Melanoma in women of childbearing age and in pregnancy in California, 1994-2015: a population-based cohort study.

BACKGROUND: Melanoma is one of the most common malignancies during pregnancy. There is debate regarding the impact of pregnancy on the prognosis of melanoma. Recent large population-based studies from the United States are lacking. OBJECTIVES: To determine the characteristics and survival of women with pregnancy-associated melanoma. METHODS: This population-based, retrospective cohort study used California Cancer Registry data linked with state-wide hospitalization and ambulatory surgery data to identify 15-44-year-old female patients diagnosed with melanoma in 1994-2015, including pregnant patients. Multivariable logistic regression compared demographic and clinical characteristics between pregnant and non-pregnant women with melanoma. Multivariable cox proportional hazards regression models assessed melanoma-specific and overall survival. RESULTS: We identified 13 108 patients, of which 1406 were pregnant. Pregnancy-associated melanoma was more frequent in Hispanic compared to non-Hispanic White women. Melanoma occurring post-partum was associated with greater tumour thickness (2.01-4.00 vs. 0.01-1.00 mm, odds ratio 1.75, 95% confidence interval: 1.03-2.98). There were otherwise no significant differences between pregnant and non-pregnant women. Worse survival was associated with Asian, Black and Native American race/ethnicity (vs. non-Hispanic White), lower neighbourhood socio-economic status, public insurance, tumour site, greater tumour thickness and lymph node involvement, but not pregnancy. CONCLUSIONS: Melanoma occurring post-partum was associated with greater tumour thickness, but pregnancy status did not affect survival after melanoma. Race/ethnicity, socio-economic status and health insurance impacted survival, emphasizing the importance of reducing health disparities.

Comparison of hair manifestations in cardio-facio-cutaneous and Costello syndromes highlights the influence of the RAS pathway on hair growth.

BACKGROUND: Abnormal hair growth is a defining feature of RASopathies, syndromes caused by germline mutations in the RAS pathway. However, detailed hair manifestations and the mechanisms of altered hair growth in RASopathies are poorly delineated. OBJECTIVES: To identify distinguishing clinical features and investigate how the RAS pathway influences hair growth by performing a systematic and detailed side-by-side comparison of hair manifestations in cardio-facio-cutaneous syndrome (CFCS) and Costello syndrome (CS), two RASopathies caused by mutations in the downstream and upstream elements of the RAS pathway, respectively. METHODS: Sixteen individuals with CFCS and 23 individuals with CS were enrolled. Mutation data were recorded. Scalp hair, eyebrows and eyelashes of individuals with CFCS or CS were examined for texture, colour, density and morphology. Scalp hairs were examined by light microscopy. RESULTS: While both syndromes displayed abnormal hair, striking differences were observed, including darker and thicker scalp hair and sparse eyebrows and eyelashes in CFCS. By contrast, synophrys, trichomegaly and abnormalities of the scalp hair shafts were observed in CS. Possible correlation with straight hair and genotype was observed in CS. CONCLUSION: The results emphasize the role of the RAS pathway in hair growth, improve accuracy of clinical diagnosis of CFCS and CS and provide a foundation for identification of therapeutic targets.

Melanocytic naevi with globular and reticular dermoscopic patterns display distinct BRAF V600E expression profiles and histopathological patterns.

BACKGROUND: BRAF (v-raf murine sarcoma viral oncogene homologue B) V600E mutations have been detected with high frequency in melanocytic naevi. Few studies have stratified analyses by naevus dermoscopic pattern. OBJECTIVES: To determine the frequency of BRAF V600E expression and histopathological pattern in acquired melanocytic naevi distinguished by a globular vs. reticular dermoscopic pattern. METHODS: We retrospectively identified histologically proven melanocytic naevi with banal reticular or globular dermoscopic patterns and evaluated BRAF V600E expression using immunohistochemistry. RESULTS: BRAF V600E expression was detected in 11 of 12 globular naevi vs. four of 13 reticular naevi (91·7% vs. 30·1%, P = 0·004). A predominantly dermal growth pattern (P < 0·001) and the presence of large junctional nests (P = 0·017) were each associated with a globular dermoscopic pattern. The presence of either a predominantly dermal growth pattern or large junctional nests was found in 13 of 15 naevi positive for BRAF V600E and in two of 10 naevi negative for BRAF V600E (86·7% vs. 20%, P = 0·002). CONCLUSIONS: The frequency of BRAF V600E mutations differs in naevi distinguished by unique dermoscopic structures and microanatomical growth patterns. Globular naevi, which most often histologically correspond to a predominantly dermal growth pattern and/or the presence of large junctional nests, are significantly more likely to express BRAF V600E than reticular naevi. These preliminary results require validation, but may directly inform future studies of naevogenesis and melanoma genesis.

A novel mutation in the cathepsin C gene in a Pakistani family with Papillon-Lefevre syndrome.

BACKGROUND: Papillon-Lefevre syndrome (PLS; OMlM 245000) is an autosomal recessive disease caused by mutations in cathepsin C (CTSC) gene and is characterized by palmoplantar keratoderma, psoriasiform lesion over the extensor surfaces and gingivitis followed by loss of teeth. CTSC gene is expressed in several tissues including the skin and cells of the immune system. In the skin, CTSC plays a role in differentiation and desquamation, whereas in the immune system, it activates serine proteases. OBJECTIVES: We analysed the molecular basis of PLS in a Pakistani family. METHODS: Genomic DNA was isolated from the sample according to standard techniques. All exons of the CTSC gene with adjacent sequences of exon-intron borders were amplified by PCR and directly sequenced. RESULTS: We identified a novel deletion mutation designated c.2ldelG (Leu7PhefsX57) in exon 1 of the CTSC gene, which probably results in the absence of CTSC protein. CONCLUSION: Our data further expand the spectrum of mutations in the CTSC gene underlying PLS.

Progress and prospects: gene therapy for performance and appearance enhancement.

While medical therapies aim at reversing, reducing or eliminating diseases, the goal of enhancements is to improve performance or appearance beyond normal levels. Distinction between the two interventions is not always clear as they often present as a continuum. Gene therapy typically aims at treating or preventing disease, but the technology can theoretically be employed for enhancement. Some of the gene therapy enhancement strategies include improving performance by increasing muscle mass, endurance, memory, and cognition and bettering appearance by controlling weight, height and hair growth. In addition to the technical challenges of making enhancement strategies safe and effective, genetic enhancement presents significant ethical/societal questions that must be addressed.

Increased risk of cancer in patients with fumarate hydratase germline mutation.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumour predisposition syndrome caused by heterozygous germline mutations in the fumarate hydratase (FH) gene. The condition is characterised by predisposition to benign leiomyomas of the skin and the uterus, renal cell carcinoma (RCC), and uterine leiomyosarcoma (ULMS). To comprehensively examine the cancer risk and tumour spectrum in Finnish FH mutation positive families, genealogical and cancer data were obtained from 868 individuals. The cohort analysis of the standardised incidence ratios (SIR) was analysed from 256 individuals. FH mutation status was analysed from all available individuals (n = 98). To study tumour spectrum in FH mutation carriers, loss of the wild type allele was analysed from all available tumours (n = 22). The SIR was 6.5 for RCC and 71 for ULMS. The overall cancer risk was statistically significantly increased in the age group of 15-29 years, consistent with features of cancer predisposition families in general. FH germline mutation was found in 55% of studied individuals. Most RCC and ULMS tumours displayed biallelic inactivation of FH, as did breast and bladder cancers. In addition, several benign tumours including atypical uterine leiomyomas, kidney cysts, and adrenal gland adenomas were observed. The present study confirms with calculated risk ratios the association of early onset RCC and ULMS with FH germline mutations in Finns. Some evidence for association of breast and bladder carcinoma with HLRCC was obtained. The data enlighten the organ specific malignant potential of HLRCC.

Elongated patellae at the final stage of Osgood-Schlatter disease: a radiographic study.

Aetiology of Osgood-Schlatter disease (OSD) is still unknown. Relative length of the patellar articular surface with the length of the patella, relative height of the tibial tubercle with the sagittal diameter of the tibia, Insall-Salvati, Blackburne-Peel, and Caton-Deschamps indexes, as well as Grelsamer-morphology type of the patella were measured from preoperative plain X-rays in 82 knees of 20-year-old males with OSD and in 87 knees of 20-year-old male controls with normal MRI findings of the knee. Seventy-eight of the OSD patients had separate ossicles. Their mean patellar morphology index was 1.44 and that of the controls was 1.28 (p<0.001), indicating significant lengthening of the patellar body among the OSD group. OSD patients had also significantly more often Grelsamer type II (elongated patellae) than the controls. Tibial tuberosity was significantly higher among OSD patients, but was not correlated with the lengthening of the patella. An increased patellar height among OSD patients was shown by the Blackburne-Peel and Caton-Deschamps indexes (p<0.001) and the Insall-Salvati index (p=0.018). OSD patients exhibit elongated patellae and patellar tendons which may result from long-standing tension of the extensor apparatus during growth spurt, when femoral growth exceeds that of the anterior structures of the knee.

Long-term outcome of undisplaced fatigue fractures of the femoral neck in young male adults.

The incidence and long-term outcome of undisplaced fatigue fractures of the femoral neck treated conservatively were examined in Finnish military conscripts between 1970 and 1990. From 106 cases identified, 66 patients with 70 fractures were followed for a mean of 18.3 years (11 to 32). The original medical records and radiographs were studied and physical and radiological follow-up data analysed for evidence of risk factors for this injury. The development of avascular necrosis and osteoarthritis was determined from the follow-up radiographs and MR scans. The impact of new military instructions on the management of hip-related pain was assessed following their introduction in 1986. The preventive regimen (1986) improved awareness and increased the detected incidence from 13.2 per 100,000 service-years (1970 to 1986) to 53.2 per 100,000 (1987 to 1990). No patient developed displacement of the fracture or avascular necrosis of the femoral head, or suffered from adverse complications. No differences were found in MRI-measured hip joint spaces at final follow-up. The mean Harris Hip Score was 97 (70 to 100) and the Visual Analogue Scale 5.85 mm (0 to 44). Non-operative treatment, including avoidance of or reduced weight-bearing, gave favourable short- and long-term outcomes. Undisplaced fatigue fractures of the femoral neck neither predispose to avascular necrosis nor the subsequent development of osteoarthritis of the hip.

Fatigue injuries of the femur.

The purpose of this study was to describe the anatomical distribution and incidence of fatigue injuries of the femur in physically-active young adults, based upon MRI studies. During a period of 70 months, 1857 patients with exercise-induced pain in the femur underwent MRI of the pelvis, hips, femora, and/or knees. Of these, 170 patients had a total of 185 fatigue injuries, giving an incidence of 199 per 100 000 person-years. Bilateral injuries occurred in 9% of patients. The three most common sites affected were the femoral neck (50%), the condylar area (24%) and the proximal shaft (18%). A fatigue reaction was seen in 57%, and a fracture line in 22%. There was a statistical correlation between the severity of the fatigue injury and the duration of pain (p = 0.001). The location of the pain was normally at the site of the fatigue injury. Fatigue injuries of the femur appear to be relatively common in physically-active patients.

No long-term effects of ultrasound therapy on bioabsorbable screw-fixed lateral malleolar fracture.

BACKGROUND AND AIMS: The present study was initiated to evaluate the long-term effects of low-intensity ultrasound therapy on bioabsorbable screw-fixed lateral malleolar fractures, which has not been studied earlier. PATIENTS AND METHODS: The study design was prospective, randomized, double-blinded, and placebo-controlled. Sixteen dislocated lateral malleolar fractures were fixed with one bioabsorbable self-reinforced poly-L-lactide screw. The patients used an ultrasound device 20 minutes daily for six weeks without knowing it was active (eight patients) or inactive (eight patients). The follow-up time was 18 months. The radiological bone morphology was assessed by multidetector computed tomography (MDCT) scans, the bone mineral density by dual-energy X-ray absorptiometry scans, and the clinical outcome by Olerud-Molander scoring and clinical examination of the ankle. RESULTS: The MDCT scans revealed that all fractures were fully healed, and no differences were observed in radiological bone morphology at the fracture site. The bone mineral density of the fractured lateral malleolus tended to increase slightly during the 18-month follow-up, the increase being symmetrical in both groups. No differences were observed in the clinical outcome or Olerud-Molander scores. CONCLUSIONS: The six-week low-intensity ultrasound therapy had no effect on radiological bone morphology, bone mineral density or clinical outcome in bioabsorbable screw-fixed lateral malleolar fractures 18 months after the injury.

Genetic analysis in Finnish families with inflammatory bowel disease supports linkage to chromosome 3p21.

In inflammatory bowel diseases (IBD), certain chromosomal candidate loci have been repeatedly identified by independent studies in different populations. To investigate the contribution of the loci on chromosomes 1, 3, 7, 12, 14, and 16 to the susceptibility of IBD in Finnish population, where the predominant feature is the excess of ulcerative colitis (UC) families compared to Crohn's disease (CD) families, we carried out linkage analyses using 93 Finnish, multiply-affected IBD families. We observed nominal evidence for linkage to chromosome 3p21, consistent with earlier reports. The lod scores peaked at D3S2432, with a maximum two-point lod score of 1.68 (P=0.0027). In addition, we studied whether risk of IBD is associated with functional variants of two positional candidate genes; the chemokine receptor CCR5 gene on chromosome 3p21 and the interleukin-4 receptor alpha-subunit gene (IL4RA) on chromosome 16. We did not find any significant correlation between a 32-bp deletion variant of CCR5 or a single nucleotide change A1902G (Gln576Arg) of IL4RA, and IBD phenotypes, with the exception that in the UC group homozygosity for the G1902 allele of IL4RA was less frequent (0.019 vs 0.049, P=0.038). In conclusion, our study, carried out in a genetically homogenous population, suggests that chromosome 3 may contain a susceptibility gene for IBD.

Factors associated with nonunion in conservatively-treated type-II fractures of the odontoid process.

In type-II fractures of the odontoid process, the treatment is either conservative in a halo vest or primary surgical stabilisation. Since nonunion, requiring prolonged immobilisation or late surgery, is common in patients treated in a halo vest, the identification of those in whom this treatment is likely to fail is important. We reviewed the data of 69 patients with acute type-II fractures of the odontoid process treated in a halo vest. The mean follow-up was 12 months. Conservative treatment was successful, resulting in bony union in 32 (46%) patients. Anterior dislocation, gender and age were unrelated to nonunion. However, nonunion did correlate with a fracture gap (> 1 mm), posterior displacement (> 5 mm), delayed start of treatment (> 4 days) and posterior redisplacement (> 2 mm). We conclude that patients presenting with these risk factors are unlikely to achieve bony union by treatment in a halo vest. They deserve careful attention during the follow-up period and should also be considered as candidates for primary surgical stabilisation.

Inherited forms of renal cell carcinoma.

It is estimated that up to 2% of renal cell cancer (RCC) clusters in families. Several forms of hereditary RCC have been characterized with specific clinical, histopathological, and genetic features. The most common of these is von Hippel-Lindau (VHL) disease caused by mutations in the VHL gene and predisposing to clear cell RCC. Predisposition to papillary RCC is present in hereditary leiomyomatosis and renal cell cancer (HLRCC) and hereditary papillary renal cell carcinoma (HPRC). Identification of the genetic defects causing these diseases has enlightened the molecular pathogenesis of RCC, and moreover, provided means to improve patient management. Genetic testing enables early diagnosis of the disease, after which individuals at-risk can be guided to regular surveillance. Screening facilitates detection of presymptomatic early tumors broadening treatment options and potentially improving prognosis. Thus, identification of individuals with inherited cancer susceptibility is important as special management of these patients improves disease outcome. The purpose of this review is to provide clues for identification and management of hereditary renal cancer patients in clinical practice.

Sensitivity of MRI for articular cartilage lesions of the patellae.

BACKGROUND AND AIMS: Reliable diagnosis of articular cartilage lesions of the patellae is often based on arthroscopy. However, unnecessary arthroscopies should be avoided. The aim of this study was to assess the sensitivity and applicability of MRI to diagnosing articular cartilage lesions of the patellae. MATERIALS AND METHODS: We identified 74 consecutive males (mean age 21 years, range 18-28) from the medical records of our institute with the sole diagnosis of articular cartilage lesions of the patellae based on arthroscopy. Magnetic resonance imaging was performed with 1.0 Tesla scanner a mean of 4 weeks before arthroscopy. Sensitivity of symptoms, and MRI for the diagnosis was calculated. RESULTS: Based on arthroscopy, 20 (27%) cases of cartilage lesions of the patellae were grade-I, 32 (43%) were grade-II, and 22 (30%) were grade-III. MRI revealed cartilage lesions of the patellae in 49 knees (66%), indicating that the sensitivity of MRI was 66% (95% CI: 53%-74%). MRI sensitivity increased with the severity of chondral lesions: all grade III to IV lesions were detected (sensitivity 100%, 95% CI: 85%-100%) by MRI. Grade of articular cartilage lesions of the patellae based on arthroscopy was not associated with clinical symptoms (p=0.61). CONCLUSIONS: The sensitivity of 1.0 Tesla MRI for detecting grade-I lesions was low and could not be used to confirm the diagnosis of articular cartilage lesions of the patellae. For the detection of more severe grade-II to III lesions, the MRI sensitivity was markedly higher. MRI may thus be considered an accurate diagnostic tool for identifying more severe cases of articular cartilage lesions of the patellae.

Multidetector computed tomography in acute knee injuries: assessment of cruciate ligaments with magnetic resonance imaging correlation.

PURPOSE: To evaluate whether non-contrast multidetector computed tomography (MDCT) for suspected acute knee fractures can also be used to evaluate cruciate ligament pathology. MATERIAL AND METHODS: A total of 42 patients (17-65 years) underwent four-section MDCT. The images were independently evaluated at clinical workstations by four radiologists. They assessed the integrity (normal or torn) and the best slice direction (axial, sagittal, or coronal) for visualization of the cruciate ligaments. Magnetic resonance imaging (MRI), performed within 4 weeks (mean 6 days) in relation to MDCT, was considered the gold standard. RESULTS: Ligament integrity at MDCT: the mean interobserver proportion of agreement for a normal anterior cruciate ligament (ACL) was 0.73, for a torn ACL 0.41, for a normal posterior cruciate ligament (PCL) 0.96, and for a torn PCL 0.54. Interobserver variation for ACL was significant (P = 0.0136-0.0260), but insignificant for PCL (P = 0.3389-0.7212). Intra-observer variation was insignificant. Visualization was best in the axial and sagittal direction for ACL and PCL, respectively. At MRI, 29 normal, one partially, and 12 completely torn ACLs, and 37 normal, four partially and one completely torn PCL were found. CONCLUSION: MDCT can detect an intact ACL and PCL with good specificity, accuracy, and negative predictive value. The assessment of torn ligaments is unreliable.

Multidetector computed tomography in acute joint fractures.

Conventional radiography plays an essential diagnostic role in the primary evaluation of acute joint trauma. In complex fractures, however, computed tomography (CT) is an imaging modality often used second to radiography. As a result of technical breakthroughs in the field, multidetector CT (MDCT) allows faster imaging and better temporal, spatial, and contrast resolution compared with conventional single-slice spiral CT. MDCT with multiplanar reformation is helpful in disclosing fracture patterns, particularly in complex joint fractures, where they reveal occult fractures and show the exact number of fracture components and their degree of displacement.

Acute knee trauma: analysis of multidetector computed tomography findings and comparison with conventional radiography.

PURPOSE: To evaluate the multidetector computed tomography (MDCT) findings of acute knee trauma and to compare radiography with MDCT in patients referred to a level 1 trauma center. MATERIAL AND METHODS: During a 5-year period, a total of 415 MDCT examinations were performed on 409 patients with acute knee trauma to reveal complex fracture anatomy or rule out a fracture. MDCT and primary radiographs were re-evaluated with respect to fracture location and trauma mechanism. Tibial plateau fractures were further analyzed depending on anatomical location: anterior-medial, anterior-lateral, posterior-lateral, and posterior-medial regions. Maximal depression of the tibial articular surface was measured. Findings on the primary knee radiographs were compared with MDCT findings. RESULTS: Of the 409 patients, 356 (87%) had a knee fracture. A total of 451 fractures were found in all anatomic regions: distal femur (n=49), proximal tibia (n=307), patella (n=23), and proximal fibula (n=72). Primary radiographs were available in 316 (76%) cases. Of these, 225 (71%) had MDCT in order to reveal the fracture anatomy better, and 91 (29%) had a subsequent MDCT after negative plain radiographs. Overall sensitivity of radiography was 83%, while negative predictive value was 49%. On radiography, tibial plateau articular depression was underestimated in all regions except when the fracture consisted of the whole half of the anterior or posterior plateau. The three main injury mechanisms were traffic accident, a simple fall, and sport. In 49 cases (15%), primary radiographs were suboptimal due to positioning. CONCLUSION: In severely injured patients, diagnostically sufficient radiographs are difficult to obtain, and therefore a negative radiograph is not reliable in ruling out a fracture. In these patients, MDCT is a fast and accurate examination and is also recommended in patients with tibial plateau fractures or complex knee injuries in order to evaluate the fracture adequately.