The role of BRAF V600 mutation in melanoma

BRAF is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. About 50 % of melanomas harbors activating BRAF mutations (over 90 % V600E). BRAFV600E has been implicated in different mechanisms underlying melanomagenesis, most of which due to the deregulated activation of the downstream MEK/ERK effectors. The first selective inhibitor of mutant BRAF, vemurafenib, after highly encouraging results of the phase I and II trial, was compared to dacarbazine in a phase III trial in treatment-naïve patients (BRIM-3). The study results showed a relative reduction of 63 % in risk of death and 74 % in risk of tumor progression. Considering all trials so far completed, median overall survival reached approximately 16 months for vemurafenib compared to less than 10 months for dacarbazine treatment. Vemurafenib has been extensively tested on melanoma patients expressing the BRAFV600E mutated form; it has been demonstrated to be also effective in inhibiting melanomas carrying the V600K mutation. In 2011, both FDA and EMA therefore approved vemurafenib for metastatic melanoma carrying BRAFV600 mutations. Some findings suggest that continuation of vemurafenib treatment is potentially beneficial after local therapy in a subset of patients with disease progression (PD). Among who continued vemurafenib >30 days after local therapy of PD lesion(s), a median overall survival was not reached, with a median follow-up of 15.5 months from initiation of BRAF inhibitor therapy. For patients who did not continue treatment, median overall survival from the time of disease progression was 1.4 months. A clinical phase I/II trial is evaluating the safety, tolerability and efficacy of vemurafenib in combination with the CTLA-4 inhibitor mAb ipilimumab. In the BRIM-7 trial vemurafenib is tested in association with GDC-0973, a potent and highly selective inhibitor of MEK1/2. Preliminary data seem to indicate that an additional inhibitor of mutated BRAF, GSK2118436, might be also active on a wider range of BRAF mutations (V600E-K-D-R); actually, treatment with such a compound is under evaluation in a phase III study among stage III-IV melanoma patients positive for BRAF mutations. Overall, BRAF inhibitors were well tolerated; common adverse events are arthralgia, rash, fatigue, alopecia, keratoacanthoma or cutaneous squamous-cell carcinoma, photosensitivity, nausea, and diarrhea, with some variants between different inhibitors

Measurement properties of quality of life measurement instruments for infants, children and adolescents with eczema: protocol for a systematic review

Background: Eczema is a common chronic or chronically relapsing skin disease that has a substantial impact on quality of life (QoL). By means of a consensus-based process, the Harmonising Outcome Measures in Eczema (HOME) initiative has identified QoL as one of the four core outcome domains to be assessed in all eczema trials. Few measurement instruments exist to measure QoL in infants and children with eczema, but there is a great variability in both content and quality (for example, reliability and validity) of the instruments used, and it is not always clear if the best instrument is being used. Therefore, the aim of the proposed research is a comprehensive systematic assessment of the measurement properties of the existing measurement instruments that were developed and/or validated for the measurement of patient-reported QoL in infants and children with eczema. Methods/Design: This study is a systematic review of the measurement properties of patient-reported measures of QoL developed and/or validated for infants and children with eczema. Medline via PubMed and EMBASE will be searched using a selection of relevant search terms. Eligible studies will be primary empirical studies evaluating, describing, or comparing measurement properties of QoL instruments for infants and children with eczema. Eligibility assessment and data abstraction will be performed independently by two reviewers. Evidence tables will be generated for study characteristics, instrument characteristics, measurement properties, and interpretability. The adequacy of the measurement properties will be assessed using predefined criteria. Methodological quality of studies will be assessed using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. A best evidence synthesis will be undertaken if more than one study has investigated a particular measurement property. Discussion: The proposed systematic review will produce a comprehensive assessment of measurement properties of existing QoL instruments in infants and children with eczema. We aim to identify one best currently available instrument to measure QoL in infants and/or children with eczema

Patients' and urologists' preferences for prostate cancer treatment: A discrete choice experiment

__Abstract__ Background: Patients' preferences are important for shared decision making. Therefore, we investigated patients' and urologists' preferences for treatment alternatives for early prostate cancer (PC). Methods: A discrete choice experiment was conducted among 150 patients who were waiting for their biopsy results, and 150 urologists. Regression analysis was used to determine patients' and urologists' stated preferences using scenarios based on PC treatment modality (radiotherapy, surgery, and active surveillance (AS)), and risks of urinary incontinence and erectile dysfunction.Results:The response rate was 110 out of 150 (73%) for patients and 50 out of 150 (33%) for urologists. Risk of urinary incontinence was an important determinant of both patients' and urologists' stated preferences for PC treatment (P<0.05). Treatment modality also influenced patients' stated preferences (P<0.05), whereas the risk of erectile dysfunction due to radiotherapy was mainly important to urologists (P<0.05). Both patients and urologists preferred AS to radical treatment, with the exception of patients with anxious/depressed feelings who preferred radical treatment to AS. Conclusion: Although patients and urologists generally may prefer similar treatments for PC, they showed different trade-offs between various specific treatment aspects. This implies that urologists need to be aware of potential differences compared with the patient's perspective on treatment decisions in shared decision making on PC treatment

Leser-Trélat syndrome in patients affected by six multiple metachronous primitive cancers

Leser-Trélat syndrome is characterized by the eruptive appearance of multiple seborrheic keratoses in association with underlying malignant disease. Usually, the sign of Leser-Trélat is associated with adenocarcinoma, most frequently of the colon, breast, or stomach, but also of the lung, kidney, liver, and pancreas. Herein, we present a case that we believe is the first report of the sign of Leser-Trélat in association with occult gastric adenocarcinoma and the anamnestic oncologic history of five other multiple primitive cancers. Epidermal growth factor receptor (EGFR) immunohistochemical expression analysis of multiple seborrheic keratoses revealed an intense membranous staining in the basal keratinocytes and in all the upper epidermal layers. Patients with the sign of Leser-Trélat should undergo a diagnostic screening programme for malignant disease along with patients with known Leser-Trélat syndrome who present with a recent acute and florid eruption of their seborrheic keratoses. We propose the importance of combining the molecular features of multiple seborrheic keratoses with EGFR immunohistochemistry analyses to determine the likelihood of Leser-Trélat syndrome and the consequent high risk of underlying multiple visceral malignancies

First-line, Fixed-Duration Nivolumab plus Ipilimumab Followed by Nivolumab in Clinically Diverse Patient Populations With Unresectable Stage III or IV Melanoma: CheckMate 401

PURPOSETo address the paucity of data in patients with historically poor outcomes, we conducted the single-arm phase IIIb CheckMate 401 study to evaluate the safety and efficacy of nivolumab plus ipilimumab followed by nivolumab monotherapy in clinically diverse patient populations with advanced melanoma.METHODSTreatment-naive patients with unresectable stage III-IV melanoma received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg (240 mg following a protocol amendment) once every 2 weeks for 24 months. The primary end point was the incidence of grade 3-5 select treatment-related adverse events (TRAEs). Overall survival (OS) was a secondary end point. Outcomes were evaluated in subgroups defined by Eastern Cooperative Oncology Group performance status (ECOG PS), brain metastasis status, and melanoma subtype.RESULTSIn total, 533 patients received at least one dose of study drug. Grade 3-5 select TRAEs affecting the GI (16%), hepatic (15%), endocrine (11%), skin (7%), renal (2%), and pulmonary (1%) systems occurred in the all-treated population; similar incidence rates were observed across all subgroups. At 21.6 months' median follow-up, 24-month OS rates were 63% in the all-treated population, 44% in the ECOG PS 2 subgroup (including patients with cutaneous melanoma only), 71% in the brain metastasis subgroup, 36% in the ocular/uveal melanoma subgroup, and 38% in the mucosal melanoma subgroup.CONCLUSIONNivolumab plus ipilimumab followed by nivolumab monotherapy was tolerable in patients with advanced melanoma and poor prognostic characteristics. Efficacy was similar between the all-treated population and patients with brain metastases. Reduced efficacy was observed in patients with ECOG PS 2, ocular/uveal melanoma, and/or mucosal melanoma, highlighting the continued need for novel treatment options for these difficult-to-treat patients

Immunostimulation and Immunoinhibition of Premalignant Lesions

BACKGROUND: The immune reaction may be either stimulatory or inhibitory to tumor growth, depending upon the local ratio of immune reactants to tumor cells. HYPOTHESIS: A tumor-stimulatory immune response may be essential for survival of a neoplasm in vivo and for the biological progression from a premalignant lesion to a malignancy. Neither a positive nor a negative correlation between the magnitude of an immune-cell infiltrate and a cancer's prognosis can reveal whether the infiltrate was stimulating or inhibiting to the tumor's growth unless the position on the nonlinear curve that relates tumor growth to the magnitude of the immune reaction is known. DISCUSSION: This hypothesis is discussed in relation to the development of human malignant melanomas and colorectal cancers

Patients’ preferences for osteoporosis drug treatment: a discrete choice experiment

Summary: Active case finding for osteoporosis is used to identify patients at high fracture risk who may benefit from preventive drug treatment. We investigated the relative weight that women place on various aspects of preventive drugs in a discrete choice experiment. Our patients said they were prepared to take preventive drugs even if side effects were expected. Int

Does the immune reaction cause malignant transformation by disrupting cell-to-cell or cell-to-matrix communications?

Tumor progression: In many (perhaps in all) tumor systems, a malignant cancer is preceded by a benign lesion. Most benign lesions do not transform to malignancy and many regress. The final transformative step to malignancy differs from the preceding steps in, among other things, that it often occurs in the absence of the original carcinogenic stimulus. Mechanism of immunostimulation: Relatively low titers of specific immune reactants are known to stimulate, but cell-to-cell or cell-to-matrix interactions appear to be major inhibitors of tumor-growth. Therefore, it seems reasonable to hypothesize that the mechanism of immunostimulation may be an interference with cell-to-cell or cell-to-matrix communication by a sub-lethal immune-reaction. Discussion: While the above hypothesis remains unproven, some evidence suggests that immunity may have a major facilitating effect on tumor growth especially at the time of malignant transformation. There is even some evidence suggesting that transformation in vivo may seldom occur in the absence of immunostimulation of the premalignant lesion. Positive selection by the immune reaction may be the reason that tumors are immunogenic

Proprioception deficiency in articular cartilage lesions of the knee

Purpose: The purpose of this study is to investigate the proprioceptive function of patients with isolated articular cartilage lesions of the knee as compared to normal controls. Methods: The Cartilage group consisted of eight subjects with radiologically and arthroscopically confirmed, isolated, unilateral, articular cartilage lesions of the knee (Outerbridge grade III or IV). They were compared to 50 normal controls. Knee proprioception was assessed by dynamic postural stabilometry using the Biodex Balance SD System. Patient-reported outcome measures (PROMs) were used to evaluate all subjects. Results: Proprioception of the injured knee of the Cartilage group was significantly poorer compared to that of the control group (p < 0.001). A significant proprioceptive deficit also was observed when the uninjured knees of the Cartilage group were compared to those in the Control group (p = 0.003). There was no significant proprioceptive difference between the injured and the contra-lateral uninjured knee of the Cartilage group (p = 0.116). A significant correlation was found between the proprioception measurements of the injured and uninjured knee of the Cartilage group (r = 0.76, p = 0.030). A significant difference was observed in all PROMs (p < 0.001) between the Cartilage and Control groups. Conclusions: Patients with isolated articular cartilage lesions of the knee had a significant proprioceptive deficit as compared to normal controls. The deficiency was profound and even affected the proprioceptive function of the contra-lateral uninjured knee. This study has shown that articular cartilage lesions have a major influence on knee proprioception. However, it remains uncertain as to whether a proprioceptive deficit leads to osteoarthritis or is a consequence of it