by which patients, physicians, payers, and policymakers may make informed health care decisions. Fundamental to CER is that the comparative data are derived from large diverse populations of patients assembled from point-of-care general primary care practices and that measured outcomes include patient value judgments. The challenge is to obtain scientifically valid data to be acted upon by decision-making stakeholders with potentially quite diversely different agenda. The process requires very thoughtful research designs modulated by complex statistical and analytic methods. This article is composed of a guiding narrative with an extensive set of tables outlining many of the details required in performing and understanding CER. It ends with short discussions of three example papers, limitations of the method, and how a practicing physician may view such reports.

Practical guide to understanding the need for clinical practice guidelines.

With recent changes in the landscape of health care, clinical practice guidelines (CPGs) have proliferated. Attitudes about guidelines differ considerably, forming 2 competing viewpoints with considerable tension between them. Some feel CPGs are unneeded or are efforts to create automated "cookie cutter" medical practice; at best, they are perceived as suggestions that may be altered by experience. Others feel they are mandates that must be followed to the letter. This article attempts to explain how and why we have arrived at this point and to explain the origins of the differing viewpoints. We begin by describing the 2 viewpoints and proceed to define the origin of medicine as a profession and to chronicle the evolution of health insurance, medical education, and scientific methods for evaluating evidence.

Practical guide to understanding multivariable analyses, Part B: conjunctive consolidation.

Conjunctive consolidation, one method of multivariable analysis by arranging data into clusters, is intuitive and transparent. An unexpected consequence in writing this article was the discovery of just how useful it is in critically analyzing articles and in designing new projects. It has stimulated a fresh understanding as to the value of multivariable thinking in all clinical research. This article is organized into the sequential steps for performing conjunctive consolidation for critically analyzing an article of interest and for completing the process, pending all required data are available. Investigators, particularly those who perform clinical research, should consider conjunctive consolidation as a valuable method of multivariable analysis with which to report data.

Practical guide to understanding multivariable analyses: Part A.

Multivariable analyses are complex statistical methods to evaluate the impact of multiple variables on outcomes of interest. Books have been written on each of these methods detailing the mathematical and statistical objectives and processes. However, we have found very little in the way of brief reports that help the nonstatistically trained physician obtain a basic understanding of multivariable analyses in order to have some understanding of the increasing literature using these methods. This work is organized in 2 parts. This article, Part A, addresses the "big 4" algebraic methods of multivariable analysis. The primary focus of Part A is to present a brief "primer" to help the reader understand the methods and uses; it expressly avoids the many details of statistical assumptions, calculations, and myriad branching alternatives. Part B will concentrate on conjunctive consolidation and will focus on enough information to allow the interested reader to actually perform the analysis. For the statistical scholar, we have included references to several voluminous serious works.

Patient recall of surgical information after day case knee arthroscopy.

PURPOSE: Day case knee arthroscopy is frequently performed on dedicated lists designed to optimise the throughput of patients. This could affect patient recall of clinical information with clinical, ethical and medicolegal consequences. The purpose of this study was to assess patient recall after knee arthroscopy and identify potential contributory factors. METHODS: Seventy-two patients undergoing day case knee arthroscopy were provided with information about their surgery post-operatively and tested for recall of the information prior to discharge. All patients underwent cognitive assessment when information was delivered and again when tested. Patient recall was correlated with demographic and anaesthetic factors and a multivariate regression model was used to identify risk factors for reduced recall. RESULTS: Recall overall was poor. Significant independent risk factors for reduced recall were reduced cognitive state at the time of information delivery and a shorter time between surgery and information delivery. Duration of anaesthesia, use of sedatives and use of opiate analgesia were not significantly correlated with recall. CONCLUSIONS: Information recall after day case knee athroscopy may be suboptimal. Allowing more time between surgery and information delivery may improve recall. However, this may be difficult during the course of a busy list and surgeons should consider using additional techniques to improve patient recall after surgery to reduce the risk of patient anxiety or non-compliance. LEVEL OF EVIDENCE: IV.

Sudden sensorineural hearing loss and delayed complete sudden spontaneous recovery.

This is a case report of a 53-yr-old female who experienced sudden sensorineural hearing loss (SSNHL) accompanied by roaring tinnitus in her right ear. The patient's hearing partially improved in the low frequencies in response to intratympanic injections. Given that her hearing loss did not improve further, the patient was fitted with a hearing aid to mask the tinnitus and restore a sense of balance between the two ears. Approximately 9 mo postonset of the SSNHL, a complete spontaneous recovery of hearing occurred. Such a delayed and complete recovery is highly unusual. This case highlights that the spontaneous recovery in hearing indicates that the pathological cause for the SSNHL involved a process that was capable of repair or regeneration, thus ruling out pathologies related to cochlear hair cell destruction or nerve fiber loss. This leaves a possibility that the event causing the onset of the SSNHL resulted in a disruption of the ion homeostatic properties of the cochlea via the production of the endocochlear potential.

Auditory brainstem response testing in neurodiagnosis: structure versus function.

This case report describes a 44-yr-old female referred by an outside facility who presented with progressive hearing loss in her left ear. Magnetic resonance imaging (MRI) results were normal, but a battery of audiological tests suggested neural hearing loss in the left ear. Following diagnosis of left neural hearing loss, the patient was successfully fit with a hearing aid on the left ear. This case report underlines the importance of using a battery of medical, radiologic, and audiological tests in the accurate determination of hearing loss site of lesion. Obvious retrocochlear dysfunction was revealed via auditory brainstem response (ABR) testing. MRI did not reveal underlying structural abnormality. Without the addition of the ABR to the diagnostic test battery, a cochlear hearing loss site of lesion would most likely have been diagnosed. Accurate diagnosis of hearing loss site of lesion is critical for patient counseling and treatment as well as for patient follow-up and monitoring.

Sequential bilateral cochlear implantation in a patient with bilateral Ménière's disease.

This case study describes a 45-yr-old female with bilateral, profound sensorineural hearing loss due to Ménière's disease. She received her first cochlear implant in the right ear in 2008 and the second cochlear implant in the left ear in 2010. The case study examines the enhancement to speech recognition, particularly in noise, provided by bilateral cochlear implants. Speech recognition tests were administered prior to obtaining the second implant and at a number of test intervals following activation of the second device. Speech recognition in quiet and noise as well as localization abilities were assessed in several conditions to determine bilateral benefit and performance differences between ears. The results of the speech recognition testing indicated a substantial improvement in the patient's ability to understand speech in noise and her ability to localize sound when using bilateral cochlear implants compared to using a unilateral implant or an implant and a hearing aid. In addition, the patient reported considerable improvement in her ability to communicate in daily life when using bilateral implants versus a unilateral implant. This case suggests that cochlear implantation is a viable option for patients who have lost their hearing to Ménière's disease even when a number of medical treatments and surgical interventions have been performed to control vertigo. In the case presented, bilateral cochlear implantation was necessary for this patient to communicate successfully at home and at work.

Practical guide to choosing an appropriate data display.

The primary objective of graphing research data is to communicate key information visually in a rapid, accurate, and concise way. Graphs might be considered visual take-home lessons of the major point(s) of the manuscript. In choosing a graph, it is tempting to concentrate only on ways of illustrating summary statements characterizing the group(s). However, individual patients are unique, and their characteristics or outcomes may not be predicted by a group summary. Consequently, if possible, graphs should demonstrate individual responses as well as group summaries. "Graphical literacy," "graphical excellence," and "graphical acumen" are achievable with work and collaboration. To produce a well-designed graph, a combination of by-subject detail and overall results should be the goal within the same illustration. The practice gap addressed in this article is that little attention from authors, reviewers, editors, and publishers seems to be paid to graphical literacy. The purpose of this article is to present some practical guidelines for choosing or evaluating more appropriate data displays.

Hyperventilation-induced nystagmus and vertigo after stereotactic radiotherapy for vestibular schwannoma.

OBJECTIVE: To describe the phenomenon of hyperventilation-induced nystagmus (HVN) after stereotactic radiotherapy for vestibular schwannoma. PATIENTS: We present 2 patients with vestibular schwannoma and no pretreatment vestibular symptoms who both received stereotactic radiotherapy. Within 2 months of completing treatment, both patients developed intense vertigo while exerting themselves. Video-oculography demonstrated an intense nystagmus with the fast phase directed toward the side of the schwannoma in both patients. INTERVENTION: Diagnostic. RESULTS: Patients who have undergone surgical resection of their vestibular schwannoma, or have a large tumor, will often demonstrate HVN with the fast phase directed away from the side of the tumor. This is distinct from patients with smaller lesions who have a fast-phase nystagmus toward the tumor's side. This second type of nystagmus is thought to originate from changes in the extracellular calcium concentration secondary to hyperventilation-induced alkalosis. CONCLUSION: We hypothesize that stereotactic radiotherapy induced greater demyelination of the vestibular nerve leading to the observable sign of HVN. These patients represent the first reported cases of HVN after stereotactic radiation and illustrate the pathophysiology of HVN, which may lead to a greater understanding of the effects of stereotactic radiotherapy.

Management of young onset colorectal cancer: divergent practice in the East of England.

AIM: According to the revised Bethesda Guidelines, colorectal cancer (CRC) occurring under age 50 years should be screened to exclude Lynch syndrome. However, in current practice in East Anglia, tumour screening is initiated only after genetics referral, reserved for those with a strong pedigree. This study aimed to determine how many patients with young-onset CRC undergo tumour screening in hospitals in East Anglia. METHOD: A retrospective case notes review over 5 years in four hospitals was undertaken to determine what proportion of those with young-onset CRC underwent referral for tumour screening and to assess local practices in terms of patient counselling and management. RESULTS: One hundred and twenty-two patients were included. There was an average yearly caseload of 6-9 patients per hospital. Documented family history was rare, as was counselling concerning metachronous and extra-colonic tumour risk and CRC risk in relatives. The rate of referral for genetic testing varied from 44% to 65%. Postoperative colonoscopic surveillance was inconsistent. CONCLUSION: Many patients with young-onset CRC are managed as sporadic cancers, without Lynch syndrome having been excluded. This may have implications for survival of patients and any affected relatives. A streamlined management algorithm for tumour screening and genetics referral is recommended.