Total knee arthroplasty after high tibial osteotomy: a registry-based case-control study of 1,036 knees.

INTRODUCTION: Total knee arthroplasty (TKA) after high tibial osteotomy (HTO) is a technically demanding procedure, and concerns have been raised that previous HTO might compromise the outcome of TKA. The aims of the study were to assess the survivorship of TKA after HTO and to determine whether the survivorship is similar to that of primary TKA without previous HTO. MATERIALS AND METHODS: Using the Finnish Arthroplasty Register and the National Hospital Discharge Register, we extracted the data of 1,036 patients [mean age 64.3 years; followup 6.7 years (0-22)] who had undergone TKA after a previous HTO between 1987 and 2008. From this cohort, we calculated the Kaplan-Meier survivorship and compared the survivorship of these cases to that of 4,143 age- and gender-matched patients who had undergone primary TKAs without previous HTO. RESULTS: In the TKA after HTO group, we found Kaplan-Meier survivorship to be 95.3% at 5 years, 91.8% at 10 years, and 88.4% at 15 years. Those survivorship values were lower than those of patients who had TKA without previous HTO (97.2, 94.5, and 90.6%, respectively) (hazard ratio 1.40; 95% confidence interval 1.09-1.81; p = 0.010). CONCLUSIONS: Previous studies have described technical difficulties during the TKA procedure after HTO, but they have found no adverse effects on the outcome. Our study supports previous research, and despite the slightly higher revision rate, TKA after HTO provides satisfactory results when compared to routine primary TKAs.

Assessing non-cancer-related health status of US cancer patients: other-cause survival and comorbidity prevalence.

With advances in prevention, screening, and treatment, cancer patients are living longer; hence, non-cancer-related health status will likely play a larger role in determining their life expectancy. In this study, we present a novel method for characterizing non-cancer--related health status of cancer patients using population-based cancer registry data. We assessed non-cancer-related health status in the context of survival from other causes of death and prevalence of comorbidities. Data from the Surveillance, Epidemiology, and End Results program (2000-2006) were used to analyze cancer patients' survival probabilities by cause of death. Other-cause survival was estimated using a left-truncated survival method with the hazard of death due to other causes characterized as a function of age. Surveillance, Epidemiology, and End Results data linked to Medicare claims (1992-2005) were used to quantify comorbidity prevalence. Relative to the US population, survival from a non-cancer-related death was higher for patients diagnosed with early stage breast and prostate cancer but lower for lung cancer patients at all stages. Lung cancer patients had worse comorbidity status than did other cancer patients. The present study represents the first attempt to evaluate the non-cancer-related health status of US cancer patients by cancer site (breast, prostate, colorectal, and lung) and stage. The findings provide insight into non-cancer-related health issues among cancer patients and their risk of dying from other causes.

Mortality as an indicator of patient safety in orthopaedics: lessons from qualitative analysis of a database of medical errors.

BACKGROUND: Orthopaedic surgery is a high-risk specialty in which errors will undoubtedly occur. Patient safety incidents can yield valuable information to generate solutions and prevent future cases of avoidable harm. The aim of this study was to understand the causative factors leading to all unnecessary deaths in orthopaedics and trauma surgery reported to the National Patient Safety Agency (NPSA) over a four-year period (2005-2009), using a qualitative approach. METHODS: Reports made to the NPSA are categorised and stored in the database as free-text data. A search was undertaken to identify the cases of all-cause mortality in orthopaedic and trauma surgery, and the free-text elements were used for thematic analysis. Descriptive statistics were calculated based on the incidents reported. This included presenting the number of times categories of incidents had the same or similar response. Superordinate and subordinate categories were created. RESULTS: A total of 257 incident reports were analysed. Four main thematic categories emerged. These were: (1) stages of the surgical journey - 118/191 (62%) of deaths occurred in the post-operative phase; (2) causes of patient deaths - 32% were related to severe infections; (3) reported quality of medical interventions - 65% of patients experienced minimal or delayed treatment; (4) skills of healthcare professionals - 44% of deaths had a failure in non-technical skills. CONCLUSIONS: Most complications in orthopaedic surgery can be dealt with adequately, provided they are anticipated and that risk-reduction strategies are instituted. Surgeons take pride in the precision of operative techniques; perhaps it is time to enshrine the multimodal tools available to ensure safer patient care.

Considerations on Integrating Prostate-Specific Membrane Antigen Positron Emission Tomography Imaging Into Clinical Prostate Cancer Trials by National Clinical Trials Network Cooperative Groups.

PURPOSE: As prostate-specific membrane antigen (PSMA) positron emission tomography (PET) becomes increasingly available in the United States, the greater sensitivity of the technology in comparison to conventional imaging poses challenges for clinical trials. The NCI Clinical Imaging Steering Committee (CISC) PSMA PET Working Group was convened to coordinate the identification of these challenges in various clinical scenarios and to develop consensus recommendations on how best to integrate PSMA PET into ongoing and upcoming National Clinical Trials Network (NCTN) trials. METHODS: NCI CISC and NCI Genitourinary Steering Committee members and leadership nominated clinicians, biostatisticians, patient advocates, and other imaging experts for inclusion in the PSMA PET Working Group. From April to July 2021, the working group met independently and in conjunction with the CISC to frame challenges, including stage migration, response assessment, trial logistics, and statistical challenges, and to discuss proposed solutions. An anonymous, open-ended survey was distributed to members to collect feedback on challenges faced. Representatives from each NCTN group were invited to present an overview of affected trials. From these discussions, the consensus document was developed and circulated for the inclusion of multiple rounds of feedback from both the Working Group and CISC. RESULTS: The current consensus document outlines the key challenges for clinical prostate cancer trials resulting from the increasing availability of PSMA PET. We discuss implications for patient selection and definition of end points and provide guidance and potential solutions for different clinical scenarios, particularly with regard to best practices in defining eligibility criteria and outcome measures. RECOMMENDATIONS: This article provides guidance regarding clinical trial design and conduct, and the interpretation of trial results.

Vorinostat for treatment of cutaneous manifestations of advanced primary cutaneous T-cell lymphoma.

PURPOSE: To discuss vorinostat approval for treatment of cutaneous manifestations of advanced cutaneous T-cell lymphoma (CTCL). EXPERIMENTAL DESIGN: Data from 1 single-arm, open-label, multicenter pivotal trial and 11 other trials submitted to support the new drug application for vorinostat in the treatment of advanced primary CTCL were reviewed. The pivotal trial assessed responses by changes in overall skin disease score using a severity-weighted assessment tool (SWAT). Vorinostat could be considered active in CTCL if observed response rate was at least 20% and the lower bound of the corresponding 95% confidence interval (95% CI) excluded 5%. Patients reported pruritus relief using a questionnaire and a visual analogue scale. RESULTS: The pivotal trial enrolled 74 patients with stage IB or higher CTCL. Median number of prior treatments was 3, and 61 patients (82%) had stage IIB or higher disease. The objective response rate in the skin disease assessed by change in the overall SWAT score from the baseline was 30% (95% CI, 18.5 to 42.6) in patients with stage IIB or higher disease. Median response duration (end of response defined by 50% increase in SWAT score from the nadir) was 168 days. Median time to tumor progression was 148 days for overall population and 169 days for patients with stage IIB or higher disease. Assessment of pruritus relief was considered unreliable. CONCLUSIONS: Vorinostat showed activity in CTCL, and skin responses were a clinical benefit. Vorinostat was approved for treatment of cutaneous manifestations of CTCL. A nonblinded, single-arm trial did not allow a reliable assessment of pruritus relief.

Blood neutrophil activation markers in severe asthma: lack of inhibition by prednisolone therapy.

BACKGROUND: Neutrophils are increased in the airways and in induced sputum of severe asthma patients. We determined the expression of activation markers from circulating neutrophils in severe asthma, and their supressibility by corticosteroids. METHODS: We compared blood neutrophils from mild, moderate-to-severe and severe steroid-dependent asthma, and non-asthmatics (n = 10 each). We examined the effect of adding or increasing oral prednisolone (30 mg/day;1 week). RESULTS: Flow cytometric expression of CD35 and CD11b, but not of CD62L or CD18, was increased in severe asthma. F-met-leu-phe increased CD11b, CD35 and CD18 and decreased CD62L expression in all groups, with a greater CD35 increase in severe asthma. In severe steroid-dependent asthma, an increase in prednisolone dose had no effect on neutrophil markers particularly CD62L, but reduced CD11b and CD62L on eosinophils. Phorbol myristate acetate-stimulated oxidative burst and IL-8 release by IL-1beta, lipopolysaccharide and GM-CSF in whole blood from mild but not severe asthmatics were inhibited after prednisolone. There were no differences in myeloperoxidase or neutrophil elastase release from purified neutrophils. CONCLUSION: Because blood neutrophils in severe asthma are activated and are not inhibited by oral corticosteroids, they may be important in the pathogenesis of severe asthma.

Letrozole in the extended adjuvant treatment of postmenopausal women with history of early-stage breast cancer who have completed 5 years of adjuvant tamoxifen.

PURPOSE: To present the basis of the decision of the Food and Drug Administration to grant accelerated approval for letrozole for extended adjuvant treatment of early-stage breast cancer in postmenopausal women after completion of adjuvant tamoxifen. EXPERIMENTAL DESIGN: The Food and Drug Administration reviewed the data from the MA17 trial, a single, multinational, randomized, double-blind, and placebo-controlled trial, submitted by the applicant to support the proposed new indication. RESULTS: MA17 consisted of a core study and Lipid and Bone Mineral Density safety substudies. It enrolled 5,187 patients. In the core study, median treatment duration was 24 months and median follow-up duration was 27.4 months. Using a conventional definition of disease-free survival, 122 events on letrozole and 193 events on placebo were observed (hazard ratio, 0.62; 95% confidence interval, 0.49-0.78; P = 0.00003). Distant disease-free survival also improved with letrozole, 55 versus 92 events (hazard ratio, 0.61; 95% confidence interval, 0.44-0.84; P = 0.003). No statistically significant improvement in overall survival was observed. Hot flushes, arthralgia/arthritis, myalgia, and new diagnosis of osteoporosis were more common on letrozole. Frequency of fractures and cardiovascular ischemic events was not significantly different. A statistically significant mean decrease in bone mineral density in the hip occurred at 24 months on letrozole. CONCLUSIONS: Letrozole administration led to a statistically significant prolongation in disease-free survival. Fractures and cardiovascular events were similar to placebo; however, new diagnoses of osteoporosis were more frequent. Short duration of treatment and follow-up precluded assessment of long-term safety and efficacy. Thus, accelerated approval was granted instead of regular approval.

Current status of clinical trials in head and neck cancer 2014.

INTRODUCTION: The last few years have seen significant increase in the number of available clinical trials in head and neck cancer. It has been difficult to stay abreast of these efforts because multiple cooperative groups and institutions are engaged in their recruitment. This review presents the state of the art of available clinical trials organized around major research themes. DATA SOURCES: Published literature, published cooperative group monographs, expert review. REVIEW METHODS: Initial themes in head and neck cancer clinical trial development were first identified along with examples. Opinions from an international panel of multidisciplinary experts were then solicited. RESULTS/DISCUSSION: Current major themes of head and neck clinical trials centered on 5 major themes: (1) recognition of human papillomavirus oropharynx cancer and optimal treatment strategies, (2) defining the role of transoral surgery in head and neck cancer treatment, (3) improving postoperative adjuvant treatment, (4) investigation of rare malignancies, and (5) the importance of biomarker-driven, innovative, and targeted therapy investigation. CONCLUSIONS: A number of exciting clinical trials are currently in development or accrual with the potential for tremendous impact and improvement of the treatment of head and neck cancer. IMPLICATIONS FOR PRACTICE: Awareness by practicing otolaryngologists and trainees of these current themes will be essential for study accrual, success, and improvement in the care of head and neck cancer.

Metal-on-metal bearings, inflammatory pseudotumours and their neurological manifestations.

Metal-on-metal bearings have become more popular for hip arthroplasty in younger patients in the last 15 years. We present a review of the neurological consequences relating to such bearing surfaces illustrated by an appropriate case report. The mechanisms of increased metal ion production and pseudotumour formation are discussed. If unexplained neurology, hip/groin pain or a localised mass around the hip are present with a metal bearing hip then urgent referral to a specialist orthopaedic surgeon is warranted for consideration of exchange arthroplasty.

A severe case of multisystem sarcoidosis complicated by aspergillosis and aspergillomas.

The authors present an atypical case of multisystem sarcoidosis presenting at a late stage with severe lupus pernio sarcoidosis skin lesions and stage IV pulmonary sarcoidosis complicated by semi-invasive chronic necrotising aspergillosis and aspergillomas. Lepromatous leprosy, tuberculosis and active atypical mycobacterial infection had to be ruled out en route to reaching the final diagnoses. His case presented us with a management dilemma, specifically concerning treatment of his sarcoidosis with corticosteroid and other immunosuppressive agents, as these risked aggravating his active invasive fungal disease. The patient's semi-invasive aspergillosis was treated first with antifungal agents for 6 months before treatment with corticosteroids and hydroxychloroquine was started. The patient has tolerated his treatments well, and over a 3-year follow-up period, has had a significant improvement in his respiratory and systemic symptoms, with some improvement in his lupus pernio sarcoidosis skin lesions.

FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma.

On October 6, 2006, the U.S. Food and Drug Administration granted regular approval to vorinostat (Zolinza(R); Merck & Co., Inc., Whitehouse Station, NJ), a histone deacetylase inhibitor, for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients with progressive, persistent, or recurrent disease on or following two systemic therapies. The pivotal study supporting approval was a single-arm open-label phase II trial that enrolled 74 patients with stage IB and higher CTCL who had failed two systemic therapies (one of which must have contained bexarotene). Patients received vorinostat at a dose of 400 mg orally once daily, which could be reduced for toxicity to 300 mg daily or 300 mg 5 days a week. The median age of patients was 61 years. Sixty-one patients (82%) had stage IIB or higher CTCL and 30 patients (41%) had Sézary syndrome. The median duration of protocol treatment was 118 days. The primary efficacy endpoint was objective response assessed by the Severity-Weighted Assessment Tool. The objective response rate was 30% (95% confidence interval [CI], 19.7%-41.5%), the estimated median response duration was 168 days, and the median time to tumor progression was 202 days. An additional single-center study enrolled 33 patients with similar baseline and demographic features as the pivotal trial. Thirteen of the 33 received vorinostat (400 mg/day). The response rate in these 13 patients was 31% (95% CI, 9.1%-61.4%). The most common clinical adverse events (AEs) of any grade were diarrhea (52%), fatigue (52%), nausea (41%), and anorexia (24%). Grade 3 or 4 clinical AEs included fatigue (4%) and pulmonary embolism (5%). Hematologic laboratory abnormalities included thrombocytopenia (26%) and anemia (14%). Chemistry laboratory abnormalities included increased creatinine (16%), increased serum glucose (69%), and proteinuria (51%). Most abnormalities were National Cancer Institute Common Terminology Criteria for Adverse Events grade 1 or 2. Grade 3 or greater chemistry abnormalities included hyperglycemia, hypertriglyceridemia, and hyperuricemia, hypoglycemia, hypokalemia, hyponatremia, hyperkalemia, hypercholesterolemia, hypophosphatemia, and increased creatinine.