Statistical controversies in clinical research: basket trials, umbrella trials, and other master protocols: a review and examples.

In recent years, cancers once viewed as relatively homogeneous in terms of organ location and treatment strategy are now better understood to be increasingly heterogeneous across biomarker and genetically defined patient subgroups. This has produced a shift toward development of biomarker-targeted agents during a time when funding for cancer research has been limited; as a result, the need for improved operational efficiency in studying many agent-and-target combinations in parallel has emerged. Platform trials, basket trials, and umbrella trials are new approaches to clinical research driven by this need for enhanced efficiency in the modern era of increasingly specific cancer subpopulations and decreased resources to study treatments for individual cancer subtypes in a traditional way. In this review, we provide an overview of these new types of clinical trial designs, including discussions of motivation for their use, recommended terminology, examples, and challenges encountered in their application.

Survival following early-stage colon cancer: an ACCENT-based comparison of patients versus a matched international general population†.

BACKGROUND: Post-treatment survival experience of early colon cancer (CC) patients is well described in the literature, which states that cure is probable for some patients. However, comparisons of treated patients' survival versus that expected from a matched general population (MGP) are limited. PATIENTS AND METHODS: A total of 32 745 patients from 25 randomized adjuvant trials conducted from 1977 to 2012 in 41 countries were pooled. Observed long-term survival of these patients was compared with expected survival matched on sex, age, country, and year, both overall and by stage (II and III), sex, treatment [surgery, 5-fluorouracil (5-FU), 5-FU + oxaliplatin], age (<70 and 70+), enrollment year (pre/post 2000), and recurrence (yes/no). Comparisons were made at randomization and repeated conditional on survival to 1, 2, 3, and 5 years. CC and MGP equivalence was tested, and observed Kaplan-Meier survival rates compared with expected MGP rates 3 years out from each landmark. Analyses were also repeated in patients without recurrence. RESULTS: Within most cohorts, long-term survival of CC patients remained statistically worse than the MGP, though conditional survival generally improved over time. Among those surviving 5 years, stage II, oxaliplatin-treated, elderly, and recurrence-free patients achieved subsequent 3-year survival rates within 5% of the MGP, with recurrence-free patients achieving equivalence. CONCLUSIONS: Conditional on survival to 5 years, long-term survival of most CC patients on clinical trials remains modestly poorer than an MGP, but achieves MGP levels in some subgroups. These findings emphasize the need for access to quality care and improved treatment and follow-up strategies.

Genetic markers of treatment response to tumour necrosis factor-α inhibitors in the treatment of psoriasis.

BACKGROUND: Anti-tumour necrosis factor (TNF)-α therapies have revolutionized the treatment of psoriasis; however, up to 50% of patients do not respond satisfactorily. Identification of pharmacogenetic markers of treatment response is an important stop in the development of individually tailored treatment. The objective of this study was to assess the association of human leucocyte antigen (HLA)-C, killer immunoglobulin receptor (KIR) and vitamin D receptor (VDR) genotypes with response to treatment by etanercept and adalimumab. METHODS: This was a study of 138 patients with severe chronic plaque psoriasis who were treated with etanercept and/or adalimumab. Patients were classified as responders if they achieved a 75% reduction in PASI (PASI75) or were almost clear of psoriasis after 24 weeks of therapy. The frequencies of HLA-C and KIR haplotypes and VDR polymorphisms were compared in responders and nonresponders. The frequency of all HLA-C and KIR genotypes were compared between the 138 patients with psoriasis and 247 healthy donors. RESULTS: The number of patients classified as responders was 46 of 94 (49%) in the etanercept group and 50 of 76 (66%) in the adalimumab group. None of the HLA-C, KIR or VDR genotypes examined was predictive of treatment response. Compared with healthy controls, patients with psoriasis were more likely to have the HLA-C*06 genotype (P < 0.001) and less likely to have the HLA-C*07 genotype (P < 0.001), whereas there was no significant difference in frequencies of any KIR subtype. CONCLUSIONS: Using the candidate gene approach to identify biomarkers of treatment response in psoriasis may have limited utility. This was a small study with limited power. Future larger studies are needed to further examine these findings and to explore alternative approaches to identify predictors of treatment response to biological agents.

Clinical and genetic predictors of response to narrowband ultraviolet B for the treatment of chronic plaque psoriasis.

BACKGROUND: There is considerable variability in the number of exposures of narrowband ultraviolet B (NB-UVB) needed to clear psoriasis and in the duration of remission. OBJECTIVES: We assessed clinical parameters as predictors of the number of exposures needed to clear psoriasis and of the duration of remission. The influence of genetic polymorphisms of the vitamin D receptor (VDR) on treatment response was also evaluated. METHODS: This was a prospective study of 119 patients with chronic plaque psoriasis treated with NB-UVB until clearance was achieved. They were then followed for up to 1 year or until relapse occurred. The frequency of the Fok1, Apa1, Bsm1, Taq1 and rs4516035 polymorphisms of the VDR gene was assessed in 93 of the 119 patients. RESULTS: Of the 119 patients, 105 completed the course of phototherapy. Using an intention to treat analysis, 83% of the initial cohort (99 of 119 patients) achieved clearance, in a median of 26 exposures (interquartile range 19-35) with a median remission duration of 16 weeks (interquartile range 9-22). Factors significantly associated with a lower number of exposures to clearance included a lower baseline Psoriasis Area and Severity Index (P = 0·004), lower baseline Dermatology Life Quality Index (P = 0·047), female sex (P = 0·043), lower body weight (P = 0·008), and a higher number of previous courses of TL-01 (P = 0·005). The only clinical factor influencing remission duration was number of exposures (P = 0·0009), with a decreased remission duration in those who required a greater number of exposures to clear. The Taq1 VDR polymorphism (rs731236) also significantly predicted remission duration (P = 0·038). Patients homozygous for the C allele, which is associated with decreased activity of the VDR, had a shorter remission duration than those heterozygous for the allele (P = 0·026) and those homozygous for the T allele (P = 0·013). CONCLUSIONS: This study highlights the fact that both genetic and clinical parameters are important in determining treatment outcomes in psoriasis.

Yeast connection among 100 patients with chronic fatigue.

PURPOSE: Patients with the "yeast connection" are characterized by fatigue and multiple systemic symptoms. The purpose of our study was to compare patients with chronic fatigue who believed they had the yeast connection to patients with chronic fatigue without the yeast connection. PATIENTS AND METHODS: One hundred consecutive patients with a chief complaint of chronic fatigue were evaluated in a specialty clinic setting at the University of Connecticut Health Center. A complete history was obtained from each patient, and a 168-item review of systems and a complete physical examination were performed. RESULTS: Eight patients believed that their fatigue was due to chronic candidiasis. Of these eight, seven had psychiatric diagnoses that were judged to underlie their fatigue. Of the remaining 92 patients with chronic fatigue, 59 had underlying psychiatric diagnoses. We were unable to find historical, physical, or laboratory differences between chronic fatigue patients with or without the yeast connection. CONCLUSION: From this study and a review of the literature, we are unable to identify findings that are specific for the yeast connection.

Anatomical differences of port-wine stains in response to treatment with the pulsed dye laser.

BACKGROUND AND DESIGN: Anecdotal reports and clinical observations have suggested that the response of port-wine stains to treatment with the pulsed dye laser is variable and dependent on the anatomical location of the lesion. To investigate anatomical variation in response to treatment, a retrospective study of 259 adults and children with port-wine stains of the head and neck treated with the pulsed dye laser was undertaken. Evaluation was performed by comparing simultaneously projected pretreatment and completion-treatment photographs. Anatomical differences in response were evaluated in three ways: (1) by anatomical subdivision of the head and neck into regions, (2) by dermatomal distribution, and (3) by response for midline lesions. The head and neck was subdivided into eight anatomical regions, which were independently evaluated for response. In addition, response for individual dermatomes and for midline lesions was evaluated. Response in all cases was assessed by determining the percentage of lightening from 0% to 100% (where 100% represents complete response) at the completion of treatment. Response grades were also assigned, using grades poor (0% to 25% lightening), fair (26% to 50% lightening), good (51% to 75% lightening), or excellent (76% to 100% lightening). RESULTS: One hundred thirty-seven adults and 122 children were included in the study. Evaluation by subdivision of the head and neck into regions revealed that in adults and children the centrofacial regions (medial aspect of the cheek, upper cutaneous lip, and nose) responded less favorably than the other grouped regions (periorbital, forehead/temple, lateral aspect of the cheek, neck, and chin); the centrofacial regions showed a good response (mean lightening, 70.7%) while the other grouped regions of the head and neck showed an excellent response (mean lightening, 82.3%). Evaluation by dermatomal distribution revealed that dermatome V2 showed a good response (mean lightening of 73.8%), while combined dermatomes V1, V3, and C2/C3 showed an excellent response (mean lightening of 82.4%). Evaluation of midline lesions revealed excellent responses in adults and children (mean lightening, 92.4%). CONCLUSIONS: Port-wine stains of the head and neck in adults and children demonstrate differences in response to treatment with the pulsed dye laser according to their anatomical location. Centrofacial lesions and lesions involving dermatome V2 in adults and children respond less favorably than lesions located elsewhere on the head and neck. Midline lesions respond very favorably in adults and children.

Ocular effects of topical and systemic steroids.

Topical and systemic steroids have proven to be invaluable agents in the treatment of a wide range of disorders, but their use is not without potential complications. Before initiation of therapy with systemic steroids, a personal or family history of cataracts, glaucoma, hypertension, diabetes, hyperlipidemia, renal stones, peptic ulceration, and current infection or pregnancy should be ascertained, because these patients have an increased risk of complications. Prior to long-term therapy with systemic steroids, blood pressure measurement, tuberculin skin test, and anergy panel are recommended. Monthly follow-up may include measurements of weight, blood pressure, electrolytes, and blood sugar and guaiac testing of the stool. To prevent the ocular complications of steroid therapy, routine screening is indicated (Table 1). Screening for cataracts, which occur most commonly as a sequela of continuous systemic steroid use, may be performed by slit-lamp examinations conducted three or four times a year for patients on long-term therapy and twice a year for patients taking intermittent topical ocular or systemic steroids. Glaucoma is more often associated with topical ocular or periocular steroids than with systemic steroids; recommended screening includes a baseline intraocular pressure measurement, then routine pressure measurements taken every few weeks initially, then every few months. Ocular rebound inflammation may develop secondary to rapid tapering or abrupt discontinuation of topical ocular steroid use and is best prevented with gradual tapering. Opportunistic infections of the eye include bacterial, viral, and fungal infections and are most often associated with the use of topical ocular steroids. Ophthalmologic evaluation is indicated promptly if patients treated with ocular steroids develop ocular discharge, pain, photophobia, or redness.

Skin-to-skin holding in the neonatal intensive care unit influences maternal milk volume.

OBJECTIVES: To evaluate the effect of early initiation of skin-to-skin (STS) holding on lactation, we compared 24-hour milk volumes of mothers of ventilated low birth weight infants in an STS group to mothers in a non-STS control group. STUDY DESIGN: Mean 24-hour milk volumes at 2, 3, and 4 weeks after delivery of mothers participating in STS holding were compared with those of a retrospective control group from the 12-month period immediately preceding the introduction of STS holding in the neonatal intensive care unit. A repeated-measures analysis of variance adjusting for baseline volumes (1 week after delivery) was used to evaluate the difference in milk volumes between STS and control groups. RESULTS: Sixteen mothers initiated STS holding during the 2-month study period. Eight mothers met study criteria by initiating STS holding during the first 4 weeks after delivery. During a 2-week period the study group had a strong linear increase in milk volume in contrast to no indicative change of the control group's milk volume. CONCLUSION: STS holding of low birth weight infants initiated in the early intensive care phase can result in a significant increase in maternal milk volume, thereby overcoming the frequently seen insufficient lactation experienced by these mothers.

Sulfate transport across the peritubular surface of the marine teleost renal tubule.

The uptake of sulfate across the peritubular surface of isolated renal tubules of seawater-acclimated winter flounder, Pseudopleuronectes americanus, consisted of two phases. The fast exchanging component appeared to be a small sulfate compartment with a saturable uptake rate; however, the Km was quite large (14.5 mM). The fast phase was partially inhibited by the anion transport inhibitor 4-acetamido-4'-isothiocyano-2,2'-disulfonic stilbene (SITS), but was unaffected by antimycin A, which indicated lack of ATP-dependence. The slowly exchanging compartment was fourfold larger than the fast, saturable with a low Km (0.65 mM), and inhibited by antimycin A, SITS, ouabain, and Na-free incubation medium. Phosphate appeared to be a noncompetitive inhibitor of this phase. These observations support the idea that the slow phase of sulfate uptake may be driven by the peritubular membrane Na gradient. This mediated, energy-dependent uptake may be part of the active sulfate secretory pump of the marine teleost renal tubule.

Multiple agminate Spitz nevi.

A five-year-old boy had multiple agminate Spitz nevi arising in an area of hyperpigmentation that developed concurrently with the nevi. Multiple Spitz nevi occurring in a single group are rare, and their presence on a hyperpigmented background is extremely uncommon. Very few such cases have been described, and all of those lesions arose on a congenital hyperpigmented patch. In contrast, the nevi in our patient appeared to arise on an acquired hyperpigmented patch that was not present at birth, and histologically did not demonstrate features of a congenital nevus. Accurate diagnosis is necessary to avoid unnecessary radical therapy.

Drug-induced toxic epidermal necrolysis treated with cyclosporin.

A 35-year-old woman developed toxic epidermal necrolysis secondary to phenytoin. Because the life-threatening eruption was resistant to prednisone and high-dose methylprednisolone therapy, cyclosporine therapy was initiated. Within 24-48 hours, the eruption stabilized and the patient improved.

Controversy: are systemic steroids indicated in the treatment of erythema multiforme?

The treatment of erythema multiforme major with systemic steroids became established during the 1950s. Recently, two retrospective case reviews comparing steroid-treated and nonsteroid-treated groups of patients with erythema multiforme found that these agents may be associated with complications. As a result, many clinicians have become uncertain as to the appropriate therapy of this disease entity. We successfully treated the condition with steroids in two children and one adolescent. The controversy over the potential efficacy of such therapy for erythema multiforme persists, however.