scholarly journals Anatomic position determines oncogenic specificity in melanoma

2020 ◽  
Author(s):  
Joshua M. Weiss ◽  
Miranda V. Hunter ◽  
Mohita Tagore ◽  
Yilun Ma ◽  
Sandra Misale ◽  
...  
Keyword(s):  
Cutaneous Melanoma ◽  
The Body ◽  
Transgenic Zebrafish ◽  
Cell Of Origin ◽  
Braf Mutations ◽  
Acral Melanoma ◽  
Rna Profiling ◽  
Positional Identity ◽  
Hands And Feet ◽  
Transcriptional State

SummaryOncogenic alterations to DNA are not transforming in all cellular contexts1,2. This may be due to pre-existing transcriptional programs in the cell of origin. Here, we define anatomic position as a major determinant of why cells respond to specific oncogenes. Cutaneous melanoma arises throughout the body, whereas the acral subtype has a unique tropism for the limbs, specifically the hands and feet3. We sequenced the DNA of cutaneous and acral melanomas from a large cohort of human patients and found a specific enrichment for BRAF mutations in cutaneous melanoma but CRKL amplifications in acral melanoma. We modeled these changes in transgenic zebrafish models and found that CRKL-driven tumors predominantly formed in the fins of the fish. The fins are the evolutionary precursors to tetrapod limbs, indicating that melanocytes in these acral locations may be uniquely susceptible to CRKL. RNA profiling of these fin/limb melanocytes, compared to body melanocytes, revealed a positional identity gene program typified by posterior HOX13 genes. This positional gene program synergized with CRKL to drive tumors at acral sites. Abrogation of this CRKL-driven program eliminated the anatomic specificity of acral melanoma. These data suggest that the anatomic position of the cell of origin endows it with a unique transcriptional state that makes it susceptible to only certain oncogenic insults.

scholarly journals Immunohistochemical BRAF V600E Expression and Intratumor BRAF V600E Heterogeneity in Acral Melanoma: Implication in Melanoma-Specific Survival

2020 ◽  
Vol 9 (3) ◽  
pp. 690 ◽  
Author(s):  
Takamichi Ito ◽  
Yumiko Kaku-Ito ◽  
Maho Murata ◽  
Kazuhisa Furue ◽  
Che-Hung Shen ◽  
...  
Keyword(s):  
Patient Outcomes ◽  
Cutaneous Melanoma ◽  
Immunohistochemical Staining ◽  
Staining Pattern ◽  
Braf V600e ◽  
Braf Mutations ◽  
Acral Melanoma ◽  
Kaplan Meier ◽  
Significant Difference ◽  
Different Genetic Background

Acral melanoma, a distinct form of cutaneous melanoma originating in the glabrous skin of the palms, soles, and nail beds, has a different genetic background from other subtypes of cutaneous melanoma. The roles of oncogenic BRAF mutations of acral melanoma in pathogenesis and patient outcomes have not been fully elucidated. We retrieved a total of 112 patients with primary acral melanoma and checked their BRAF V600E status using immunohistochemical staining of VE1 antibody. Among these cases, 21 acral melanoma samples (18.8%) showed positive BRAF V600E staining, and of those, 11 samples (9.8%) showed a heterogeneous staining pattern, with a mixture of VE1-positive and VE1-negative cells. BRAF V600E positivity was significantly associated with thicker melanoma (p = 0.0015). There was no significant difference in clinicopathological factors between homogeneous and heterogeneous VE1-positive acral melanoma. Both patients with BRAF V600E-positive acral melanoma and those with heterogeneous BRAF V600E had significantly shorter melanoma-specific survival than those with BRAF V600E-negative melanoma in Kaplan–Meier analysis (p = 0.0283 and p = 0.0065, respectively). These findings provide novel insights into the pathobiology of acral melanoma.

Adjuvant PD-1 inhibitor versus high-dose interferon α-2b for Chinese patients with cutaneous and acral melanoma: A retrospective cohort analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21516-e21516
Author(s):  
Jiuhong Wang ◽  
Jingjing Li ◽  
Xing Liu ◽  
Xizhi Wen ◽  
Dandan Li ◽  
...  
Keyword(s):  
Cutaneous Melanoma ◽  
Chinese Patients ◽  
Interferon Α ◽  
High Dose ◽  
Free Survival ◽  
Acral Melanoma ◽  
Treatment Groups ◽  
Melanoma Patients ◽  
Metastatic Sites ◽  
High Dose Interferon

e21516 Background: The clinical efficacy of PD-1 inhibitors as an adjuvant treatment for Asian melanoma patients has not yet been determined. Methods: Thus, this single-centre, retrospective study analysed the clinical data of 90 Chinese patients with completely resected, stage III cutaneous or acral melanoma who received either adjuvant PD-1 inhibitor or high-dose interferon α-2b (HDI). Propensity score matching (PSM) was used to control baseline differences between the two treatment groups. The primary end point was recurrence-free survival (RFS), and the secondary end points included distance metastasis-free survival (DMFS) and incidence of first distant metastatic sites. Results: Anti-PD-1 treatment resulted in significantly longer RFS (18-month RFS, 53.3% versus 26.7%; 95% CI, 0.097-0.975; P < 0.05) and DMFS (18-month DMFS, 70.9% versus 46.1%; 95% CI, 0.13-0.945; P < 0.05) than HDI in cutaneous melanoma patients. However, adjuvant anti-PD-1 treatment had no advantage over HDI in acral melanoma patients (18-month RFS, 30.0% versus 35.9%; P > 0.05; 18-month DMFS, 36.5% versus 63.6%; P > 0.05). The incidence of lung metastasis at first in the anti-PD-1 group was found to be significantly lower (12.5% versus 48.5%; P < 0.05) in cutaneous melanoma patients than in acral melanoma patients, but no difference in metastatic sites were observed between the two treatment groups among acral melanoma patients. The incidence of treatment-related AEs was similar between the two treatment groups. Conclusions: In conclusion, adjuvant anti-PD-1 treatment was well tolerated and yielded a significantly better prognosis than HDI in Chinese patients with stage IIIB/C cutaneous melanoma, but a significant difference was not observed in those with acral melanoma.

scholarly journals SAT-249 Polyarticular Osteoarthritis: A Disabling Manifestation of Acromegaly

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Azkia Khan ◽  
Hashim Ejaz ◽  
Vijaykumar Sekar ◽  
Sofia Syed
Keyword(s):  
Pituitary Adenoma ◽  
Endocrine System ◽  
Mass Effect ◽  
Free Testosterone ◽  
The Body ◽  
Medical Attention ◽  
Serum Prolactin ◽  
Oral Glucose ◽  
Patient Reported ◽  
Hands And Feet

Abstract Background Acromegaly is a slow-onset rare endocrinopathy that is characterized by chronic overproduction of growth hormone (GH) and insulin-like growth factor-1 (IGF-1). Excess GH and IGF-1 levels lead to insulin resistance, which is implicated in most of the complications associated with acromegaly. We present a case of acromegaly, wherein the patient presented with worsening polyarthralgia and decreasing mobility. As the patient was undergoing workup for rapidly progressing osteoarthritis, the internist became suspicious of patient’s changing physical appearance. Case A 53-year-old man with medical history of diabetes mellitus and hypertension was referred to endocrine clinic on account of high IGF-1 levels, 909 ng/ml (normal: 37-245 ng/ml). He was seeking medical attention because of rapidly progressing polyarthralgia and stiffness for the last two years. His symptoms were intensifying despite use of non-steroidal anti-inflammatory drugs and intra-articular steroid injections. Imaging revealed severe degenerative changes and narrowing of joint space in bilateral hip, knee and glenohumeral joints. Internist observed that the patient was exhibiting stigmata of acromegaly such as enlargement of hands and feet, prognathism and dental space widening. Patient reported headaches, blurry vision, sleep apnea, dysphagia and right ear exostosis. Colonoscopy revealed hyperplastic polyps. Repeat IGF- 1 levels were 910 ng/ml (Normal: 37-245 ng/ml). Oral glucose tolerance test showed failure of suppression of GH. Serial GH levels were 4.50, 5.08, 6.74, 5.81 and 5.21 ng/ml (Normal: 0.01- 0.97 ng/ml). Tests for other endocrinopathies revealed the following results: serum prolactin 4 ng/ml (Normal &lt;18 ng/ml), serum cortisol 7.9 ug/dl (Normal: 6-27 ug/dl), 24 hour urine cortisol 23mcg/24 hours (Normal: 3.5-45 mcg/24 hours), serum TSH 2.25 uIU/ml (Normal: 0.34- 3 uIU/ml), serum T4 level 0.7 ng/dl (Normal: 0.6-1.6 ng/dl) and serum T3 level 144.9ng/dl (Normal: 87-178 ng/dl). Serum total and free testosterone levels were 111 ng/dl (Normal: 240-950 ng/dl) and 3.89 ng/dl (Normal: 4.06-15.6 ng/dl) respectively and were suggestive of hypogonadism. MRI Brain showed 12x10x8mm pituitary adenoma. He was referred for transsphenoidal surgery for resection of pituitary adenoma. Conclusion Polyarticular osteoarthritis is an early manifestation of acromegaly. Systemic diseases associated with acromegaly are the primary reason for which most patients seek medical attention. It is important to look for coexisting endocrinopathies whenever the diagnosis of acromegaly is established, since mass effect of pituitary adenoma can wreak havoc on the endocrine system of the body. High index of suspicion, early diagnosis and prompt treatment are the key to reverse some but not all comorbid conditions associated with acromegaly.

Athetosis and Dystonia

2020 ◽  
pp. 105-136
Author(s):  
Hiroshi Shibasaki ◽  
Mark Hallett ◽  
Kailash P. Bhatia ◽  
Stephen G. Reich ◽  
Bettina Balint
Keyword(s):  
Cerebral Palsy ◽  
Voluntary Movement ◽  
Botulinum Toxin Injection ◽  
The Body ◽  
Focal Dystonia ◽  
Anoxic Encephalopathy ◽  
Abnormal Posture ◽  
Repetitive Movements ◽  
Generalized Dystonia ◽  
Hands And Feet

Athetosis is characterized by irregular, slow, writhing, bizarre movements seen in hands and feet. Athetosis is classified as minor athetosis and major athetosis based on its magnitude. Minor athetosis is seen in patients with mild cerebral palsy. Major athetosis is caused by organic lesions of the striatum, including cerebral palsy, as a residual state of encephalitis, and after anoxic encephalopathy. In these conditions, athetosis is commonly seen in combination with dystonia. Dystonia is characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements or postures or both. In many cases of dystonia, the affected part of the body shows an abnormal writhing posture in the resting condition, and slow, writhing involuntary movements are superimposed on the abnormal posture with voluntary movement. For childhood-onset patients, dystonia is most commonly generalized; in adults, typically there is focal dystonia. Focal dystonia includes blepharospasm, cervical dystonia, writer’s cramp, and musician’s cramp. It is often task-specific and can be treated with local botulinum toxin injection. Generalized dystonia is caused by long use of neuroleptic drugs (tardive dystonia) and a variety of neurodegenerative diseases.

scholarly journals Frequent Occurrence of NRAS and BRAF Mutations in Human Acral Naevi

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 546 ◽  
Author(s):  
Philipp Jansen ◽  
Ioana Cosgarea ◽  
Rajmohan Murali ◽  
Inga Möller ◽  
Antje Sucker ◽  
...  
Keyword(s):  
Malignant Tumors ◽  
Gene Mutations ◽  
Diagnostic Value ◽  
Clinicopathological Parameters ◽  
Braf Mutations ◽  
Acral Melanoma ◽  
Targeted Next Generation Sequencing ◽  
Melanocytic Tumors ◽  
Frequent Mutations ◽  
Melanoma Subtypes

Acral naevi are benign melanocytic tumors occurring at acral sites. Occasionally they can progress to become malignant tumors (melanomas). The genetics of acral naevi have not been assessed in larger studies. In our study, a large cohort of 130 acral naevi was screened for gene mutations known to be important in other naevi and melanoma subtypes by targeted next-generation sequencing. Mutation status was correlated with clinicopathological parameters. Frequent mutations in genes activating the MAP kinase pathway were identified, including n = 87 (67%) BRAF, n = 24 (18%) NRAS, and one (1%) MAP2K1 mutations. BRAF mutations were almost exclusively V600E (n = 86, 99%) and primarily found in junctional and compound naevi. NRAS mutations were either Q61K or Q61R and frequently identified in dermal naevi. Recurrent non-V600E BRAF, KIT, NF1, and TERT promoter mutations, present in acral melanoma, were not identified. Our study identifies BRAF and NRAS mutations as the primary pathogenic event in acral naevi, however, distributed differently to those in non-acral naevi. The mutational profile of acral naevi is distinct from acral melanoma, which may be of diagnostic value in distinguishing these entities.

scholarly journals Left Right Judgement Task and Sensory, Motor, and Cognitive Assessment in Participants with Wrist/Hand Pain

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
René Pelletier ◽  
Daniel Bourbonnais ◽  
Johanne Higgins ◽  
Maxime Mireault ◽  
Michel Alain Danino ◽  
...  
Keyword(s):  
Motor Imagery ◽  
Stroop Test ◽  
The Body ◽  
Imagery Ability ◽  
Hand Pain ◽  
Pain Medications ◽  
Severity Scores ◽  
Pressure Pain Thresholds ◽  
Sensory Motor ◽  
Hands And Feet

The Left Right Judgement Task (LRJT) involves determining if an image of the body part is of the left or right side. The LRJT has been utilized as part of rehabilitation treatment programs for persons with pain associated with musculoskeletal injuries and conditions. Although studies often attribute changes and improvement in LRJT performance to an altered body schema, imaging studies suggest that the LRJT implicates other cortical regions. We hypothesized that cognitive factors would be related to LRJT performance of hands and feet and that sensory, motor, and pain related factors would be related to LRJT in the affected hand of participants with wrist/hand pain. In an observational cross-sectional study, sixty-one participants with wrist/hand pain participated in a study assessing motor imagery ability, cognitive (Stroop test), sensory (Two-Point Orientation Discrimination, pressure pain thresholds), motor (grip strength, Purdue Pegboard Test), and pain related measures (West Haven Yale Multidimensional Pain Inventory) as well as disability (Disability of the Arm, Shoulder and Hand). Multiple linear regression found Stroop test time and motor imagery ability to be related to LRJT performance. Tactile acuity, motor performance, participation in general activities, and the taking of pain medications were predictors of LRJT accuracy in the affected hand. Participants who took pain medications performed poorly in both LRJT accuracy (p=0.001) and reaction time of the affected hand (p=0.009). These participants had poorer cognitive (p=0.013) and motor function (p=0.002), and higher pain severity scores (p=0.010). The results suggest that the LRJT is a complex mental task that involves cognitive, sensory, motor, and behavioural processes. Differences between persons with and without pain and improvement in LRJT performance may be attributed to any of these factors and should be considered in rehabilitation research and practice utilizing this task.

scholarly journals STUDIES ON CILIA

1965 ◽  
Vol 26 (3) ◽  
pp. 805-834 ◽  
Author(s):  
Peter Satir
Keyword(s):  
Cross Section ◽  
Length Change ◽  
The Body ◽  
Cell Of Origin ◽  
Ciliary Movement ◽  
The Matrix ◽  
Morphological Specialization ◽  
Dense Band ◽  
The Cross ◽  
Different Order

Termination of peripheral filaments of the axoneme of gill cilia of fresh-water mussels (Elliptio or Anodonta) occurs in characteristic fashion: (a) subfiber b of certain doublets ends leaving a single simplified tubular unit; (b) the wall of the unit becomes thick and may even obliterate the interior; and (c) the filament drops out of the 9 + 2 pattern. The order in which doublets begin simplifying is also characteristic. This may be determined by numbering the filaments, those with the bridge being 5–6, with the direction of numbering determined by the apparent enantiomorphic configuration (I to IV) of the cross-section. Shorter filaments can be identified in simplifying tips with mixed double and single peripheral units. In this material, laterofrontal cirri show a morphological specialization in the region where individual cilia simplify. The cilia studied run frontally from the body of the cirrus and point in the direction of effective stroke. The longest filaments (Nos. 3, 4, 5, 6, 7) appear as the doublets at the bottom of the cross-section, nearest the surface of the cell of origin. Above them, and above the central pair, a dark band (a section of a dense rod) runs through the matrix. The remaining filaments are the single units. Effective-pointing frontal and lateral ciliary tips end in a fashion similar to laterofrontal tips, although no dense band is present. For all effective-pointing tips studied, the order in which the peripheral filaments end appears to be Nos. (9, 1), 8, 2, 7, 6, 3, 4, 5. However, recovery-pointing lateral tips show a different order: Nos. 7, 6, 8, 5, 9, 4, 1 (3, 2), although the longer filaments are still at the bottom of the cross-section. In simple models of ciliary movement involving contraction of the peripheral filaments, filaments at the top of the cross-section should be longer, if any are. Such models are not supported by the evidence here. These results can be interpreted as supporting sliding-filament models of movement where no length change of peripheral filaments occurs.

BRAF mutations in patients with large cell neuroendocrine carcinoma of the colon (LCNECC).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 567-567
Author(s):  
Karuna Ganesh ◽  
Nitya Prabhakar Raj ◽  
Rona D. Yaeger ◽  
Michael F. Berger ◽  
Jinru Shia ◽  
...  
Keyword(s):  
Neuroendocrine Carcinoma ◽  
Impact Analysis ◽  
Cell Cancer ◽  
Braf Inhibitor ◽  
Large Cell ◽  
Small Cell ◽  
Braf V600e ◽  
Cell Of Origin ◽  
Braf Mutations ◽  
Carcinoma Of The Colon

567 Background: LCNECC is a rare, poorly differentiated neoplasm with a median survival of 13 months. The cell of origin, genetic mediators and optimal clinical management of LCNECC are unknown. Current guidelines recommend treatment with platinum and etoposide, but nearly all patients rapidly fail therapy. Identification of actionable genomic alterations in LCNECC may lead to improved outcomes. Methods: We identified 123 patients (1.1%) with LCNECC or non-small cell high-grade neuroendocrine carcinoma of the colon or rectum, out of 11134 colorectal cancers treated at MSKCC from 1991-2015. Genomic testing had been performed on 8 tumors: 5 using mass spectrometry based genotyping of 8 genes and 3 using hybridization exon capture of 341 cancer-associated genes (MSK IMPACT). Results: BRAF V600E mutations were identified in 5/8 (62.5%) LCNECCs. One patient each had KRAS Q61H and G12V mutations. Only 2/8 patients had TP53 mutations. All 5 patients with BRAF V600E mutations had non-regional lymphadenopathy, consistent with the metastatic pattern seen in BRAF-mutant colorectal adenocarcinoma (CRC). One patient, a 52-year old female with metastatic LCNECC, was first treated with cisplatin/irinotecan but progressed after 2 cycles. She was treated with FOLFOX, with dramatic clinical and radiological response lasting 7 months. BRAFV600E mutation was identified, and she was treated with dabrafenib+trametinib with radiologically stable disease at 2 months. In sum, 4/6 evaluable patients treated with first line FOLFOX, and 3/3 patients receiving second line FOLFOX after disease progression on cisplatin-based therapy achieved radiological responses. Conclusions: BRAF and KRAS hotspot mutations are near universal features of LCNECC, suggesting that LCNECC is an ERK driven tumor. BRAF inhibitor therapy was associated with clinical benefit in one LCNECC patient. Mutations in TP53, RB1 and PTEN, frequent in small cell cancer, are uncommon in LCNECC. Moreover, several patients responded to FOLFOX, a standard of care for CRC. Together, the mutation patterns and therapy responses suggest some similarities between LCNECC and CRC. MSK IMPACT analysis of further LCNECCs is underway and will be reported at the meeting.

Analysis of Chinese acral and mucosal melanoma patient genomic and neoantigen profiles in cancer vaccine development: A pilot study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14300-e14300 ◽  
Author(s):  
Xianling Guo ◽  
Song Gao ◽  
Li Yang ◽  
Juemin Fang ◽  
Guochao Wei ◽  
...  
Keyword(s):  
Pilot Study ◽  
Cutaneous Melanoma ◽  
Vaccine Development ◽  
Mucosal Melanoma ◽  
The Cancer Genome Atlas ◽  
Driver Mutations ◽  
Data Set ◽  
Acral Melanoma ◽  
Tumor Mutational Burden ◽  
Melanoma Patients

e14300 Background: Acral and mucosal melanoma are rare subtypes accounting for about 3% of all melanoma cases. The cutaneous melanoma genomic landscape is well defined; however, little is known about the acral and mucosal melanoma mutational spectrum. In this pilot study, we evaluated the genomic and neo-antigen profiles and tumor mutational burden (TMB) from acral and mucosal melanoma patients with the aim of designing personalized vaccines and longitudinally tracking patients’ clinical courses. Methods: Tumor whole exome sequencing and neo-antigen profiling of 5 acral and 3 mucosal melanoma patients at Shanghai Tenth Peoples Hospital, Tongji University, China between April 2018 and January 2019 was performed using YuceBio’s proprietary analytics platform. Watsonä for Genomics, an artificial intelligence decision-support system, was used for variant interpretation and annotation. A comparative analysis was performed on Chinese acral melanoma data with the published Caucasian acral cohort from the Translational Genomics Research Institute (TGen) and The Cancer Genome Atlas (TCGA) predominantly Caucasian cutaneous melanoma data set. Results: TMB in our acral/mucosal melanoma cohort was 2.26/Megabase (Mb) compared to over 20/Mb in published cutaneous melanoma studies. Tumor neo-antigen burden (TNAB) in our group was 1.03 neo-epitopes/Mb. Low TNAB levels were associated with low TMB levels in all tumors. Incidence of BRAF and NRAS mutant cases in our cohort was 0% (0/8) and 13% (1/8) respectively compared to 19% (5/27) and 7% (2/27) of the Caucasian acral population in the TGen dataset. Incidence of BRAF and NRAS mutations in the TCGA cutaneous melanoma dataset was 54% (237/440) and 28% (125/440), respectively. Conclusions: TMB was significantly lower in acral/mucosal than in cutaneous melanoma and may be a surrogate for TNAB. Detection of BRAF and NRAS mutations, the two most prevalent driver mutations in cutaneous melanoma, were significantly lower frequencies in both Chinese and Caucasian acral melanoma patients in this study, suggesting alternate cancer drivers may exist in this subtype. Strategies to address challenges of low TNAB in vaccine development are being explored.

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