Circulating tumor DNA to monitor treatment response and detect acquired resistance in patients with metastatic melanoma

Repeat tumor biopsies to study genomic changes during therapy are difficult, invasive and data are confounded by tumoral heterogeneity. The analysis of circulating tumor DNA (ctDNA) can provide a non-invasive approach to assess prognosis and the genetic evolution of tumors in response to therapy. Mutation-specific droplet digital PCR was used to measure plasma concentrations of oncogenic BRAF and NRAS variants in 48 patients with advanced metastatic melanoma prior to treatment with targeted therapies (vemurafenib, dabrafenib or dabrafenib/trametinib combination) or immunotherapies (ipilimumab, nivolumab or pembrolizumab). Baseline ctDNA levels were evaluated relative to treatment response and progression-free survival (PFS). Tumor-associated ctDNA was detected in the plasma of 35/48 (73%) patients prior to treatment and lower ctDNA levels at this time point were significantly associated with response to treatment and prolonged PFS, irrespective of therapy type. Levels of ctDNA decreased significantly in patients treated with MAPK inhibitors (p < 0.001) in accordance with response to therapy, but this was not apparent in patients receiving immunotherapies. We show that circulating NRAS mutations, known to confer resistance to BRAF inhibitors, were detected in 3 of 7 (43%) patients progressing on kinase inhibitor therapy. Significantly, ctDNA rebound and circulating mutant NRAS preceded radiological detection of progressive disease. Our data demonstrate that ctDNA is a useful biomarker of response to kinase inhibitor therapy and can be used to monitor tumor evolution and detect the early appearance of resistance effectors.     

Rheumatoid forefoot deformity: a comparison study of 2 functional methods of reconstruction

OBJECTIVE: To compare the functional, radiographic, and pedobarographic results of different reconstructive methods for severe rheumatoid forefoot deformities. METHODS: A total of 138 feet in 79 patients with RA forefoot reconstructions between 1978 and 1997 were reviewed through a detailed questionnaire, clinical examination, standardized radiographs, and pedobarographic analysis. Five subgroups based on procedure to the 1st ray were identified, then divided into 2 functional categories: Group 1: stable 1st ray by means of arthrodesis or no surgery; and Group 2: a resection procedure to 1st metatarsophalangeal (MTP) joint. RESULTS: Sixty-one patients (106 feet) attended clinical review; 18 returned the questionnaire. There were 65 women and 14 men, with a mean age of 59 years (range 24-80): with 52 feet in Group 1 and 86 feet in Group 2. Mean age at surgery for both groups was 52 years (range 23-79). Mean age at the time of review was 55 years (Group 1) and 60.5 years (Group 2). Length of followup was significantly different: Group 1 averaged 36 months; Group 2, 102 months (p < 0.001). At review, no significant difference was noted in SF-36, comorbidities, WOMAC, or Foot Function Index. The disability score as defined by the American Rheumatological Society was significantly different: Group 1, 2.1 +/- 0.5; and Group 2, 2.4 +/- 0.6 (p = 0.006). Group 1 did significantly better in terms of walking distance, satisfaction with postoperative appearance of foot, relief of plantar pain, less plantar calluses, and higher AOFAS HMIP and LMIP scores. Postoperative complications occurred in 16 feet (11%); 15 feet required reoperation (10.6%). Major resection of the 1st MTP joint was associated with a significant increase in the 1st and 2nd intermetatarsal angle on radiographic review. The pattern of pressure distribution on the plantar aspect was similar regardless of the surgical procedure. The maximum contact area, maximum peak pressure, and maximum pressure time integral were located under the region of the 1st metatarsal, with a progressive decrease in values under the more lateral rays and under the lesser toes. Significantly higher pressures were seen under the 1st, 2nd, and 3rd metatarsal regions in Group 2 (1st MTP joint resection). Toe function was absent or minimal in the majority of Group 2. CONCLUSION: Forefoot arthroplasty by means of a resection or stabilization provides significant pain relief. Maintenance of a stable 1st MTP joint and resection of the lesser metatarsal heads with K-wire stabilization will result in a more cosmetic forefoot, more even distribution of forefoot pressures, and more satisfied patients.     

A controlled release system for simultaneous delivery of three human perivascular stem cell‐derived factors for tissue repair and regeneration

Transplanted stem/progenitor cells improve tissue healing and regeneration anatomically and functionally, mostly due to their secreted trophic factors. However, harsh conditions at the site of injury, including hypoxia, oxidative and inflammatory stress, increased fibrosis and insufficient angiogenesis, and in some cases immunological response or incompatibility, are detrimental to stem cell survival. To overcome the complexity and deficiencies of stem cell therapy, the coacervate delivery platform is deemed promising because it offers controlled and sustained release using heparin to recapitulate the binding and stabilization of extracellular proteins by heparan sulphates in native tissues. Here we show that recombinant alternatives of three key factors [vascular endothelial growth factor (VEGF), monocyte chemoattractant protein‐1 (MCP‐1) and interleukin‐6 (IL‐6)], commonly produced by perivascular stem cells under various stress conditions, can be successfully incorporated into a heparin‐based coacervate. We characterized the release profile of the triply incorporated factors from the complex coacervate. The coacervate‐released factors were able to exert their desired biological activities in vitro: VEGF stimulated human umbilical vein endothelial cell proliferation, MCP‐1 elevated macrophage migration and IL‐6 increased IgM production by IL‐6‐dependent cell line. Thus, a controlled release system can be used for simultaneous delivery of three stem cell‐derived factors and could be useful for tissue repair and regenerative medicine.     

Complications from minimally invasive lumbar interbody fusion: Experience from 100 patients

Minimally invasive lumbar fusion is well described and is reported to offer significant advantages to patients in terms of blood loss, a reduction in post-operative pain and a quicker recovery. However, this technique may expose patients to a greater risk of complications when compared to open lumbar instrumented fusion that may negate these advantages. Between January 2007 and March 2001, we conducted a prospective observational study of 100 consecutive patients (48 males and 52 females, mean age of 54 years) to investigate complications occurring from minimally invasive lumbar interbody fusion surgery using an image-guided technique. All patients underwent post-operative CT scans to assess implant placement. Scanning was repeated at 6 months to assess bony fusion. We observed the following complications: 2.5% (11/435) pedicle screw misplacement, 1.7% (2/120) interbody cage misplacement; 0.8% (1/120) interbody cage migration; 0.8% (1/120) patients requiring a post-operative blood transfusion; 2% (2/100) venous thrombo-embolism and 3% (3/100) patients with complications thought to be related to the use of bone morphogenic protein. There were no occurrences of infection and no cerebrospinal fluid leaks. We concluded that the rate of complications from minimally invasive lumbar interbody fusion is low, and compares favourably with the rates of complication from open procedures. Moreover, computerised navigation systems can be used in place of real-time fluoroscopy to guide implant placement, without an increase in the rate of complications.     

Rates of comorbid symptoms in children with ASD,ADHD, and comorbid ASD and ADHD

The current diagnostic criteria do not allow co-diagnosis of autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD). As a result, there has been little research on how these two disorders co-occur in the ASD population. The current study aimed to extend the literature in this area by examining comorbid rates in three different diagnostic groups (ASD, ADHD, and comorbid ASD + ADHD) using the Autism Spectrum Disorders-Comorbidity for Children (ASD-CC). Children with comorbid ASD and ADHD evinced higher rates of comorbid symptoms than children with ASD or ADHD alone. Additionally, children with comorbid ASD and ADHD endorsed more severe comorbid symptoms. Implications regarding these findings are discussed.     

Primary Hodgkin lymphoma of the central nervous system: Two case reports and review of the literature

CNS involvement by systemic Hodgkin lymphoma (HL) is quite rare, but the disease limited to the CNS is an exceptionally rare entity. The incidence of CNS‐HL has been estimated at 0.2–0.5% of cases, but a more recent study has modified that figure to less than 0.02%. Like the conventional form, the diagnosis of primary CNS‐HL rests upon distinct morphological and immunohistochemical characteristics, including diagnostic Reed‐Sternberg cells, in addition to staging studies demonstrating a lack of disease elsewhere. The paucity of cases in the literature precludes reliable clinical and demographic data, as well as a consensus on treatment and prognosis. We present two cases of primary cerebellar HL, one with 10‐year follow‐up, and a relevant review of the literature.     

The Utility of the Rey Word Recognition Test in the Detection of Suspect Effort

The Rey Word Recognition Test potentially represents an underutilized tool for clinicians to use in the detection of suspect effort. The present study examined the predictive accuracy of the test by examining the performance of three groups of participants: (a) 92 noncredible patients (as determined by failed psychometric and behavioral criteria and external motive to feign), (b) 51 general clinical patients with no motive to feign, and (c) 31 learning disabled college students. Results demonstrated gender differences in performance that necessitated separate cutoff scores for men and women. Use of a cutoff score of ≤7 words correctly recognized identified 80.5% of noncredible female patients while maintaining specificity of >90%. However, to achieve this level of specificity in male noncredible patients, the cutoff score had to be lowered to ≤5, with resultant sensitivity of only 62.7%. A combination variable (recognition correct minus false positive errors + number of words recognized from the first 8 words) showed enhanced sensitivity in identifying suspect effort in a subset of the noncredible sample who were claiming cognitive symptoms secondary to traumatic brain injury (i.e., cutoff score of ≤9 = 81.6% sensitivity with 90% specificity). Results indicate that the Rey Word Recognition Test is an accurate and cost-effective method for the detection of noncredible cognitive performance.