Median Nerve and Carpal Tunnel Morphology Before and After Endoscopic Carpal Tunnel Release: A 6-Year Follow-up Study.

BACKGROUND: Our purpose was to describe structural and morphological features of the median nerve and carpal tunnel on magnetic resonance imaging (MRI) studies obtained before, immediately after, 6 weeks after, and 6 years after endoscopic carpal tunnel release (ECTR). METHODS: In this prospective cohort study, 9 patients with a diagnosis of carpal tunnel syndrome (CTS) underwent ECTR. Standardized MRI studies were obtained before ECTR, immediately after ECTR, and 6 weeks and 6 years after surgery. Structural and morphological features of the median nerve and carpal tunnel were measured and assessed for each study with comparisons made between each time point. RESULTS: All 9 patients had complete symptom resolution postoperatively. On the immediate postoperative MRI, there was a discrete gap in the transverse carpal ligament in all patients. There was retinacular regrowth noted at 6 weeks in all cases. The median nerve cross-sectional area and the anterior-posterior dimension of the carpal tunnel at the level of the hamate increased immediately after surgery and these changes were maintained at 6 years. CONCLUSIONS: We defined structural and morphological changes on MRI for the median nerve and carpal tunnel in patients with continued symptom resolution 6 years after ECTR. Changes in median nerve and carpal tunnel morphology that occur immediately after surgery remain unchanged at mid-term follow-up in asymptomatic patients. Established imaging criteria for CTS may not apply to postoperative patients. Magnetic resonance imaging appears to be of limited clinical utility in the workup of persistent or recurrent CTS.

The Use of Preoperative Dynamic Ultrasound to Predict Ulnar Nerve Stability Following In Situ Decompression for Cubital Tunnel Syndrome.

PURPOSE: To assess the use of preoperative, dynamic ultrasound to predict ulnar nerve instability following in situ decompression for cubital tunnel syndrome. METHODS: Prior to undergoing in situ decompression, 43 consecutive patients underwent dynamic ultrasound to assess the stability of the ulnar nerve during elbow flexion. The dynamic ultrasound findings were compared with the intraoperative assessment of nerve stability following in situ decompression. RESULTS: The preoperative dynamic ultrasound agreed with intraoperative findings in 38 of 43 patients (88%). Physical examination of ulnar nerve stability agreed with the intraoperative findings in 5 of 43 patients (12%). For the 5 of 43 cases in which the dynamic ultrasound did not correlate with the degree of ulnar nerve stability after in situ decompression, dynamic ultrasound overestimated the degree of ulnar nerve stability in 4 cases. CONCLUSIONS: Preoperative dynamic ultrasound can be used to accurately predict the degree of ulnar nerve instability following in situ decompression. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic II.

Trauma-Induced Resolution of Solitary Osteochondroma of the Distal Femur.

Osteochondromas are benign lesions manifested as bony protrusions capped by cartilage. The exact cause of these growths is not known, and there is no treatment other than surgical excision if the lesion becomes symptomatic. Spontaneous resolution is an uncommon phenomenon that is not completely understood. A 12-year-old girl presented with a mass behind the left knee diagnosed as an osteochondroma. She was followed with serial radiographs because the lesion was minimally symptomatic. At 2.5 years after presentation, the patient reported feeling a "pop" with knee hyperflexion, and radiographic follow-up confirmed a decrease in the size of the growth. The protrusion continued to decrease in size until it was no longer detectable with radiographs, physical examination, and advanced imaging. Spontaneously resolving osteochondromas have been previously documented, but the literature is limited. There were just over 20 cases reported as of the writing of this article, and only 1 other case includes postresolution magnetic resonance imaging. This report of localized trauma inducing spontaneous resolution provides additional evidence and insight supporting previous theories on spontaneous resolution of osteochondromas, which may assist in counseling patients and their families regarding expected natural history. [Orthopedics.2016; 39(5):e1001-e1004.].

Magnetic resonance imaging after endoscopic carpal tunnel release.

PURPOSE: To determine with magnetic resonance imaging (MRI) the morphologic changes in the carpal tunnel and median nerve 3 months after endoscopic carpal tunnel release (ECTR). METHODS: We enrolled patients who had complete resolution of numbness and pain by 6 weeks after ECTR. Patients who met these inclusion criteria received an MRI at 3 months after surgery. Images were analyzed to determine whether median nerve morphology changes and discrete gap or separation of the flexor retinaculum could be appreciated on MRI. RESULTS: There were 17 patients screened and 15 met the inclusion criteria. Three-month MRI in all patients demonstrated changes in the flexor retinaculum over the median nerve. In all 15 patients, a distinct gap or separation in the fibers of the flexor retinaculum overlying the median nerve could not be appreciated. Median nerve width-to-height ratios at the level of the pisiform and at the hook of the hamate were 2.4 and 2.1, respectively. Median nerve cross-sectional area was 14.1 at the pisiform and 13.3 at the hook of the hamate. CONCLUSIONS: MRI of patients 3 months after successful ECTR does not demonstrate a discrete gap or separation in the flexor retinaculum overlying the median nerve but may be useful for evaluating median nerve morphology. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic II.

Pitfalls of wrist MR imaging.

The radiologist serves as an indispensable consultant for those patients with wrist pain, by determining the causes of the pain and severity of the injury, helping to determine treatment options, and providing preoperative guidance for surgery, if planned. This article reviews normal anatomic variants and potential danger areas encountered by the radiologist when interpreting magnetic resonance imaging of the wrist.

MR imaging of knee instability.

The primary stabilizers of the knee can be functionally compartmentalized into the cruciate ligaments, the medial and posteromedial stabilizers, and the lateral and posterolateral stabilizers. This complex anatomy provides global knee stability. This article familiarizes the reader with the normal MR imaging appearance of these structures, and the changes following injury. The posteromedial and posterolateral corners are emphasized because recent research has improved the understanding of their importance, and their repair and reconstruction are becoming more common. Accurate identification of injury is important to ensuring optimal patient outcome.

Agents, biomarkers, and cohorts for chemopreventive agent development in prostate cancer.

Chemoprevention is the use of agents to slow progression of, reverse, or inhibit carcinogenesis thereby lowering the risk of developing invasive or clinically significant disease. With its long latency, high incidence and significant morbidity and mortality, prostate cancer is a relevant target for chemoprevention. Developing rational chemopreventive strategies for prostate cancer requires well-characterized agents, suitable cohorts, and reliable intermediate biomarkers of cancer. Chemopreventive agent requirements are experimental or epidemiologic data showing efficacy, safety on chronic administration, and a mechanistic rationale for activity. Current promising agents include antiandrogens and antiestrogens; steroid aromatase inhibitors; retinoids and their modulators; 5alpha-reductase inhibitors; vitamins D, E, and analogs; selenium compounds; carotenoids; soy isoflavones; dehydroepiandrostenedione and analogs; 2-difluoromethylornithine; lipoxygenase inhibitors; apoptosis inducers; and nonsteroidal anti-inflammatory drugs. Identifying biomarkers and validating them as surrogate endpoints for cancer incidence are critical for prostate chemoprevention trials. Potentially useful biomarkers for prostate chemoprevention are associated with histologic, proliferative, differentiation-related, biochemical, and genetic/regulatory features of prostatic disease. In that the prostate is not easily visualized, critical issues also include adequacy and consistency of tissue sampling. Various drugs for the chemoprevention of prostate cancer are now under evaluation in phase 1, 2, and 3 clinical trials. Cohort selection should be based on various patient characteristics (stage of the disease, previous cancers or premalignant lesions, or high risk factors) and should be conducted within the context of standard treatment.

Randomized trial of fenretinide in superficial bladder cancer using DNA flow cytometry as an intermediate end point.

Retinoids have shown a potential activity in preventing tumor recurrence in superficial bladder cancer. We assessed the activity of the synthetic retinoid fenretinide in superficial bladder cancer using DNA flow cytometry and conventional cytology as surrogate biomarkers. A total of 99 subjects with resected superficial bladder cancer (pTa, pT1) were randomized to either fenretinide (200 mg day p.o. for 24 months) or no intervention. Cystoscopy and bladder washing for DNA flow cytometry end points (proportion of DNA aneuploid histograms, hyperdiploid fraction, and percentage of apoptotic cells) and proportion of abnormal cytological examinations were repeated every 4 months for up to 36 months. The primary study end point was the proportion of DNA aneuploid histograms after 12 months. This figure was 48.9% in the fenretinide arm and 41.9% in the control arm (odds ratio, 1.16; 95% confidence interval, 0.44-3.07). There was no difference in any other response biomarker between the two groups up to 36 months, nor was any biomarker able to predict recurrence risk. Recurrence-free survival was comparable between the arms (27 events in the fenretinide arm versus 21 in the control arm; P = 0.36). Twelve subjects in the fenretinide arm complained of diminished dark adaptability, and nine subjects in the fenretinide arm versus one control subject had mild dermatological alterations. We conclude that fenretinide showed a lack of effect on the DNA content distribution and the morphology of urothelial cells obtained in serial bladder washings. Recurrence-free survival was comparable between groups. Because our data are hampered by the lack of predictivity of the selected biomarkers, additional studies are necessary to assess the activity of fenretinide in preventing bladder cancer.

Effect of subacute ibuprofen dosing on rectal mucosal prostaglandin E2 levels in healthy subjects with a history of resected polyps.

Nonsteroidal antiinflammatory drugs are among the most promising chemopreventive agents for colorectal cancer. Although the mechanism by which nonsteroidal antiinflammatory drugs exert such effects remains to be further characterized, their best known pharmacological effect is inhibition of prostaglandin synthetase, which leads to decreases in tissue prostaglandin levels. We conducted a randomized, double-blind, controlled study to examine the effect of daily ibuprofen treatment on the rectal mucosal prostaglandin E2 (PGE2) levels in healthy subjects with a history of resected polyps. Study participants (n = 27) completed a 2-week run-in period and were then randomized to take a single, daily dose of ibuprofen (300 or 600 mg) or of a placebo for 4 weeks. Rectal biopsy specimens were taken before and after the run-in period and at 2 and 4 weeks after the ibuprofen/placebo treatment. Notably large between- and within-subject variability in the rectal mucosal PGE2 content was seen. The changes in PGE2 levels after ibuprofen/placebo treatment correlated with the baseline PGE2 content. After adjustment of the baseline values, 2 weeks of 300 mg/day of ibuprofen treatment resulted in significantly more suppression of PGE2 levels than that observed after the placebo treatment (55% versus 22% suppression from baseline; P = 0.033). Although other ibuprofen treatment schedules and doses appeared to result in suppression in the PGE2 levels, the suppression was not statistically significant because of the large variability in this measurement. Because lower doses are associated with fewer adverse effects, a dose of 300 mg of ibuprofen/day should be considered for future Phase II chemoprevention studies. Stratifying study participants, based on their baseline PGE2 levels and inclusion of a larger number of study subjects, are recommended for future trials where the rectal mucosal PGE2 level is to be used as a surrogate end point biomarker.

Variability of human milk neutral oligosaccharides in a diverse population.

BACKGROUND: A complex array of free oligosaccharides is a distinctive compositional feature of human milk. Although these oligosaccharides have been studied for several years, their variability and distribution have not been systematically studied, and their nutritional and functional roles have not been elucidated. This report describes a study in which a large number of human milk samples were analyzed for the presence and content of nine neutral oligosaccharides. The resultant data were used to probe for distribution trends by donor groups and stage of lactation. METHODS: Milk samples from 435 women residing in 10 countries were analyzed using a simple preparation procedure, gel filtration, and high-performance anion-exchange chromatography. RESULTS: All samples contained structures based on lacto-N-neotetraose and lacto-N-tetraose. This contrasts with the fucosyloligosaccharides tested, none of which was detected in 100% of the samples. Unexpected distribution trends were observed. For example, 100% of the samples from Mexico (n = 156) contained 2'-fucosyllactose, whereas only 46% of the samples from the Philippines (n = 22) contained this structure. Concentration ranges for the analyzed oligosaccharides revealed quantitative and qualitative distribution trends. CONCLUSIONS: The oligosaccharide composition of human milk varied among samples. The geographical origin of the donors was one of the factors that accounted for this variability. This can be explained by genetically determined traits that are not uniformly distributed. Results indicated that further systematic studies are needed to ascertain the effect of other factors, such as lactation stage or diet.

Progress in cancer chemoprevention: development of diet-derived chemopreventive agents.

Because of their safety and the fact that they are not perceived as "medicine," food-derived products are highly interesting for development as chemopreventive agents that may find widespread, long-term use in populations at normal risk. Numerous diet-derived agents are included among the >40 promising agents and agent combinations that are being evaluated clinically as chemopreventive agents for major cancer targets including breast, prostate, colon and lung. Examples include green and black tea polyphenols, soy isoflavones, Bowman-Birk soy protease inhibitor, curcumin, phenethyl isothiocyanate, sulforaphane, lycopene, indole-3-carbinol, perillyl alcohol, vitamin D, vitamin E, selenium and calcium. Many food-derived agents are extracts, containing multiple compounds or classes of compounds. For developing such agents, the National Cancer Institute (NCI) has advocated codevelopment of a single or a few putative active compounds that are contained in the food-derived agent. The active compounds provide mechanistic and pharmacologic data that may be used to characterize the chemopreventive potential of the extract, and these compounds may find use as chemopreventives in higher risk subjects (patients with precancers or previous cancers). Other critical aspects to developing the food-derived products are careful analysis and definition of the extract to ensure reproducibility (e.g., growth conditions, chromatographic characteristics or composition), and basic science studies to confirm epidemiologic findings associating the food product with cancer prevention.

Randomized trial of fenretinide to prevent second breast malignancy in women with early breast cancer.

BACKGROUND: Fenretinide, a vitamin A analogue, has been shown to inhibit breast carcinogenesis in preclinical studies. We determined the efficacy of fenretinide in preventing a second breast malignancy in women with breast cancer. METHODS: We randomly assigned 2972 women, aged 30-70 years, with surgically removed stage I breast cancer or ductal carcinoma in situ to receive for 5 years either fenretinide orally (200 mg/day) or no treatment. The primary end point was the incidence of contralateral breast cancer or ipsilateral breast cancer 7 years after randomization. Other end points considered post hoc were the same outcomes stratified by menopausal status, incidence of distant metastases, overall mortality, and tumors in other organs. The hazards of breast cancer occurrence were determined by Cox proportional hazards regression analysis. Statistical tests were two-sided. RESULTS: At a median observation time of 97 months, there were no statistically significant differences in the occurrence of contralateral breast cancer (P =.642) or ipsilateral breast cancer (P =.177) between the two arms. However, an interaction was detected between fenretinide treatment and menopausal status in both outcomes (P for interaction in both outcomes =.045), with a possible beneficial effect in premenopausal women (contralateral breast cancer: adjusted hazard ratio [HR] = 0.66, and 95% confidence interval [CI] = 0.41-1.07; ipsilateral breast cancer: adjusted HR = 0.65, and 95% CI = 0.46-0. 92) and an opposite effect in postmenopausal women (contralateral breast cancer: adjusted HR = 1.32, and 95% CI = 0.82-2.15; ipsilateral breast cancer: adjusted HR = 1.19, and 95% CI = 0.75-1. 89). There were no statistically significant differences between the two arms in tumors in other organs, incidence of distant metastasis, and all-cause mortality. CONCLUSIONS: Fenretinide treatment of women with breast cancer for 5 years appears to have no statistically significant effect on the incidence of second breast malignancies overall, although a possible benefit was detected in premenopausal women. These studies, particularly the post hoc analyses, are considered exploratory and need to be confirmed.

Chemoprevention of prostate cancer: concepts and strategies.

Chemoprevention is the administration of agents to prevent induction and inhibit or delay progression of cancers. For prostate, as for other cancer targets, successful chemopreventive strategies require well-characterized agents, suitable cohorts, and reliable intermediate biomarkers of cancer for evaluating chemopreventive efficacy. Agent requirements are experimental or epidemiological data showing chemopreventive efficacy, safety on chronic administration, and a mechanistic rationale for the observed chemopreventive activity. On this basis, promising chemopreventive drugs in prostate include retinoids, antiandrogens, antiestrogens, steroid aromatase inhibitors, 5alpha-reductase inhibitors, vitamins D and E, selenium, lycopene, and 2-difluoromethylornithine. Phase II trials are critical for evaluating chemopreventive efficacy. Cohorts in these trials should be suitable for measuring the chemopreventive activity of the agent and the intermediate biomarkers chosen as endpoints. Many cohorts proposed for phase II trials are patients with previous cancers or premalignant lesions. For such patients, trials should be conducted within the context of standard treatment. Two cohorts currently used in phase II prostate cancer chemoprevention trials are patients with PIN and patients scheduled for prostate cancer surgery. Biomarkers should fit expected biological mechanisms, be assayed reliably and quantitatively, measured easily, and correlate to decreased cancer incidence. Protocols for adequately sampling tissue are essential. Changes in PIN provide prostate biomarkers with the ability to be quantified and a high correlation to cancer. PIN measurements include nuclear polymorphism, nucleolar size and number of nucleoli/nuclei, and DNA ploidy. Other potentially useful biomarkers are associated with cellular proliferation kinetics (e.g. PCNA and apoptosis), differentiation (e.g. blood group antigens, vimentin), genetic damage (e.g. LOH on chromosome 8), signal transduction (e.g. TGFalpha, TGFbeta, IGF-I, c-erbB-2 expression), angiogenesis, and biochemical changes (e.g. PSA levels).

Progress in cancer chemoprevention.

More than 40 promising agents and agent combinations are being evaluated clinically as chemopreventive drugs for major cancer targets. A few have been in vanguard, large-scale intervention trials--for example, the studies of tamoxifen and fenretinide in breast, 13-cis-retinoic acid in head and neck, vitamin E and selenium in prostate, and calcium in colon. These and other agents are currently in phase II chemoprevention trials to establish the scope of their chemopreventive efficacy and to develop intermediate biomarkers as surrogate end points for cancer incidence in future studies. In this group are fenretinide, 2-difluoromethylornithine, and oltipraz. Nonsteroidal anti-inflammatories (NSAID) are also in this group because of their colon cancer chemopreventive effects in clinical intervention, epidemiological, and animal studies. New agents are continually considered for development as chemopreventive drugs. Preventive strategies with antiandrogens are evolving for prostate cancer. Anti-inflammatories that selectively inhibit inducible cyclooxygenase (COX)-2 are being investigated in colon as alternatives to the NSAID, which inhibit both COX-1 and COX-2 and derive their toxicity from COX-1 inhibition. Newer retinoids with reduced toxicity, increased efficacy, or both (e.g., 9-cis-retinoic acid) are being investigated. Promising chemopreventive drugs are also being developed from dietary substances (e.g., green and black tea polyphenols, soy isoflavones, curcumin, phenethyl isothiocyanate, sulforaphane, lycopene, indole-3-carbinol, perillyl alcohol). Basic and translational research necessary to progress in chemopreventive agent development includes, for example, (1) molecular and genomic biomarkers that can be used for risk assessment and as surrogate end points in clinical studies, (2) animal carcinogenesis models that mimic human disease (including transgenic and gene knockout mice), and (3) novel agent treatment regimens (e.g., local delivery to cancer targets, agent combinations, and pharmacodynamically guided dosing).

Programmed tooth preparation for fixed partial dentures.

This article describes a method for efficient and precise tooth preparation for fixed partial dentures. Diagnostic procedures are also reviewed.

Designs for cast metal restorations.

This article reviewed clinical conditions that assist selection of specific design decisions for the tooth preparation for cast metal restorations. This decision should result in a conservative restoration for a given clinical situation. A paradigm is included to assist the dentist in the decision-making process.

Plasma alpha-tocopherol concentrations after supplementation with water- and fat-soluble vitamin E.

The objective of this study was to examine differences in plasma alpha-tocopherol concentrations after oral administration of pharmacologic doses of vitamin E to normal healthy subjects as RRR-alpha-tocopheryl glycol 1000 succinate (TPGS; water-miscible form) and RRR-alpha-tocopheryl acetate (TA; fat-soluble form). The study was designed to evaluate the administration of three different single doses and multiple doses for 4 wk with both preparations. Administration of 400 IU (269 mg), 800 IU (537 mg), and 1200 IU (807 mg) TPGS as a single dose resulted in slight elevation of plasma alpha-tocopherol concentrations. Administration of multiple daily doses at all three amounts of TPGS for 28 consecutive days resulted in a slight elevation of plasma alpha-to-copherol concentrations. A significant increase in plasma alpha-to-copherol concentrations was observed after ingestion of a single dose or equivalent multiple doses of TA at all three doses. As reported in the literature, in cases of cholestasis and other forms of lipid malabsorption, oral administration of TPGS is the treatment of choice. It appears that for normal adults and patients with normal lipid absorption, fat-soluble forms of vitamin E are preferable for therapeutic and prophylactic uses.

Risk biomarkers and current strategies for cancer chemoprevention.

Quantifiable, well-characterized cancer risk factors demonstrate the need for chemoprevention and define cohorts for chemopreventive intervention. For chemoprevention, the important cancer risk factors are those that can be measured quantitatively in the subject at risk. These factors, called risk biomarkers, can be used to identify cohorts for chemoprevention. Those modulated by chemopreventive agents may also be used as endpoints in chemoprevention studies. Generally, the risk biomarkers fit into categories based on those previously defined by Hulka: 1) carcinogen exposure, 2) carcinogen exposure/effect, 3) genetic predisposition, 4) intermediate biomarkers of cancer, and 5) previous cancers. Besides their use in characterizing cohorts for chemoprevention trials, some risk biomarkers can be modulated by chemopreventive agents. These biomarkers may be suitable surrogate endpoints for cancer incidence in chemoprevention intervention trials. The criteria for risk biomarkers defining cohorts and serving as endpoints are the same, except that those defining cohorts are not necessarily modulated by chemopreventive agents. A primary criterion is that the biomarkers fit expected biological mechanisms of early carcinogenesis-i.e., differential expression in normal and high-risk tissue, on or closely linked to the causal pathway for the cancer, and short latency compared with cancer. They must occur in sufficient number to allow their biological and statistical evaluation. Further, the biomarkers should be assayed reliably and quantitatively, measured easily, and correlated to cancer incidence. Particularly important for cancer risk screening in normal subjects is the ability to use noninvasive techniques that are highly specific, sensitive, and quantitative. Since carcinogenesis is a multipath process, single biomarkers are difficult to correlate to cancer, as they may appear on only one or a few of the many possible causal pathways. As shown in colorectal carcinogenesis, the risks associated with the presence of biomarkers may be additive or synergistic. That is, the accumulation of genetic lesions is the more important determinant of colorectal cancer compared with the presence of any single lesion. Thus, batteries of biomarker abnormalities, particularly those representing the range of carcinogenesis pathways, may prove more useful than single biomarkers both in characterizing cohorts at risk and defining modulatable risks. Risk biomarkers are already being integrated into many chemoprevention intervention trials. One example is the phase II trial of oltipraz inhibition of carcinogen-DNA adducts in a Chinese population exposed to aflatoxin B1. Also, urine samples from subjects in this trial will be screened for the effect of oltipraz on urinary mutagens. A second example is a chemoprevention protocol developed for patients at high risk for breast cancer; the cohort is defined both by hereditary risk and the presence of biomarker abnormalities. Modulation of the biomarker abnormalities is a proposed endpoint. Also, dysplastic lesions, such as prostatic intraepithelial neoplasia, oral leukoplakia and colorectal adenomas, have been used to define high-risk cohorts and as potential modulatable surrogate endpoints in chemoprevention trials.