Five-year analysis of neoadjuvant dabrafenib and trametinib for stage III melanoma.

BACKGROUND: Neoadjuvant dabrafenib plus trametinib has a high pathological response rate and impressive short-term survival in patients with resectable stage III melanoma. We report 5-year outcomes from the phase II NeoCombi trial. PATIENTS AND METHODS: NeoCombi (NCT01972347) was a single-arm, open-label, single-centre, phase II trial. Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, American Joint Committee on Cancer seventh edition clinical stage IIIB-C BRAF V600E/K-mutant melanoma and Eastern Cooperative Oncology Group performance status ≤1. Patients received 52 weeks of treatment with dabrafenib 150 mg (orally twice per day) plus trametinib 2 mg (orally once per day), with complete resection of the pre-therapy tumour bed at week 12. RESULTS: Between 20 August 2014 and 19 April 2017, 35 patients were enrolled. At data cut-off (17 August 2021), the median follow-up was 60 months [95% confidence interval (CI) 56-72 months]. Overall, 21 of 35 (60%) patients recurred, including 12 (57%) with first recurrence in locoregional sites (followed by later distant recurrence in 6) and 9 (43%) with first recurrence in distant sites, including 3 in the brain. Most recurrences occurred within 2 years, with no recurrences beyond 3 years. At 5 years, recurrence-free survival (RFS) was 40% (95% CI 27% to 60%), distant metastasis-free survival (DMFS) was 57% (95% CI 42% to 76%), and overall survival was 80% (95% CI 67% to 94%). Five-year survival outcomes were stratified by pathological response: RFS was 53% with pathological complete response (pCR) versus 28% with non-pCR (P = 0.087), DMFS was 59% versus 55% (P = 0.647), and overall survival was 88% versus 71% (P = 0.205), respectively. CONCLUSIONS: Neoadjuvant dabrafenib plus trametinib has high pathological response rates in clinical stage III melanoma, but low rates of RFS, similar to those achieved with adjuvant targeted therapy alone. Patients with a pCR to dabrafenib plus trametinib still had a high risk of recurrence, unlike that seen with immunotherapy where recurrences are rare.

Representativeness of initial skin biopsies showing pure desmoplastic melanoma: implications for management.

Desmoplastic melanoma (DM) is an uncommon subtype of melanoma with distinct clinicopathological features. It is classified into pure desmoplastic melanoma (PDM) when the proportion of desmoplastic melanoma is ≥90% of the dermally-invasive component, and mixed desmoplastic melanoma (MDM) when the proportion of desmoplastic melanoma is <90%. Studies have reported a lower sentinel lymph node biopsy (SLNB)-positivity rate in PDM compared to MDM and non-DM. As a result, some have recommended not performing SLNB in PDM patients. When PDM is identified in a partial biopsy of a melanoma, there is a risk that sampling bias may under-recognise MDM, but to the best of our knowledge this has not been previously assessed or quantified. The aim of this study was to assess the concordance of the proportion of desmoplastic melanoma in an initial partial biopsy of PDM with the proportion in the entire tumour following complete excision, in patients with cutaneous melanoma. A secondary aim was to determine how frequently this potentially resulted in a patient not receiving a SLNB. Seventy-eight cases of cutaneous melanoma were identified from the Melanoma Institute Australia (MIA) database and 23 cases from the Memorial Sloan Kettering Cancer Centre (MSKCC), where an initial biopsy contained PDM and a subsequent wide excision had residual invasive melanoma. Clinicopathological features were analysed in all patients, including whether a SLNB was performed, the results of SLNB, and any subsequent recurrence. Ninety percent (91/101) of cases were still classified as PDM in the complete wide excision specimen while 10% (10/101) of cases were reclassified as MDM, which was a significant change in classification of final desmoplastic melanoma subtype (p<0.001). The proportion of desmoplastic melanoma was also significantly different between the initial and excisional biopsies (p=0.004). Forty-eight (48/101) patients had a SLNB, of which two (4.5%) were positive for metastatic melanoma; both cases were PDM in the excision specimen. Of the 10 cases demonstrating MDM in the excision specimen, the initial biopsy was a punch biopsy in six cases, shave biopsy in two cases and subcutaneous tissue was sampled in two patients (one punch biopsy, one incisional biopsy). Four of these 10 patients underwent SLNB which was negative in all cases. Twenty-two patients developed recurrence in the follow-up period (median 30 months, range 1-192 months), three with MDM in their excision specimen. One patient did not have a SLNB and developed regional lymph node recurrence. In this study there was a 10% risk that the percentage of desmoplastic melanoma in an initial biopsy of PDM was not representative of the entire lesion, resulting in reclassification as MDM in the excision specimen. If a SLNB is not performed in such cases, a positive SLNB may be missed (one patient in our study) which could impact treatment options for the patient. We recommend caution in not offering a SLNB in the setting of an initial biopsy of PDM if the biopsy is small compared with the overall lesion. If a SLNB is not procured at the time of wide excision in such cases, the SLNs should still be mapped by lymphoscintigraphy to facilitate careful follow up and to enable earlier detection and treatment of nodal disease.

Lentigo maligna: defining margins and predictors of recurrence utilizing clinical, dermoscopic, confocal microscopy and histopathology features.

BACKGROUND: Lentigo maligna (LM) is a subtype of melanoma in situ with poorly defined margins and a high recurrence rate. The biological behaviour of LM appears to differ widely between cases, from biologically indolent to biologically active variants, with some patients experiencing multiple recurrences. It is not known whether this is secondary to inadequate margins, field cancerization or the innate biology of the lesion itself. OBJECTIVES: (a) Describe the margins of LM in detail by analysing LM in three zones, that is centre, edge and surround using reflectance confocal microscopy (RCM) and histopathology; (b) ascertain association of histological distance of LM and atypical melanocytic hyperplasia from the surgical margin with multi-recurrent (MR) disease and (c) identify features (clinical, dermoscopy, RCM and histopathology) associated with MR LM. METHODS: (1) Descriptive observational study comparing the centre, edge and surround of LM on histopathology and RCM; (2) retrospective cohort study comparing parameters associated with MR and non-recurrent (NR) LM. RESULTS: 30 patients (median follow-up time 6.2 years) were included. On histopathology, confluent or near confluent lentiginous proliferation, melanocyte density >15 per 0.5 mm and adnexal spread were best for distinguishing surround from edge of LM. On RCM, predominant melanocytes, lentiginous proliferation and pleomorphism distinguished surround from centre/edge. MR patients had a median histological distance of LM from the surgical margin of 2mm (versus NR patients with an average distance of 4mm). MR patients had a greater proportion of more florid features, compared with NR on histopathology at both the centre and the edge but were similar in the surround. CONCLUSION: These data may help pathologists and confocalists better define margins of LM. More florid features in MR patients, despite a similar background of sun-damaged skin, suggest the innate biology of the lesion rather than the field of cancerization may explain MR LM.

Not all melanomas are created equal: a review and call for more research into nodular melanoma.

Among the histogenic subtypes of melanoma, nodular melanoma (NM) is the major contributor for thicker and fatal melanomas and it has been associated with melanoma-specific death in thin tumours, highlighting an important subgroup of 'aggressive thin' melanomas. This review provides a synthesis of the distinct characteristics of NM, with respect to epidemiology and risk factors, clinical presentation, histopathology, molecular and dermoscopic aspects, and screening practices. The real challenges are to find better biomarkers of aggressiveness and to know whether the control of such aggressive melanomas can be influenced by targeted interventions such as early detection, drug interventions and preventive strategies.

Pathological response and tumour bed histopathological features correlate with survival following neoadjuvant immunotherapy in stage III melanoma.

BACKGROUND: Guidelines for pathological evaluation of neoadjuvant specimens and pathological response categories have been developed by the International Neoadjuvant Melanoma Consortium (INMC). As part of the Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo) clinical trial of neoadjuvant combination anti-programmed cell death protein 1/anti-cytotoxic T-lymphocyte-associated protein 4 immunotherapy for stage III melanoma, we sought to determine interobserver reproducibility of INMC histopathological assessment principles, identify specific tumour bed histopathological features of immunotherapeutic response that correlated with recurrence and relapse-free survival (RFS) and evaluate proposed INMC pathological response categories for predicting recurrence and RFS. PATIENTS AND METHODS: Clinicopathological characteristics of lymph node dissection specimens of 83 patients enrolled in the OpACIN-neo clinical trial were evaluated. Two methods of assessing histological features of immunotherapeutic response were evaluated: the previously described immune-related pathologic response (irPR) score and our novel immunotherapeutic response score (ITRS). For a subset of cases (n = 29), cellular composition of the tumour bed was analysed by flow cytometry. RESULTS: There was strong interobserver reproducibility in assessment of pathological response (κ = 0.879) and percentage residual viable melanoma (intraclass correlation coefficient = 0.965). The immunotherapeutic response subtype with high fibrosis had the strongest association with lack of recurrence (P = 0.008) and prolonged RFS (P = 0.019). Amongst patients with criteria for pathological non-response (pNR, >50% viable tumour), all who recurred had ≥70% viable melanoma. Higher ITRS and irPR scores correlated with lack of recurrence in the entire cohort (P = 0.002 and P ≤ 0.0001). The number of B lymphocytes was significantly increased in patients with a high fibrosis subtype of treatment response (P = 0.046). CONCLUSIONS: There is strong reproducibility for assessment of pathological response using INMC criteria. Immunotherapeutic response of fibrosis subtype correlated with improved RFS, and may represent a biomarker. Potential B-cell contribution to fibrosis development warrants further study. Reclassification of pNR to a threshold of ≥70% viable melanoma and incorporating additional criteria of <10% fibrosis subtype of response may identify those at highest risk of recurrence, but requires validation.

Histopathological features of complete pathological response predict recurrence-free survival following neoadjuvant targeted therapy for metastatic melanoma.

BACKGROUND: Recent clinical trials demonstrated the safety and efficacy of neoadjuvant dabrafenib and trametinib (DT) among patients with surgically resectable clinical stage III BRAFV600E/K mutant melanoma. Although patients achieving a complete pathological response (pCR) exhibited superior recurrence-free survival (RFS) versus those who did not, 30% of pCR patients relapsed. We sought to identify whether histopathological features of the pathological response further delineated risk of relapse. METHODS: Surgical resection specimens from DT-treated patients in two phase 2 clinical trials were reviewed. Histopathological features, including relative amounts of viable tumour, necrosis, melanosis, and fibrosis (hyalinized or immature/proliferative) were assessed for associations with patient outcomes. RESULTS: Fifty-nine patients underwent surgical resection following neoadjuvant DT. Patients achieving pCR (49%) had longer RFS compared with patients who did not (P = 0.005). Patients whose treated tumour showed any hyalinized fibrosis had longer RFS versus those without (P = 0.014), whereas necrosis (P = 0.012) and/or immature/proliferative fibrosis (P = 0.026) correlated with shorter RFS. Multivariable analyses showed absence of pCR or presence of immature fibrosis independently predicted shorter RFS. Among pCR patients, mature/hyalinized-type fibrosis correlated with improved RFS (P = 0.035). CONCLUSIONS: The extent and composition of the pathological response following neoadjuvant DT in BRAFV600E/K mutant melanoma correlates with RFS, including pCR patients. These findings support the need for detailed histological analysis of specimens collected after neoadjuvant therapy.

TGFß1 single-nucleotide polymorphism C-509T alters mucosal cell function in pediatric eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a chronic Th2 antigen-driven disorder associated with tissue remodeling. Inflammation and remodeling lead to esophageal rigidity, strictures, and dysphagia. TGFß1 drives esophageal remodeling including epithelial barrier dysfunction and subepithelial fibrosis. A functional SNP in the TGFß1 gene that increases its transcription (C-509T) is associated with elevated numbers of esophageal TGFß1-expressing cells. We utilized esophageal biopsies and fibroblasts from TT-genotype EoE children to understand if TGFß1 influenced fibroblast and epithelial cell function in vivo. Genotype TT EoE esophageal fibroblasts had higher baseline TGFß1, collagen1α1, periostin, and MMP2 (p < 0.05) gene expression and distinct contractile properties compared with CC genotype (n = 6 subjects per genotype). In vitro TGFß1 exposure caused greater induction of target gene expression in genotype CC fibroblasts (p < 0.05). Esophageal biopsies from TT-genotype subjects had significantly less epithelial membrane-bound E-cadherin (p < 0.01) and wider cluster distribution at nanometer resolution. TGFß1 treatment of stratified primary human esophageal epithelial cells and spheroids disrupted transepithelial resistance (p < 0.001) and E-cadherin localization (p < 0.0001). A TGFß1-receptor-I inhibitor improved TGFß1-mediated E-cadherin mislocalization. These data suggest that EoE severity can depend on genotypic differences that increase in vivo exposure to TGFß1. TGFß1 inhibition may be a useful therapy in subsets of EoE patients.

Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma.

Background: Clinical trials have recently evaluated safety and efficacy of neoadjuvant therapy among patients with surgically resectable regional melanoma metastases. To capture informative prognostic data connected to pathological response in such trials, it is critical to standardize pathologic assessment and reporting of tumor response after this treatment. Methods: The International Neoadjuvant Melanoma Consortium meetings in 2016 and 2017 assembled pathologists from academic centers to develop consensus guidelines for pathologic examination and reporting of surgical specimens from AJCC (8th edition) stage IIIB/C/D or oligometastatic stage IV melanoma patients treated with neoadjuvant-targeted or immune therapy. Patterns of pathologic response are provided context to inform these guidelines. Results: Based on our collective experience and guided by efforts in well-established neoadjuvant settings like breast cancer, procedures directing handling of pre- and post-neoadjuvant therapy-treated melanoma specimens are provided to facilitate comparison of findings across different trials and centers. Definitions of pathologic response are provided together with guidelines for reporting and quantifying the extent of pathologic response. Finally, the spectrum of histopathologic responses observed following neoadjuvant-targeted and immune-checkpoint therapy is described and illustrated. Conclusions: Standardizing pathologic evaluation of resected melanoma metastases following neoadjuvant-targeted or immune-checkpoint therapy allows more robust stratification of patient outcomes. This includes recognizing the spectrum of histopathologic response patterns to neoadjuvant therapy and a standard approach to grading pathologic responses. Such an approach will facilitate comparison of results across clinical trials and inform ongoing correlative studies into the mechanisms of response and resistance to agents applied in the neoadjuvant setting.

The smart approach: feasibility of lentigo maligna superficial margin assessment with hand-held reflectance confocal microscopy technology.

BACKGROUND: Lentigo maligna may be challenging to clear surgically. OBJECTIVE: To evaluate feasibility of using superficial skin cuts as RCM imaging anchors for attaining negative surgical margins in lentigo maligna. METHODS: Included patients presented with lentigo maligna near cosmetically sensitive facial structures. We evaluated, with hand-held-RCM, microscopic clearance of melanoma beyond its dermoscopically detected edges. Evaluated margins were annotated using shallow skin cuts. If a margin was positive at 'first-step' RCM evaluation, we sequentially advanced the margin radially outward at that segment by 2-mm intervals until an RCM-negative margin was identified. Prior to final surgical excision, we placed sutures at the outmost skin cuts to allow comparison of RCM and histopathological margin assessments. Primary outcome measure was histopathological verification that RCM-negative margins were clear of melanoma. RESULTS: The study included 126 first-step margin evaluations in 23 patients, median age 70 years (range: 43-91). Seventeen patients (74%) had primary in-situ melanoma and six (26%) invasive melanoma, mean thickness 0.3 mm (range 0.2-0.4 mm). Six cases (26%) showed complete negative RCM margins on 'first-step', 11 (48%) were negative at 'second-step', and four (17%) at 'third-step'. In two additional cases (9%), margins clearance could not be determined via RCM due to widespread dendritic cells proliferation. The RCM-negative margins in all 21 cases proved clear of melanoma on histopathology. Of the 15 cases that returned at 1-year follow-up, none showed any residual melanoma on dermoscopic and RCM examinations. Interobserver reproducibility showed fair agreement between bedside RCM reader and blinded remote-site reader, with Spearman's rho of 0.48 and Cohen's kappa of 0.43; using bedside reader as reference, the remote reader's sensitivity was 92% and specificity 57% in positive margin detection. CONCLUSIONS: Margin mapping of lentigo maligna with hand-held-RCM, using superficial skin cuts, appears feasible. This approach needs validation by larger studies.

Midbrain functional connectivity and ventral striatal dopamine D2-type receptors: link to impulsivity in methamphetamine users.

Stimulant use disorders are associated with deficits in striatal dopamine receptor availability, abnormalities in mesocorticolimbic resting-state functional connectivity (RSFC) and impulsivity. In methamphetamine-dependent research participants, impulsivity is correlated negatively with striatal D2-type receptor availability, and mesocorticolimbic RSFC is stronger than that in controls. The extent to which these features of methamphetamine dependence are interrelated, however, is unknown. This question was addressed in two studies. In Study 1, 19 methamphetamine-dependent and 26 healthy control subjects underwent [18F]fallypride positron emission tomography to measure ventral striatal dopamine D2-type receptor availability, indexed by binding potential (BPND), and functional magnetic resonance imaging (fMRI) to assess mesocorticolimbic RSFC, using a midbrain seed. In Study 2, an independent sample of 20 methamphetamine-dependent and 18 control subjects completed the Barratt Impulsiveness Scale in addition to fMRI. Study 1 showed a significant group by ventral striatal BPND interaction effect on RSFC, reflecting a negative relationship between ventral striatal BPND and RSFC between the midbrain and striatum, orbitofrontal cortex and insula in methamphetamine-dependent participants, but a positive relationship in the control group. In Study 2, an interaction of the group with RSFC on impulsivity was observed. Methamphetamine-dependent users exhibited a positive relationship of midbrain RSFC to the left ventral striatum with cognitive impulsivity, whereas a negative relationship was observed in healthy controls. The results indicate that ventral striatal D2-type receptor signaling may affect the system-level activity within the mesocorticolimbic system, providing a functional link that may help explain high impulsivity in methamphetamine-dependent individuals.

Effect of mode of birth on purine and malondialdehyde in umbilical arterial plasma in normal term newborns.

OBJECTIVE: To examine the effect of mode of birth on plasma purine and malondialdehyde levels in normal term infants. STUDY DESIGN: Umbilical arterial cord blood was obtained immediately after birth from a convenience sample of 119 normal term newborns born by vaginal delivery, with or without oxytocin augmentation or by elective cesarean delivery. Plasma was analyzed for purine and/or malondialdehyde levels. Numeric data were analyzed utilizing independent samples t-test and ordinal data were analyzed using Mann-Whitney test. Correlation coefficients were obtained using Spearman's rho. RESULT: Uric acid levels were significantly elevated (P<0.001) in neonates undergoing vaginal birth, compared to neonates born by elective cesarean delivery. When the effect of oxytocin and length of labor was analyzed, neonates born to mothers on oxytocin had lower hypoxanthine, significantly lower xanthine (P=0.05) and higher uric acid levels. In addition, malondialdehyde levels were significantly higher (P<0.006) in neonates born to mothers who received oxytocin compared to neonates born to mothers without oxytocin augmentation. We also found significant correlations between malondialdehyde (MDA) and hypoxanthine (r=-0.465, P<0.039) and between MDA and xanthine (r=-0.753, P=0.003) in neonates born via oxytocin-augmented birth. Mode of birth had no statistically significant effect on clinical outcomes, although infants born by elective cesarean had higher incidence of acute respiratory distress and transient tachypnea of the newborn compared to those born vaginally. CONCLUSION: Neonates born by elective cesarean had the lowest purine levels in cord blood compared to neonates born vaginally. Oxytocin augmentation is associated with some degree of uterine hyperstimulation which may enhance the ATP degradation pathway resulting in the rapid conversion of hypoxanthine to xanthine and xanthine to uric acid. Significantly higher MDA levels in neonates whose mothers received oxytocin as well as significant correlation between MDA and the purines hypoxanthine and xanthine, suggest free-radical production, most likely due to xanthine oxidase activation. However, despite differences in plasma purine and malondialdehyde levels, no significant differences were seen in neonatal outcome. Further studies are required to fully characterize the effect of mode of birth on purine metabolism and free-radical production.

Providing a community-based cancer risk assessment service for a socially and ethnically diverse population.

BACKGROUND: Patients from ethnic minorities are under-represented in referrals to cancer genetics services. In a regional genetics centre that serves two London boroughs, the existing service attracts 3% of its referrals from Black and Minority Ethnic (BME) and other ethnic groups, despite the fact that these groups make up 34% of the population. OBJECTIVES: To improve access to familial cancer risk assessment in a socially and ethnically diverse population. SETTING: The London boroughs of Lambeth and Southwark. DESIGN: Community-based, nurse-led clinics were established for people who were concerned about their familial cancer risk. Patients were asked to triage themselves by answering three questions. Self-referral was encouraged. MAIN OUTCOME MEASURES: Data were gathered on ethnicity of clients, cancer risk, source of referral and patient and health professional satisfaction with the service. RESULTS: Of the 415 people who have accessed the service, 46% were from not White British groups and 67% referred themselves to the service, demonstrating the success of this model in reaching 'hard to reach' groups. Thirty-seven percent of patients were assessed as being at population risk and 63% were assessed as being at moderate risk or higher, showing that the clinics were meeting an unmet need in the community.

Regulation of SREBP processing and membrane lipid production by phospholipids in Drosophila.

Animal cells exert exquisite control over the physical and chemical properties of their membranes, but the mechanisms are obscure. We show that phosphatidylethanolamine, the major phospholipid in Drosophila, controls the release of sterol regulatory element-binding protein (SREBP) from Drosophila cell membranes, exerting feedback control on the synthesis of fatty acids and phospholipids. The finding that SREBP processing is controlled by different lipids in mammals and flies (sterols and phosphatidylethanolamine, respectively) suggests that an essential function of SREBP is to monitor cell membrane composition and to adjust lipid synthesis accordingly.

Gamma-hydroxybutyric acid: patterns of use, effects and withdrawal.

Gamma-hydroxybutyric acid (GHB) is gaining popularity as a drug of abuse. Reports of toxicity and lethality associated with GHB use have increased. This survey study was designed to identify patterns of GHB use, its effects, and withdrawal syndrome. A survey inquiring about the effects of GHB was administered to 42 users. The results showed that GHB was used to increased feelings of euphoria, relaxation, and sexuality. Adverse effects occurred more frequently in daily users and polydrug users than in occasional GHB users. Loss of consciousness was reported by 66%, overdose by 28%, and amnesia by 13% of participants during GHB use and by 45% after GHB use. Three daily users developed a withdrawal syndrome that presented with anxiety, agitation, tremor, and delirium. Participants described GHB intoxication as having similarities to sedative-hypnotic or alcohol intoxication. Regular use has been shown to produce tolerance and dependence. Participants dependent on GHB reported using multiple daily doses around the clock. High frequency users appeared at the greatest risk for developing withdrawal delirium and psychosis after abrupt discontinuation of GHB use.

Seasonal changes in serum leptin, food intake, and body weight in photoentrained woodchucks.

Male woodchucks (Marmota monax) were maintained in northern vs. southern hemisphere photoperiods, provided feed and water ad libitum, and evaluated every 2 wk for 23 mo for body weight, absolute and relative food intake, body temperature, serum testosterone, and serum concentrations of leptin measured using an anti-mouse leptin enzyme-linked immunoassay. During late spring and summer, body weight increased 56 +/- 4% above winter nadirs, and during the autumn and early winter weights decreased 27 to 43% below midsummer maxima. Serum leptin initially increased during increases in body weight, in the late spring, reached peak values (490 +/- 32 pg/ml) in summer during the initial decline in body weight, and later decreased along with body weight to reach basal values (20 +/- 5 pg/ml) in late winter. Spontaneous declines in food intakes in summer began 2-6 wk before resulting declines in body weight and occurred during increases in leptin >100 pg/ml. The rate of decline in food intakes was greatest when serum leptin was at or near peak values. Food intake increased in late winter when leptin was low and 7-10 wk before resulting increases in body weight. Testis recrudescence occurred when leptin was declining to near basal levels. The results suggest that leptin is involved in the hormonal regulation of the circannual cycle in the drive for voluntary food intake in this species.

Substance abuse policy and peace in the Middle East: a Palestinian and Israeli partnership.

This paper describes the working exchange between Israelis, Palestinians and international experts who engaged in a process to promote communications, cooperation and coordination of efforts directed toward peace as well as the prevention and treatment of drug abuse in the region. From 1997 to 1999, a program of training workshops and courses, drug prevention and treatment skills development and collaborative research was conducted on the basis of mutual respect and cooperation among Palestinians and Israelis. By tapping into the issue of substance abuse and by focusing on its professional and academic dimensions, this initiative engaged representative delegations of the police force, academia, treatment centers and various government ministries. While events of this period underscored the dependence of "bottom-up" peace initiatives on the prevailing political situation, the experience revealed the vital role of NGO frameworks in providing a safety net for promoting and sustaining relations as well as addressing an issue of common concern. This case study shows that addiction professionals, both clinicians and researchers, can be instrumental in conflict resolution as well as the prevention and treatment of drug abuse.

The sterol regulatory element-binding protein pathway: control of lipid homeostasis through regulated intracellular transport.

The sterol regulatory element-binding proteins (SREBPs) are membrane-bound transcription factors that play a central role in cellular lipid homeostasis through the end-product feedback regulation of lipid synthesis. This feedback pathway is best understood in the case of cholesterol. Accumulation of cholesterol suppresses the proteolytic release of the transcriptionally active amino-terminal fragment of SREBP from the membrane-bound precursor. Experiments reported during the past year have led to a more complete understanding of the mechanisms that regulate the processing of SREBPs and their role in cellular lipid homeostasis. Regulation of lipid homeostasis is intimately associated with intracellular membrane trafficking; SREBPs undergo regulated transport from the endoplasmic reticulum to the Golgi apparatus in response to cellular lipid demand. The regulated step in this transport is the budding of a complex of SREBP and SREBP cleavage-activating protein into vesicles. In the present review we focus on recent results that give a more detailed picture of the mechanisms that are involved in end-product feedback regulation of lipid homeostasis.

Benefit determination under managed care for substance abuse treatment clients.

The purposes of this study were to examine the process of benefit determination, approval, and variation among Substance Abuse Treatment (SAT) clients. A convenience sample of 20 SAT clients admitted to 1 of 2 treatment programs within Matrix Center were followed. Clients of clinicians who agreed to participate were given an invitation letter to hear more about the study. After informed consent, clients granted 3 interviews and gave permission for the researcher to examine client records to ascertain the benefit determination process. Referral sources were the clients' insurances, their MDs, a counselor, hospital, Employee Assistance Program, case manager, and another treatment program. Ten of the insurances were PPOs, 9 were HMOs, and 1 was a contract. All but 2 had benefits managed by a behavioral care organization (MBCO). Case managers of the MBCOs were all clinicians, most frequently ACSWs. All programs authorized outpatient care and the first approval authorized from 6 to 52 visits. From 1 to 5 different authorizations were used for each client. The co-pay ranged from $0 to $35 per visit. This study illustrates the details of how benefits for substance abuse treatment under managed care are negotiated and used.

Cocaine and methamphetamine: differential addiction rates.

Clients admitted to treatment centers for stimulant addiction were categorized as either regular users of cocaine or of methamphetamine based on an algorithm involving 5 specific criteria. A subsample consisting of 90 regular users of cocaine and nonusers of methamphetamine, and 39 regular users of methamphetamine and nonusers of cocaine, was selected for comparison. Analyses showed that, when compared with cocaine users, the methamphetamine users exhibited a shorter period of time from 1st use to regular use (period of initial use) and from 1st use to treatment entry (period of pretreatment use). Relative to cocaine use, the use of methamphetamine appears to induce a faster rate of progression toward regular use and subsequent need for treatment.

Cognitive impairment in individuals currently using methamphetamine.

Although there are increasing reports of methamphetamine use, studies examining the cognitive consequences of methamphetamine have not been performed on a population currently using the drug. To characterize this population, 65 people currently using MA regularly and 65 non-users were given a battery of cognitive tests. The battery included recall, recognition, Digit Symbol, Trail Making A & B, Stroop, Wisconsin Card Sort, backward digit span, and the FAS test of verbal fluency. The methamphetamine users were significantly more impaired on recall tasks, digit symbol, Stroop color words, and Trail Making B, but scores fell within the normal ranges on the other measures.