PubMed Health⌕ Search

Biomedical subjects

Stephan Ariyan

Publications and source records attributed to Stephan Ariyan.

14 recordsLinked to original sources
PubMed2006

Rab33A: characterization, expression, and suppression by epigenetic modification.

Rab33A, a member of the small GTPase superfamily, is an X-linked gene that is expressed in brain, lymphocytes, and normal melanocytes, but is downregulated in melanoma cells. We demonstrate that in normal melanocytes Rab33A colocalizes with melanosomal proteins and that a constitutively active GTPase mutant suppresses their transport to the melanosomes. In the brain, Rab33A is present throughout the cortex, as well as in the hippocampal CA fields. A survey of melanocytic lesions demonstrated that aberrant downregulation of Rab33A is an early event that is already prevalent in melanocytes of giant congenital nevi. Analyses of bisulfite-modified DNA revealed that Rab33A is regulated by DNA methylation of a specific promoter region proximal to the transcription initiation site, and that suppression of Rab33A in melanoma cells recapitulates normal processes that control silencing of X-linked genes, but not tissue specific gene expression. This information is important for understanding carcinogenesis as well as other aberrant processes because Rab33A may have an important role in disorders involving X-chromosome-linked genes associated with vesicular transport.

Amino Acid Sequence↗
PubMed2006

Prospective multi-institutional study of reverse transcriptase polymerase chain reaction for molecular staging of melanoma.

PURPOSE: To evaluate the prognostic significance of molecular staging using reverse transcriptase polymerase chain reaction (RT-PCR) in detecting occult melanoma cells in sentinel lymph nodes (SLNs) and circulating bloodstream. PATIENTS AND METHODS: In this multicenter study, eligibility criteria included patient age 18 to 71 years, invasive melanoma > or = 1.0 mm Breslow thickness, and no clinical evidence of metastasis. SLN biopsy and wide excision of the primary tumor were performed. SLNs were examined by serial-section histopathology and S-100 immunohistochemistry. A portion of each SLN was frozen for RT-PCR. In addition, RT-PCR was performed on peripheral-blood mononuclear cells (PBMCs). RT-PCR analysis was performed using four markers: tyrosinase, MART1, MAGE3, and GP-100. Disease-free survival (DFS), distant-DFS (DDFS), and overall survival (OS) were analyzed. RESULTS: A total of 1,446 patients with histologically negative SLNs underwent RT-PCR analysis. At a median follow-up of 30 months, there was no difference in DFS, DDFS, or OS between the RT-PCR-positive (n = 620) and RT-PCR-negative (n = 826) patients. Analysis of PBMC from 820 patients revealed significant differences in DFS and DDFS, but not OS, for patients with detection of more than one RT-PCR marker in peripheral blood. CONCLUSION: In this large, prospective, multi-institutional study, RT-PCR analysis on SLNs and PBMCs provides no additional prognostic information beyond standard histopathologic analysis of SLNs. Detection of more than one marker in PBMC is associated with a worse prognosis. RT-PCR remains investigational and should not be used to direct adjuvant therapy at this time.

Adult↗
PubMed2006

Gender-related differences in outcome for melanoma patients.

OBJECTIVE: To better understand the factors associated with the well-established gender difference in survival for patients with melanoma. SUMMARY BACKGROUND DATA: Gender is an important factor in patients with cutaneous melanoma. Male patients have a worse outcome when compared with females. The reasons for this difference are poorly understood. METHODS: This prospective multi-institutional study included patients aged 18 to 70 years with melanomas > or =1.0 mm Breslow thickness. Wide excision and sentinel lymph node (SLN) biopsy was performed in all patients. Clinicopathologic factors, including gender, were assessed and correlated with disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS). RESULTS: A total of 3324 patients were included in the covariate analyses; 1829 patients had follow-up data available and were included in the survival analyses. Median follow-up was 30 months. On univariate analysis, men (n = 1906) were more likely than women to be older than 60 years (P < 0.0001), have thicker melanomas (P < 0.0001), have primary tumor regression (P = 0.0054), ulceration (P < 0.0001), and axial primary tumor location (P < 0.0001). On multivariate analysis, age (P = 0.0002), thickness (P < 0.0001), ulceration (P = 0.015), and location (P < 0.0001) remained significant in the model. There was no difference in the rate of SLN metastasis between men and women (P = 0.37) on multivariate analysis. When factors affecting survival were considered, the prognosis was worse for men as validated by lower DFS (P = 0.0005), DDFS (P < 0.0001), and OS (P < 0.0001). CONCLUSIONS: Male gender is associated with a greater incidence of unfavorable primary tumor characteristics without an increased risk for nodal metastasis. Nonetheless, gender is an independent factor affecting survival.

Adolescent↗
PubMed2004

Expression profiling reveals novel pathways in the transformation of melanocytes to melanomas.

Affymetrix and spotted oligonucleotide microarrays were used to assess global differential gene expression comparing normal human melanocytes with six independent melanoma cell strains from advanced lesions. The data, validated at the protein level for selected genes, confirmed the overexpression in melanoma cells relative to normal melanocytes of several genes in the growth factor/receptor family that confer growth advantage and metastasis. In addition, novel pathways and patterns of associated expression in melanoma cells not reported before emerged, including the following: (a) activation of the NOTCH pathway; (b) increased Twist expression and altered expression of additional transcriptional regulators implicated in embryonic development and epidermal/mesenchymal transition; (c) coordinated activation of cancer/testis antigens; (d) coordinated down-regulation of several immune modulation genes, in particular in the IFN pathways; (e) down-regulation of several genes implicated in membrane trafficking events; and (f) down-regulation of growth suppressors, such as the Prader-Willi gene NECDIN, whose function was confirmed by overexpression of ectopic Flag-necdin. Validation of differential expression using melanoma tissue microarrays showed that reduced ubiquitin COOH-terminal esterase L1 in primary melanoma is associated with worse outcome and that increased expression of the basic helix-loop-helix protein Twist is associated with worse outcome. Some differentially expressed genes reside on chromosomal regions displaying common loss or gain in melanomas or are known to be regulated by CpG promoter methylation. These results provide a comprehensive view of changes in advanced melanoma relative to normal melanocytes and reveal new targets that can be used in assessing prognosis, staging, and therapy of melanoma patients.

Animals↗
PubMed2004

Reliability of identification of 655 sentinel lymph nodes in 263 consecutive patients with malignant melanoma.

BACKGROUND: The purpose of this study of sentinel lymph node biopsies (SLN) was threefold: to compare the reliability of lymphazurin blue dye to radioactive technetium 99m sulfur colloid (TC); to evaluate the reliability of frozen section examinations of sentinel lymph nodes; and to determine how much SLN dissections prolonged operative time. STUDY DESIGN: We evaluated the records of 263 consecutive patients with intermediate and high-risk melanomas (1.0 mm or thicker, or Clark Level IV or greater), who were treated by a single surgeon at the Yale Melanoma Unit between October 1, 1997, and September 30, 2001, and followed for more than 18 months. RESULTS: A total of 655 SLN were identified and removed from these 263 consecutive patients. Radioactive colloid was found to be more reliable (100%) in identifying the SLN than lymphazurin blue dye (51%) in the nodes of the patients. Twenty-eight patients (11%) had positive sentinel lymph nodes, and 2 patients (7%) had false-negative frozen sections. Three patients (11%) had false-negative frozen sections; tumor was found subsequently on permanent sections only after special immunohistochemical stains were used. The location or removal of SLN did not prolong the operative procedure unreasonably, requiring an average of 7 to 20 minutes for removal of SLN, and 33 minutes for frozen section reports, during which time the primary tumor resection and wound coverage were performed. CONCLUSIONS: SLN were found in all 263 patients. All SLN were identified reliably with radioactive colloid. Because blue dye was found in only half of the radioactive nodes, it is not appropriate to use this as the only marker for locating the SLN. This large series of patients attests to the reliability of frozen sections in identifying SLN harboring metastases, with 82% of the patients with nodal metastases identified in this fashion.

Follow-Up Studies↗
PubMed2004

Microsurgical free flap reconstruction outcomes in head and neck cancer patients after surgical extirpation and intraoperative brachytherapy.

OBJECTIVES: The management of recurrent or persistent head and neck cancer poses a challenging problem. Salvage surgery for these individuals consists of ablative surgery, interstitial brachytherapy, and microsurgical free flap reconstruction. This study reviews complications after such reconstruction. METHODS: We reviewed 139 consecutive head and neck cancer patients undergoing free flap reconstruction from January 1994 to May 2002. These included 66 patients with recurrent head and neck cancer undergoing intraoperative brachytherapy (IOBT) and free flap reconstruction and 73 undergoing free flap reconstructions only. A total of 142 reconstructions were performed, with three patients in IOBT group receiving two free flap reconstructions per patient, giving us a total of 69 reconstructions in the IOBT group versus 73 in the non-IOBT group. Nine patients were excluded from the IOBT group because of nonsynchronous use of brachytherapy and reconstruction, and 10 patients were excluded from the other group because they had prior radiotherapy or surgical treatment, leaving us with a total of 123 reconstructions, 60 in the IOBT group and 63 in the non-IOBT group. The IOBT group patients received iodine Vicryl seed implants, palladium seed implants, or both, to deliver an average dose of 79.3 +/- 31.8 Gy (mean +/- 1SD) to the surgical bed. RESULTS: All patients were followed for evidence of local wound complications. The IOBT group showed multiple complications in 23 (38.33%) of 60 reconstructions, the most common being wound dehiscence in 11. This, when compared with the non-IOBT group complications (15.87%), was found to be statistically significant (chi test, P <.01). CONCLUSION: IOBT increases the rate of complications in patients undergoing microvascular free tissue transfer. This, however, should not deter or alter the aggressiveness of cancer therapy used for managing recurrent head and neck cancer.

Adolescent↗
PubMed2004

Her2/neu is not a commonly expressed therapeutic target in melanoma -- a large cohort tissue microarray study.

Melanoma is among the most chemotherapy-resistant malignancies. Numerous new agents have been developed that target specific molecules on cancer cells, including the monoclonal antibody trastuzumab, which targets Her2/neu and has been very beneficial in the treatment of breast cancer. There are conflicting reports in the literature about Her2/neu expression in melanoma specimens, but all of the cohorts studied have been small. We therefore examined Her2/neu expression in a very large cohort of melanoma specimens in order to determine the value of exploring trastuzumab therapy for melanoma patients. Immunohistochemical staining was performed on two tissue microarrays, together containing 600 intact specimens. Expression was evaluated semi-quantitatively and correlated with tumour stage and other clinicopathological data. Of the 600 specimens in the cohort, 31 patients (5.2%) had positive Her2/neu expression. Among the primary cutaneous specimens (n=269), 7% had positive Her2/neu staining, while 3.6% of the recurrent or metastatic specimens (n=331) had positive Her2/neu staining (P=0.06). Among the primary lesions there was no significant correlation between Her2/neu expression, Clark level and ulceration; however, Her2/neu expression was associated with lesions with a Breslow depth of < 2 mm (P=0.05). Using this very large cohort of melanoma specimens, we found only a few cases with aberrant Her2/neu expression, many of them being primary cutaneous lesions rather than recurrent or metastatic lesions. Our findings suggest that drugs that specifically target Her2/neu are not likely to be useful for the treatment of metastatic melanoma or as adjuvant therapy for melanoma patients at high risk for recurrence.

Cohort Studies↗
PubMed2004

Pulse oximetry declines due to intradermal isosulfan blue dye: a controlled prospective study.

BACKGROUND: Isosulfan blue dye is widely used in sentinel node surgery for malignant melanoma. Intravascular dye injection is known to interfere with pulse oximetry (SpO2), but the effects of intradermal dye injection are not well known. Our aim was to determine the effects of intradermal dye injection on SpO2. METHODS: This was a controlled, prospective study of 84 consecutive patients undergoing wide local excision of malignant melanoma and sentinel lymph node biopsy. The control group (n=24) received no dye. The dye group (n=60) received isosulfan blue dye intradermally at the biopsy site. SpO2 declines of > or =2% were considered significant. RESULTS: Two patients in the control group (8%) and 20 patients in the dye group (33%) had a clinically significant SpO2 decline (P<.02). In those with significant declines in the dye group, the amount ranged from 2% to 4%. The latency of decline from the time of injection was 22.8 +/- 12.7 minutes. CONCLUSIONS: Patients who receive intradermal dye injection for sentinel lymph node surgery have a 4-fold increased rate of developing declines in SpO2. With the increasing trend toward using intradermal dye administration to map lymphatic drainage in melanoma and breast surgery, declines in SpO2 readings can be expected to occur frequently. To our knowledge, this is the first report of the effects of intradermal dye injection on SpO2 readings in a large series of patients.

Chi-Square Distribution↗
PubMed2003

Use of the operating microscope and loupes for head and neck free microvascular tissue transfer: a retrospective comparison.

OBJECTIVE: To analyze whether less cumbersome loupes are as equally efficacious as the microscope for magnification for free tissue transfers in head and neck reconstruction. DESIGN: A 7-year retrospective review of 151 consecutive microvascular free tissue transfers compares the operating microscope with loupe magnification. SETTING: A tertiary care medical center. PATIENTS: A total of 151 consecutive patients undergoing microvascular reconstructions. INTERVENTION: Microvascular reconstruction of ablative head and neck cancer defects using either microscopic or loupe-provided magnification. MAIN OUTCOME MEASURES: Medical records were reviewed for demographic data, preoperative radiation status, type of defect and flap, length of procedure, complications, and length of stay. RESULTS: Two teams shared the reconstructions, with all microvascular anastomoses created or directly supervised by one of us (D.A.R.). One team used the operating microscope for magnification (84 cases), while the other used loupes (67 cases). Complication rates were statistically similar for the 2 techniques, the length of procedure tended to be shorter in the loupe group, and the length of stay was statistically similar in both groups. CONCLUSIONS: A review of the literature validates the usefulness of loupe magnification in free tissue transfer surgery. To our knowledge, this is the largest number of head and neck reconstruction cases presented comparing these techniques. Loupes offer the surgeon comfort and easy access to and uncomplicated visualization of the operating field. Furthermore, loupes may decrease operating time and help avoid complicated equipment. Therefore, loupe magnification should be considered in head and neck reconstruction without the fear of increased morbidity.

Adolescent↗
PubMed2002

Preservation of muscle fascia to decrease lymphedema after complete axillary and ilioinguinofemoral lymphadenectomy for melanoma.

BACKGROUND: In patients with melanoma, there is considerable concern about the clearance of clinically negative nodes, partly because of the unacceptable morbidity reported after regional lymphadenectomy. The advent of sentinel lymph node biopsies has allowed us to select those patients with positive sentinel lymph nodes for completion node dissections. The purpose of this article is to demonstrate that when complete lymph node dissection is indicated, it can be performed with a low risk of lymphedema using the fascia-preserving technique. STUDY DESIGN: The records of 209 consecutive patients with melanoma who underwent fascia-preserving axillary (n = 116) or ilioinguinofemoral (n = 93) lymphadenectomy by a single surgeon between January 1984 and April 1998 were reviewed. In each operation, care was taken not to disrupt the muscle fascia at the site of lymphadenectomy. RESULTS: In the fascia-preserving axillary group, there were 59 men and 47 women with mean age of 53 years (range 21 to 79 years). There were three recurrences (3%) outside the borders of dissection. Transient upper extremity edema (8%) resolved over a median of 5 months, and permanent upper extremity edema occurred in 5% of patients. In the ilioinguinofemoral group, there were 19 men and 37 women with a mean age of 52 years (range 21 to 88 years). There was one recurrence (2%) outside the borders of dissection. Transient lower extremity edema (48%) resolved over a median of 12 months, and permanent lower extremity edema occurred in 14% of patients. CONCLUSIONS: Preservation of the muscle fascia during lymph node dissection results in a lower incidence of permanent edema, with no increased risk of recurrence.

Adult↗
PubMed2002

Merkel cell carcinoma: five case reports using sentinel lymph node biopsy and a review of 110 new cases.

Merkel cell carcinoma is an uncommon cutaneous tumor that is considered locally aggressive and often spreads regionally through lymphatic channels. Evaluation of surgical treatment methods has been hampered by the low incidence of this tumor. Current standards of treatment include wide surgical excision and regional lymphadenectomy if clinically suspicious nodes are present. However, the development and increasing use of sentinel node imaging and biopsy have expanded the diagnostic options. This article presents information on 110 Merkel cell carcinomas treated in Connecticut between 1990 and 1997. Statistics on gender, age, disease location, treatment, and mortality are reviewed. Using the census data for Connecticut, the annual incidence for this disease was calculated to be 0.42 cases per 100,000 people. A series of five cases treated with wide excision and sentinel lymph node biopsy is also presented.

Adult↗