First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743.

BACKGROUND: In the phase III CheckMate 743 study (NCT02899299), first-line nivolumab plus ipilimumab significantly improved overall survival (OS) versus chemotherapy in patients with unresectable malignant pleural mesothelioma (MPM). We report updated data with 3-year minimum follow-up. PATIENTS AND METHODS: Adults with previously untreated, histologically confirmed, unresectable MPM and Eastern Cooperative Oncology Group performance status of ≤1 were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks) for up to 2 years, or six cycles of platinum plus pemetrexed chemotherapy. This report includes updated efficacy and safety outcomes, exploratory biomarker analyses including four-gene inflammatory expression signature score, and a post hoc efficacy analysis in patients who discontinued treatment due to treatment-related adverse events (TRAEs). RESULTS: With a median follow-up of 43.1 months, nivolumab plus ipilimumab continued to prolong OS versus chemotherapy. Median OS was 18.1 versus 14.1 months [hazard ratio (95% confidence interval), 0.73 (0.61-0.87)], and 3-year OS rates were 23% versus 15%, respectively. Three-year progression-free survival rates were 14% versus 1%, and objective response rates were 40% versus 44%. At 3 years, 28% versus 0% of responders had an ongoing response. Improved survival benefit with nivolumab plus ipilimumab versus chemotherapy was observed across subgroups, including histology. A high score of the four-gene inflammatory signature appeared to correlate with improved survival benefit with nivolumab plus ipilimumab. No new safety signals were observed with nivolumab plus ipilimumab, despite patients being off therapy for 1 year. In patients who discontinued nivolumab plus ipilimumab due to TRAEs, median OS was 25.4 months, and 34% of responders maintained their responses for ≥3 years after discontinuation. CONCLUSIONS: With 3 years' minimum follow-up, nivolumab plus ipilimumab continued to provide long-term survival benefit over chemotherapy and a manageable safety profile, supporting the regimen as standard-of-care treatment for unresectable MPM, regardless of histology.

Metastatic spinal cord compression from basal cell carcinoma of the skin treated with surgical decompression and vismodegib: case report and review of Hedgehog signalling pathway inhibition in advanced basal cell carcinoma.

We report a case of a 66-year-old man with locally advanced and metastatic basal cell carcinoma (BCC) causing spinal cord compression, which was treated with spinal surgery and subsequent vismodegib. The patient presented with a large fungating chest wall lesion and a metastasis in T8 that was causing cord compression. He had neurosurgical decompression of the T8 lesion and fixation of the spine. Punch biopsy from the fungating chest wall lesion showed a BCC with some malignant squamous differentiation (basosquamous). Histopathological examination of the metastatic lesion in T8 at the time of surgical decompression identified features identical to the punch biopsy. The patient was referred to the oncology clinic for adjuvant treatment. In light of his metastatic disease and the large area over his chest wall that could not fully be covered by radiotherapy, he was treated with the novel oral Hedgehog signalling pathway (HHSP) inhibitor vismodegib, which led to marked improvement.

The effects of viewing pro-eating disorder websites: a systematic review.

OBJECTIVE: To determine health-related effects of viewing pro-eating disorder (Pro-ED) websites. METHODS: A systematic review was carried out addressing: 1. The effect of viewing pro-ED websites on eating disorder behaviour 2. The effect of viewing pro-ED websites on viewers' negative and positive affect. RESULTS: Seven studies were included. Pro-ED viewers compared with controls showed higher levels of dieting and exercise (3 studies, 2 suggesting causation); higher levels of drive for thinness, body dissatisfaction and perfectionism (2 studies, both associative); a reduced likelihood of binging/purging (one study); increased negative affect (two studies); and a positive correlation between viewing pro-ED websites, disease duration and hospitalisations (one study). CONCLUSION: Viewing pro-ED websites may increase eating disorder behaviour but might not cause it. It may cause increased negative affect after a single short website exposure. For those with eating disorders, viewing is positively correlated with disease duration and hospitalisations. Professionals should be aware of these sites and their potential damage for health.

MRI in the classical MM1 and the atypical MV2 subtypes of sporadic CJD: an inter-observer agreement study.

BACKGROUND AND PURPOSE: To establish radiological features in the atypical MV2 subtype of sCJD compared with the classical MM1 subtype, as well as region- and sequence-dependent inter-observer correlation. METHODS: MRI hyperintensity of basal ganglia (BG), cortex and thalamus was evaluated in 31 MM1 and 32 MV2 patients. Each MR scan was analyzed independently by two neuroradiologists blinded to PRNP genotype/prion protein type. RESULTS: Cumulative T2-sensitivity for BG hyperintensity was higher in the MV2 subtype (84% for both observers versus 61% in observer 1/42% in observer 2 in MM1 patients). Significant inter-observer agreement was found for BG and thalamus on T2, FLAIR, PD and DWI, but for cortex only on DWI. Thalamic changes were significantly more frequent in MV2 than in MM1 patients (cumulative sensitivity 86% vs. 12.5% on DWI). DISCUSSION: The high frequency of thalamic hyperintensity in the MV2 subtype allowed differentiation from MM1 patients. Good inter-observer agreement was found for BG and thalamus in all sequences. DWI showed the highest inter-observer correlation independent of the investigated brain region and was therefore not only highly sensitive but also relatively independent of investigator bias. Since inter-observer correlation for cortical hyperintensity in T2, FLAIR and PD is relatively low, the cortical changes should not be over-interpreted with these sequences.

Doxorubicin-induced impairment of wound healing in rats.

The mortality rate induced by 3 doses of iv doxorubicin was evaluated in F344 rats, and a dose of 8 mg doxorubicin/kg body weight was the maximum dose tolerated with an acceptable mortality rate. Rats treated with 8 mg doxorubicin/kg prior to or on the day of wounding demonstrated decreased wound breaking strength in incisional wounds at all intervals after wounding. Decreased amounts of collagen and DNA and less cellularity were noted in wound chambers from rats treated in the same manner. In both the incisional wound and wound chamber models, rats treated with doxorubicin 7 days after wounding showed a less dramatic healing impairment. No difference in collagen types was noted between chambers from the doxorubicin-treated and untreated rats. Doxorubicin also produced a significant reduction in platelet and white blood cell counts 1 week after it was administered. The data indicate that doxorubicin impedes healing by decreasing wound cellularity and collagen synthesis.

Errors in pressure gradient measurement by continuous wave Doppler ultrasound: type, size and age effects in bioprosthetic aortic valves.

The accuracy of continuous wave Doppler ultrasound in deriving pressure gradients across bioprosthetic heart valves was evaluated in an in vitro pulse duplicator. Simultaneous pressure transducer and Doppler measurements were made in new and explanted aortic bioprosthetic valves of several sizes and four types: Carpentier-Edwards, Ionescu-Shiley, Hancock standard and Hancock modified. The mean and peak gradients calculated by the modified Bernoulli equation from Doppler velocity measurements were always greater than those measured manometrically, despite corrections for location dependence of the manometric gradient (or pressure recovery). The relation between manometric and ultrasonically determined gradient was found to be statistically dependent on the valve type (mean gradient p less than 0.0001; peak gradient p = 0.0003) and size (mean gradient p = 0.0089; peak gradient p = 0.0107). Effects of implantation were observed, but were not shown to be significant. It is concluded that the continuous wave Doppler velocity data overestimated prosthetic valve pressure gradient in all cases, even when pressure recovery was taken into account. Clinicians should be wary of Doppler data when making major diagnostic or therapeutic decisions.

Transforming growth factor-beta improves healing of radiation-impaired wounds.

Exogenously applied TGF-beta 1 has been shown to increase wound strength in incisional wounds early in the healing process. An impaired wound healing model was first established in guinea pigs by isolating flaps of skin and irradiating the flaps to 15 Gray in one fraction using a 4-MeV linear accelerator. Incisions made 2 d after irradiation were excised 7 d later, and showed decreased linear wound bursting strength (WBS) as compared to non-irradiated control wounds on the contralateral side of each animal (p = 0.001). The effect of TGF-beta on healing of radiation-impaired wounds was studied using this model. Skin on both left and right sides of guinea pigs was irradiated as above. A linear incision was made in each side. Collagen with either 1, 5, or 20 micrograms of TGF-beta was applied to one side prior to closure with staples, whereas the contralateral side received saline in collagen. Wounds given either 1 or 5 micrograms of TGF-beta were found to be stronger than controls at 7 d (p less than 0.05), whereas those receiving the higher 20-micrograms dose were weaker than controls (p less than 0.05). Thus, TGF-beta in lower doses improved healing at 7 d but very large amounts of the growth factor actually impaired healing. In situ hybridization done on wound samples showed increased type I collagen gene expression by fibroblasts in wounds treated with 1 micrograms TGF-beta over control wounds. These results indicate that TGF-beta improved wound healing as demonstrated by increased WBS. This improvement is accompanied by an up-regulation of collagen gene expression by resident fibroblasts.

Dynamic coronary tone in precipitation, exacerbation and relief of angina pectoris.

Until recently, understanding of the pathogenesis of angina pectoris was based primarily on the concept of a fixed stenosis of one or more coronary arteries: Myocardial ischemia and angina occurred when myocardial oxygen consumption (MVO2) outstripped the capacity of the diseased coronary artery to delivery oxygen. Therapeutic strategies focused on interventions designed to reduce MVO2. The concept of dynamic obstruction, first applied to coronary spasm induced at rest and more recently to spasm induced by exercise, adds an additional important pathophysiologic mechanism responsible for causing angina pectoris. This study deals with the possibility that the concept of "spasm," as commonly understood, is too narrowly defined. It develops the hypothesis that subcritical increases in large vessel coronary tone occur, either in a "normal" coronary artery or in one with an existing lesion, that augment the degree of large vessel coronary resistance but not enough to exceed the vasodilator reserve of the coronary arterioles. Hence, although total coronary resistance, and thereby coronary flow, is unaltered at rest, the impingement on arteriolar vasodilator reserve would diminish the capacity to augment flow in response to increases in MVO2. Such coronary constriction would not precipitate angina at rest but would increase anginal threshold. Conversely, dilatation of a stenotic coronary artery could decrease the degree of obstruction and increase anginal threshold. This concept of dynamic coronary obstruction in the presence of "normal" or diseased coronary arteries implies a direct role for coronary vasodilators in some patients with angina pectoris, even when frank coronary spasm is absent. Also implicit in this hypothesis is the concept that dynamic and fixed components to obstruction may contribute variably to the degree of obstruction in different patients. Some patients with largely fixed obstruction would benefit mainly from attempts to lower MVO2 with nitrates and beta blocking agents. Dynamic coronary obstruction may constitute the major mechanism responsible for angina in other patients. In these persons nitrates or calcium channel blocking agents might provide the most efficacious form of therapy. Both fixed and dynamic obstruction may play an important role in symptom production in yet other patients. In such persons attempts to decrease MVO2 and the magnitude of coronary obstruction might provide the most successful form of therapy.

Hemodynamic principles in the control of coronary blood flow.

The effects of atherosclerotic epicardial stenoses on coronary vascular resistance can be understood in terms of basic principles of fluid mechanics. Resistance is directly related to the pressure drop across the stenosis and inversely related to flow. Even with a fixed anatomic stenosis, however, resistance is not fixed; it increases as flow across the stenosis increases. This exacerbates the pressure drop across the stenosis that develops as a result of flow; at high flows, large pressure drops can occur. This characteristic of flow through stenotic lesions can contribute to a "steal" phenomenon between either epicardial or intramural coronary arteries. Studies have also shown the clinical importance and influence of dynamic alterations in coronary resistance, occurring either at the large or small vessel level. In addition, compressive forces exerted by the myocardium or by elevated intraventricular pressures can increase coronary vascular resistance, and thus interfere with myocardial perfusion. All of these factors must be considered in order to obtain a comprehensive understanding of the mechanisms leading to myocardial ischemia and, therefore, to the clinical syndrome of angina pectoris.

Acute hepatitis due to fluoxetine therapy.

Fluoxetine-induced hepatotoxicity is generally considered of minimal clinical importance and is not well recognized. Asymptomatic increases in liver enzyme values have been observed in 0.5% of patients who take long-term fluoxetine therapy. This report details 2 cases of acute hepatitis believed to be caused by fluoxetine. Three cases of acute hepatitis caused by fluoxetine have been reported previously. The mechanism of fluoxetine-induced hepatotoxicity is unknown. Although routine monitoring of liver function may not be cost-effective, physicians should be alert to the possibility of fluoxetine-associated hepatitis and consider early discontinuation of the drug if this condition is suspected.

Definition of a production specification for xenotransplantation. A European perspective.

In the absence of regulatory guidance on animal production for xenotransplantation and the need to conform to European, U.K. and international standards of animal health and welfare, Imutran set up a forum of experts in 1994 to assess the risks associated with the possible transmission of diseases from pig to man after transplantation of porcine tissue. This risk assessment set the specification for Qualified Pathogen-Free pig production and the animal testing required to demonstrate that the specification has been achieved. The invasive sampling required for detailed health monitoring of individual source animals is in conflict with the aim of producing healthy, normal animals that are not subject to undue stress, and produces predominantly retrospective data on a donor. Imutran has developed a sampling regime that qualifies age-class cohorts and the whole herd by the routine testing of representative sentinel animals. Imutran set up a pilot production unit in 1995 and this unit has remained populated beyond a 30-month period and has received in excess of 20 cohorts of animals by hysterectomy re-derivation. Rigorous testing of sentinels and noninvasive testing of individuals have demonstrated that this pilot unit has achieved the required specification on a routine basis in a system that has been designed to meet European ethical and animal welfare concerns, within the constraints of the strict U.K. animal research laws and an ISO 9001 quality environment.

Preoperative or postoperative doxorubicin hydrochloride (adriamycin): which is better for wound healing?

The purpose of this study was to determine if any interval between preoperative or postoperative administration of doxorubicin hydrochloride (Adriamycin) and wounding would limit the impairment in healing induced by Adriamycin. The question was evaluated in 7 cm incisional wounds on the dorsal midline of rats. Preoperative Adriamycin was administered 42, 28, 21, 14, and 7 days before wounding, and wound breaking strengths (WBS) of the incisional wounds were measured 7, 18, and 28 days after wounding. Postoperative Adriamycin was administered 0, 7, 14, 21, and 28 days after wounding, and WBS were measured 7, 14, 28, 35, and 42 days after wounding. A similar and significant degree of impairment was induced in healing by all preoperative Adriamycin regimens evaluated. Postoperative Adriamycin administered up to 21 days after wounding induced a healing deficit that manifested 1 to 2 weeks after Adriamycin administration. Adriamycin administered 28 days after surgery induced no demonstrable impairment in WBS. In addition, Adriamycin never decreased the WBS of a wound after a certain degree of strength had been obtained. These results lead us to warn against the use of preoperative Adriamycin and support the use of postoperative Adriamycin administered 28 days after a surgical procedure.

Elucidating the pathophysiology of syringomyelia.

OBJECT: Syringomyelia causes progressive myelopathy. Most patients with syringomyelia have a Chiari I malformation of the cerebellar tonsils. Determination of the pathophysiological mechanisms underlying the progression of syringomyelia associated with the Chiari I malformation should improve strategies to halt progression of myelopathy. METHODS: The authors prospectively studied 20 adult patients with both Chiari I malformation and symptomatic syringomyelia. Testing before surgery included the following: clinical examination; evaluation of anatomy by using T1-weighted magnetic resonance (MR) imaging; evaluation of the syrinx and cerebrospinal fluid (CSF) velocity and flow by using phase-contrast cine MR imaging; and evaluation of lumbar and cervical subarachnoid pressure at rest, during the Valsalva maneuver, during jugular compression, and following removal of CSF (CSF compliance measurement). During surgery, cardiac-gated ultrasonography and pressure measurements were obtained from the intracranial, cervical subarachnoid, and lumbar intrathecal spaces and syrinx. Six months after surgery, clinical examinations, MR imaging studies, and CSF pressure recordings were repeated. Clinical examinations and MR imaging studies were repeated annually. For comparison, 18 healthy volunteers underwent T1-weighted MR imaging, cine MR imaging, and cervical and lumbar subarachnoid pressure testing. Compared with healthy volunteers, before surgery, the patients had decreased anteroposterior diameters of the ventral and dorsal CSF spaces at the foramen magnum. In patients, CSF velocity at the foramen magnum was increased, but CSF flow was reduced. Transmission of intracranial pressure across the foramen magnum to the spinal subarachnoid space in response to jugular compression was partially obstructed. Spinal CSF compliance was reduced, whereas cervical subarachnoid pressure and pulse pressure were increased. Syrinx fluid flowed inferiorly during systole and superiorly during diastole on cine MR imaging. At surgery, the cerebellar tonsils abruptly descended during systole and ascended during diastole, and the upper pole of the syrinx contracted in a manner synchronous with tonsillar descent and with the peak systolic cervical subarachnoid pressure wave. Following surgery, the diameter of the CSF passages at the foramen magnum increased compared with preoperative values, and the maximum flow rate of CSF across the foramen magnum during systole increased. Transmission of pressure across the foramen magnum to the spinal subarachnoid space in response to jugular compression was normal and cervical subarachnoid mean pressure and pulse pressure decreased to normal. The maximum syrinx diameter decreased on MR imaging in all patients. Cine MR imaging documented reduced velocity and flow of the syrinx fluid. Clinical symptoms and signs improved or remained stable in all patients, and the tonsils resumed a normal shape. CONCLUSIONS: The progression of syringomyelia associated with Chiari I malformation is produced by the action of the cerebellar tonsils, which partially occlude the subarachnoid space at the foramen magnum and act as a piston on the partially enclosed spinal subarachnoid space. This creates enlarged cervical subarachnoid pressure waves that compress the spinal cord from without, not from within, and propagate syrinx fluid caudally with each heartbeat, which leads to syrinx progression. The disappearance of the abnormal shape and position of the tonsils after simple decompressive extraarachnoidal surgery suggests that the Chiari I malformation of the cerebellar tonsils is acquired, not congenital. Surgery limited to suboccipital craniectomy, C-I laminectomy, and duraplasty eliminates this mechanism and eliminates syringomyelia and its progression without the risk of more invasive procedures.

Nutrient intake of patients with cystic fibrosis.

Nutrient intake, anthropometric measurements, and pulmonary function were assessed in 26 young adult patients with cystic fibrosis (CF). Mean nutrient intakes, excluding those from vitamins and nutrient supplements, were less than the Recommended Dietary Allowances for folate for men and women and for iron and vitamin B-6 for women. Male cystic fibrosis patients consumed significantly more of 11 of 16 nutrients in comparison with men with Crohn's disease and men with functional gastrointestinal complaints. Female cystic fibrosis patients consumed significantly more of 9 of 16 nutrients than did women with gastrointestinal complaints. The relative body weight was less than 85% of standard in 65% of men and 50% of women with CF. Relative body weight was correlated with variables indicative of airflow obstruction, reduced vital capacity, and hyperinflation of lung volumes.

Three-dimensional distributions of elements in biological samples by energy-filtered electron tomography.

By combining electron tomography with energy-filtered electron microscopy, we have shown the feasibility of determining the three-dimensional distributions of phosphorus in biological specimens. Thin sections of the nematode, Caenorhabditis elegans were prepared by high-pressure freezing, freeze-substitution and plastic embedding. Images were recorded at energy losses above and below the phosphorus L2,3 edge using a post-column imaging filter operating at a beam energy of 120 keV. The unstained specimens exhibited minimal contrast in bright-field images. After it was determined that the specimen was sufficiently thin to allow two-window ratio imaging of phosphorus, pairs of pre-edge and post-edge images were acquired in series over a tilt range of +/-55 degrees at 5 degrees increments for two orthogonal tilt axes. The projected phosphorus distributions were aligned using the pre-edge images that contained inelastic contrast from colloidal gold particles deposited on the specimen surface. A reconstruction and surface rendering of the phosphorus distribution clearly revealed features 15-20 nm in diameter, which were identified as ribosomes distributed along the stacked membranes of endoplasmic reticulum and in the cytoplasm. The sensitivity of the technique was estimated at < 35 phosphorus atoms per voxel based on the known total ribosomal phosphorus content of approximately 7000 atoms. Although a high electron dose of approximately 10(7)e/nm2 was required to record two-axis tilt series, specimens were sufficiently stable to allow image alignment and tomographic reconstruction.

The effect of ultrasonics and thermal treatment on wounds.

A method of local treatment of wounds to accelerate healing would be a major benefit in those patients in whom abnormal healing is expected. Earlier studies has suggested that local ultrasonic treatment of wounds would stimulate the healing process. We have evaluated the effect of local ultrasound (5 MHz) and thermal treatments on healing in a dermal wound model. Various intensities of ultrasound and heat were employed for 5 min/day (0.05 W/cm2) and 10 min/day (0.05W/cm2), with healing assessed by wound breaking strength measurements obtained 14 days after injury. Subcutaneous temperature measurements demonstrated that equal intensities of ultrasound and heat produced equivalent temperature changes in the tissues. None of the treatments employed resulted in greater wound breaking strengths than the controls, and the higher intensities of ultrasound (0.1 and 0.15 W/cm2) and heat (0.15 W/cm2) resulted in decreased wound breaking strength. Our results failed to support brief daily treatments of local ultrasound or heat as stimulants of wound healing.

Breast cancer risk and residence near industry or traffic in Nassau and Suffolk Counties, Long Island, New York.

A case-control interview study was used to evaluate the relationship between breast cancer risk and residential proximity to industrial facilities and traffic for pre- and postmenopausal women in Nassau and Suffolk Counties on Long Island, New York. A geographic information system was used to assign industry and traffic counts to 1-km2 grid cells (5-kM2 grid cells for traffic) and to assign potential exposure values to study subjects, based on 20-y residential histories. A significantly elevated risk of breast cancer was observed among postmenopausal subjects who were ever potentially exposed to chemical facilities (Nassau County adjusted odds ratio [OR] = 1.61, 95% confidence interval [95% CI] = 1.06-2.43; Suffolk County adjusted OR = 1.58, 95% CI = 0.71-3.51. This elevated risk, however, was not observed among premenopausal subjects. Risk increased for post-menopausal subjects as number of chemical facilities increased from one (adjusted OR = 1.45, 95% CI = 0.93-2.25) to two or more (adjusted OR = 3.47, 95% CI = 1.06-11.38). Crude and adjusted ORs for high traffic density were elevated among Nassau--but not Suffolk--county subjects and were not significant statistically.

Crown lengthening: a clinical review.

The use of crown lengthening surgery as an adjunct to restorative therapy was first suggested by Rosen and Gitnick. This technique is designed to increase the clinical crown heights of teeth requiring restoration following extensive wear through attrition, abrasion and erosion. This loss of tooth tissue and resulting clinical crown height may be localized to a few teeth or affect the entire dentition. This clinical problem is reflected by the increasing number of reports of treatment of the worn dentition.

Collaborative development of a patient simulator for educating nurses in hemofiltration therapies.

As the complexity and variety of the treatment modalities in critical care continue to expand, the clinician is faced with the task of providing a safe environment for the education of staff and the evaluation of these new modalities. The use of simulators, similar to the one described in this article, is one economical solution that can provide this education and evaluation. For instance, the major components of the hemofiltration simulator can be fabricated and purchased for under $1,000. This estimate excludes the medical cart, which retails for $437. The success of such a solution, however, necessitates that the simulator meet the defined clinical needs while meeting or exceeding the biomedical equipment standards set by AAMI or other regulatory agencies that might govern the use of such devices.

Application of piezo film technology for the quantitative assessment of pruritus.

A method to quantitate scratching has been developed for assessing the efficacies of interventions purported to ameliorate pruritus. The technique employs a piezo film sensor attached to the finger and the supporting electronics to amplify, transmit, and process the signals generated by the piezo film. The piezo film is essentially a contact microphone on the fingernail of the scratching subject. The method is currently incorporated into clinical trials, and preliminary results are promising.