Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer.

We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development.

A non-canonical tricarboxylic acid cycle underlies cellular identity.

The tricarboxylic acid (TCA) cycle is a central hub of cellular metabolism, oxidizing nutrients to generate reducing equivalents for energy production and critical metabolites for biosynthetic reactions. Despite the importance of the products of the TCA cycle for cell viability and proliferation, mammalian cells display diversity in TCA-cycle activity1,2. How this diversity is achieved, and whether it is critical for establishing cell fate, remains poorly understood. Here we identify a non-canonical TCA cycle that is required for changes in cell state. Genetic co-essentiality mapping revealed a cluster of genes that is sufficient to compose a biochemical alternative to the canonical TCA cycle, wherein mitochondrially derived citrate exported to the cytoplasm is metabolized by ATP citrate lyase, ultimately regenerating mitochondrial oxaloacetate to complete this non-canonical TCA cycle. Manipulating the expression of ATP citrate lyase or the canonical TCA-cycle enzyme aconitase 2 in mouse myoblasts and embryonic stem cells revealed that changes in the configuration of the TCA cycle accompany cell fate transitions. During exit from pluripotency, embryonic stem cells switch from canonical to non-canonical TCA-cycle metabolism. Accordingly, blocking the non-canonical TCA cycle prevents cells from exiting pluripotency. These results establish a context-dependent alternative to the traditional TCA cycle and reveal that appropriate TCA-cycle engagement is required for changes in cell state.

Efficacy of MEK inhibition in patients with histiocytic neoplasms.

Histiocytic neoplasms are a heterogeneous group of clonal haematopoietic disorders that are marked by diverse mutations in the mitogen-activated protein kinase (MAPK) pathway1,2. For the 50% of patients with histiocytosis who have BRAFV600 mutations3-5, RAF inhibition is highly efficacious and has markedly altered the natural history of the disease6,7. However, no standard therapy exists for the remaining 50% of patients who lack BRAFV600 mutations. Although ERK dependence has been hypothesized to be a consistent feature across histiocytic neoplasms, this remains clinically unproven and many of the kinase mutations that are found in patients who lack BRAFV600 mutations have not previously been biologically characterized. Here we show ERK dependency in histiocytoses through a proof-of-concept clinical trial of cobimetinib, an oral inhibitor of MEK1 and MEK2, in patients with histiocytoses. Patients were enrolled regardless of their tumour genotype. In parallel, MAPK alterations that were identified in treated patients were characterized for their ability to activate ERK. In the 18 patients that we treated, the overall response rate was 89% (90% confidence interval of 73-100). Responses were durable, with no acquired resistance to date. At one year, 100% of responses were ongoing and 94% of patients remained progression-free. Cobimetinib treatment was efficacious regardless of genotype, and responses were observed in patients with ARAF, BRAF, RAF1, NRAS, KRAS, MEK1 (also known as MAP2K1) and MEK2 (also known as MAP2K2) mutations. Consistent with the observed responses, the characterization of the mutations that we identified in these patients confirmed that the MAPK-pathway mutations were activating. Collectively, these data demonstrate that histiocytic neoplasms are characterized by a notable dependence on MAPK signalling-and that they are consequently responsive to MEK inhibition. These results extend the benefits of molecularly targeted therapy to the entire spectrum of patients with histiocytosis.

Immunochemotherapy plus lenalidomide for high-risk mantle cell lymphoma with measurable residual disease evaluation.

Chemoimmunotherapy followed by consolidative high-dose therapy with autologous stem cell rescue was a standard upfront treatment for fit patients with mantle cell lymphoma (MCL) in first remission; however, treatment paradigms are evolving in the era of novel therapies. Lenalidomide is an immunomodulatory agent with known efficacy in treating MCL. We conducted a single-center, investigator-initiated, phase II study of immunochemotherapy incorporating lenalidomide, without autologous stem cell transplant consolidation, enriching for patients with high-risk MCL (clinicaltrials gov. Identifier: NCT02633137). Patients received four cycles of lenalidomide-R-CHOP, two cycles of R-HiDAC, and six cycles of R-lenalidomide. The primary endpoint was rate of 3-year progression-free survival. We measured measurable residual disease (MRD) using a next-generation sequencing-based assay after each phase of treatment and at 6 months following end-oftreatment. We enrolled 49 patients of which 47 were response evaluable. By intent-to-treat, rates of overall and complete response were equivalent at 88% (43/49), one patient with stable disease, and two patients had disease progression during study; 3-year progression-free survival was 63% (primary endpoint not met) and differed by TP53 status (78% wild-type vs. 38% ALT; P=0.043). MRD status was prognostic and predicted long-term outcomes following R-HiDAC and at 6 months following end-of-treatment. In a high-dose therapy-sparing, intensive approach, we achieved favorable outcomes in TP53- wild-type MCL, including high-risk cases. We confirmed that sequential MRD assessment is a powerful prognostic tool in patients with MCL.

A phase 2 biomarker-driven study of ruxolitinib demonstrates effectiveness of JAK/STAT targeting in T-cell lymphomas.

Signaling through JAK1 and/or JAK2 is common among tumor and nontumor cells within peripheral T-cell lymphoma (PTCL). No oral therapies are approved for PTCL, and better treatments for relapsed/refractory disease are urgently needed. We conducted a phase 2 study of the JAK1/2 inhibitor ruxolitinib for patients with relapsed/refractory PTCL (n = 45) or mycosis fungoides (MF) (n = 7). Patients enrolled onto 1 of 3 biomarker-defined cohorts: (1) activating JAK and/or STAT mutations, (2) ≥30% pSTAT3 expression among tumor cells by immunohistochemistry, or (3) neither or insufficient tissue to assess. Patients received ruxolitinib 20 mg PO twice daily until progression and were assessed for response after cycles 2 and 5 and every 3 cycles thereafter. The primary endpoint was clinical benefit rate (CBR), defined as the combination of complete response, partial response (PR), and stable disease lasting at least 6 months. Only 1 of 7 patients with MF had CBR (ongoing PR > 18 months). CBR among the PTCL cases (n = 45) in cohorts 1, 2, and 3 were 53%, 45%, and 13% (cohorts 1 & 2 vs 3, P = .02), respectively. Eight patients had CBR > 12 months (5 ongoing), including 4 of 5 patients with T-cell large granular lymphocytic leukemia. In an exploratory analysis using multiplex immunofluorescence, expression of phosphorylated S6, a marker of PI3 kinase or mitogen-activated protein kinase activation, in <25% of tumor cells was associated with response to ruxolitinib (P = .05). Our findings indicate that ruxolitinib is active across various PTCL subtypes and support a precision therapy approach to JAK/STAT inhibition in patients with PTCL. This trial was registered at www.clincialtrials.gov as #NCT02974647.

Low incidence of cardiotoxicity in patients with non-Hodgkin lymphoma receiving EPOCH after prior anthracycline exposure.

OBJECTIVE: To describe the incidence of cardiotoxicity in patients with anthracycline exposure who subsequently receive EPOCH for non-Hodgkin lymphoma (NHL). METHODS: We conducted a retrospective cohort study of adults with anthracycline exposure who subsequently received EPOCH for NHL at Memorial Sloan Kettering Cancer Center. The primary outcome was cumulative incidence of arrhythmia, heart failure (HF), left ventricular (LV) dysfunction, or cardiac death. RESULTS: Among 140 patients, most had diffuse large B-cell lymphoma. Inclusive of EPOCH, median cumulative doxorubicin-equivalent dose was 364 mg/m2 ; exposure was 400 mg/m2 or higher in 41%. With median 36-month follow-up, 23 cardiac events were noted in 20 patients. Cumulative incidence of cardiac events at 60 months was 15% (95% confidence interval [CI]: 9%-21%). When limited to LV dysfunction/HF, cumulative incidence at 60 months was 7% (95% CI: 3%-13%), with most events occurring after the first year. Univariate analysis indicated only history of cardiac disease and dyslipidemia to be associated with cardiotoxicity; no other risk factors, including cumulative anthracycline dose, were identified. CONCLUSIONS: In this retrospective cohort, representing the largest experience in this setting with extended follow-up, cumulative incidence of cardiac events was low. Rates of LV dysfunction or HF were particularly low, suggesting infusional administration may mitigate risk despite prior exposure.

Genetic Determinants of Outcome in Intrahepatic Cholangiocarcinoma.

BACKGROUND AND AIM: Genetic alterations in intrahepatic cholangiocarcinoma (iCCA) are increasingly well characterized, but their impact on outcome and prognosis remains unknown. APPROACH AND RESULTS: This bi-institutional study of patients with confirmed iCCA (n = 412) used targeted next-generation sequencing of primary tumors to define associations among genetic alterations, clinicopathological variables, and outcome. The most common oncogenic alterations were isocitrate dehydrogenase 1 (IDH1; 20%), AT-rich interactive domain-containing protein 1A (20%), tumor protein P53 (TP53; 17%), cyclin-dependent kinase inhibitor 2A (CDKN2A; 15%), breast cancer 1-associated protein 1 (15%), FGFR2 (15%), polybromo 1 (12%), and KRAS (10%). IDH1/2 mutations (mut) were mutually exclusive with FGFR2 fusions, but neither was associated with outcome. For all patients, TP53 (P < 0.0001), KRAS (P = 0.0001), and CDKN2A (P < 0.0001) alterations predicted worse overall survival (OS). These high-risk alterations were enriched in advanced disease but adversely impacted survival across all stages, even when controlling for known correlates of outcome (multifocal disease, lymph node involvement, bile duct type, periductal infiltration). In resected patients (n = 209), TP53mut (HR, 1.82; 95% CI, 1.08-3.06; P = 0.03) and CDKN2A deletions (del; HR, 3.40; 95% CI, 1.95-5.94; P < 0.001) independently predicted shorter OS, as did high-risk clinical variables (multifocal liver disease [P < 0.001]; regional lymph node metastases [P < 0.001]), whereas KRASmut (HR, 1.69; 95% CI, 0.97-2.93; P = 0.06) trended toward statistical significance. The presence of both or neither high-risk clinical or genetic factors represented outcome extremes (median OS, 18.3 vs. 74.2 months; P < 0.001), with high-risk genetic alterations alone (median OS, 38.6 months; 95% CI, 28.8-73.5) or high-risk clinical variables alone (median OS, 37.0 months; 95% CI, 27.6-not available) associated with intermediate outcome. TP53mut, KRASmut, and CDKN2Adel similarly predicted worse outcome in patients with unresectable iCCA. CDKN2Adel tumors with high-risk clinical features were notable for limited survival and no benefit of resection over chemotherapy. CONCLUSIONS: TP53, KRAS, and CDKN2A alterations were independent prognostic factors in iCCA when controlling for clinical and pathologic variables, disease stage, and treatment. Because genetic profiling can be integrated into pretreatment therapeutic decision-making, combining clinical variables with targeted tumor sequencing may identify patient subgroups with poor outcome irrespective of treatment strategy.

Prephase rituximab/prednisone therapy and aging-related, proinflammatory cytokine milieu in older, vulnerable patients with newly diagnosed diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) predominantly affects older adults with suboptimal therapeutic outcomes due to increased treatment-related mortality and toxicities in vulnerable patients, clinically defined by geriatric impairments such as functional limitation, multimorbidity, or cognitive deficits. In this prospective pilot study, we evaluated a rituximab/prednisone prephase treatment strategy in 33 older, vulnerable patients with newly diagnosed DLBCL, defined by either age ≥70 years or age 60-70 years with Karnofsky performance scale (KPS) <80. A single dose of rituximab 375 mg/m2 between 3-10 days and oral prednisone for at least 5 days prior to the first dose of chemoimmunotherapy was administered. All patients completed prephase treatment and all but one commenced anthracycline-based chemoimmunotherapy. Only one early cycle death occurred. Toxicity events, defined by either unplanned hospitalization, unplanned dose reduction/delay, or chemotherapy discontinuation, occurred in 22 patients (67%). Sixteen patients (48%) experienced grade 3 or higher non-hematologic toxicities and/or grade 4 or higher hematologic toxicities. With a median follow-up of 4.4 years, both 5-year progression-free survival and overall survival were at 81% (95% confidence interval: 69-96). Importantly, we found that phenotypic impairments in basic and instrumental activities of daily living, physical function, mobility, KPS, and Cancer and Aging Research Group chemotherapy toxicity risk score were significantly associated with senescence-associated, proinflammatory cytokine milieu which was readily reversed with prephase treatment, potentially explaining its clinical effectiveness. Prephase therapy with rituximab/prednisone should be considered for all older, vulnerable DLBCL patients prior to curative intent, anthracycline-based chemoimmunotherapy. This trial was registered as clinicaltrials gov. Identifier: NCT89028394.

Real-World Assessment of Patient Care and Practice Efficiency With the Introduction of Subcutaneous Rituximab.

INTRODUCTION: A subcutaneous (SC) formulation of the anti-CD20 monoclonal antibody, rituximab (Rituxan), is approved in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL). Rituximab-SC (R-SC) has been associated with time and clinic resource savings vs the original intravenous formulation (R-IV). Insight into the resource implications of widening R-SC adoption in a US oncology setting is needed. METHODS: A single-institution, retrospective observational analysis was conducted in adult patients with DLBCL, FL, or CLL. The primary outcome measure was chair occupancy time (difference between patient room-in and room-out times). Prescribing patterns were a secondary outcome. RESULTS: Overall, 1190 patients were analyzed (treatment time frame: pre-R-SC adoption: n = 490 [41%], pre- and post R-SC adoption: n = 189 [16%], post R-SC adoption: n = 511 [43%]). Of the patients in the post-R-SC period, 374 (73%) received R-IV, 52 (10%) received R-IV and R-SC, and 85 (17%) received R-SC. When administered, R-SC reduced combination therapy chair time vs R-IV by a mean 37% (93.2 minutes; P < .001). Monotherapy (any route) reduced chair time vs combination by a mean 35.2 minutes (P < .001), with a further 40.2-minute reduction with R-SC (P < .001), a 62% (133.4-minute) total chair time savings vs R-IV. Doctors were more likely to prescribe R-SC to patients with FL than DLBCL. CONCLUSIONS: R-SC is associated with significantly reduced chair time vs R-IV in a US oncology setting. Widespread adoption would be expected to improve practice efficiency and patient access to care, and to reduce health care resource burden.

Cardiac outcomes of trastuzumab therapy in patients with HER2-positive breast cancer and reduced left ventricular ejection fraction.

PURPOSE: Asymptomatic decline in left ventricular ejection fraction (LVEF) or heart failure (HF) occurs in up to 25% of patients treated with trastuzumab and can result in incomplete breast cancer therapy. The cardiac safety of continuing trastuzumab in patients with asymptomatic LVEF decline is unknown. We report the cardiac outcomes of patients treated with trastuzumab after a significant asymptomatic LVEF decline. METHODS: Patients with HER2-positive breast cancer and asymptomatic LVEF decline to < 50% during trastuzumab were identified from an institutional echocardiogram database. Patients who received trastuzumab with a LVEF < 50% were classified as the continued group, whereas patients who had trastuzumab held until LVEF improved to ≥ 50% or who had trastuzumab permanently discontinued were classified as the interrupted group. Cardiac events were defined as HF (New York Heart Association class III-IV) or cardiovascular death. RESULTS: Sixty patients were included; the median age was 54 years. In 23 patients who continued trastuzumab, 14 (61%) tolerated trastuzumab without a cardiac event, 6 (26%) developed worsening LVEF (range 25-42%) leading to trastuzumab discontinuation, and three (13%) developed a cardiac event (1 HF, 2 possible/probable cardiovascular deaths). In 37 patients with interrupted trastuzumab, 15 (41%) were re-challenged with trastuzumab after LVEF improved to > 50%, 21 (57%) were not re-challenged, and one (3%) developed HF. More patients in the continued trastuzumab group had metastatic disease (39% vs. 5%, p = 0.002). The final LVEF after median follow-up of 633 days was similar between patients with trastuzumab continuation versus interruption (54% vs. 56%, p = 0.29). CONCLUSION: Continuation of trastuzumab after an asymptomatic LVEF decline to < 50% in patients who are expected to benefit from additional anti-HER2 therapy is a promising approach that warrants further investigation.

The toxicity and efficacy of concomitant chemoradiotherapy in patients aged 70 years and older with oropharyngeal carcinoma in the intensity-modulated radiotherapy era.

BACKGROUND: Despite controversy surrounding its benefit, the use of concomitant chemoradiotherapy (CCRT) in patients with oropharyngeal squamous cell carcinoma (OPSCC) who are aged > 70 years is increasing. However, to the authors' knowledge, few studies to date have compared the outcomes of different systemic treatments in this population. METHODS: Records from 74 patients aged ≥ 70 years with stage III to stage IVB OPSCC who were undergoing CCRT from 2002 to 2013 at a single institution were reviewed. Patients were stratified according to the systemic therapy received, including cisplatin, carboplatin with either 5-fluorouracil or paclitaxel (CARB), or cetuximab to compare oncologic outcome and toxicity. RESULTS: The median follow-up was 36 months. The median age of the patients was 75.3 years (range, 70-91 years), with significantly older patients receiving cetuximab (P = .03). A total of 28, 20, and 26 patients, respectively, received CCRT with cisplatin, CARB, and cetuximab. RT interruptions of > 1 day were needed in 4% of patients receiving cisplatin, 20% of patients receiving CARB, and 15% of patients receiving cetuximab (P = .19). Unplanned hospitalizations during CCRT occurred in 25%, 55%, and 58%, respectively, of patients receiving cisplatin, CARB, and cetuximab (P = .03). There were 2 treatment-related deaths, both of which occurred among the patients who were treated with cetuximab. At 5 years, locoregional control was achieved in 100%, 88%, and 60% (P<.001), respectively, and the overall survival rate was 87%, 61%, and 47% (P = .03), respectively, among patients treated with cisplatin, CARB, and cetuximab. CONCLUSIONS: Toxicity from CCRT remains a challenge for older adults with OPSCC. Herein, the authors found no evidence that this toxicity was mitigated by treatment with cetuximab. Nevertheless, a subset of patients aged ≥70 years appear to tolerate cisplatin-based treatment with acceptable toxicity and excellent outcomes. Further identification of this patient subgroup is crucial to optimize therapy for older patients with OPSCC. Cancer 2017;123:1345-1353. © 2016 American Cancer Society.

Genomics of primary chemoresistance and remission induction failure in paediatric and adult acute myeloid leukaemia.

Cure rates of children and adults with acute myeloid leukaemia (AML) remain unsatisfactory partly due to chemotherapy resistance. We investigated the genetic basis of AML in 107 primary cases by sequencing 670 genes mutated in haematological malignancies. SETBP1, ASXL1 and RELN mutations were significantly associated with primary chemoresistance. We identified genomic alterations not previously described in AML, together with distinct genes that were significantly overexpressed in therapy-resistant AML. Defined gene mutations were sufficient to explain primary induction failure in only a minority of cases. Thus, additional genetic or molecular mechanisms must cause primary chemoresistance in paediatric and adult AML.

Retrospective Evaluation of Palifermin Use in Nonhematopoietic Stem Cell Transplant Pediatric Patients.

BACKGROUND: Palifermin has been proven to decrease the frequency of severe oral mucositis in adult patients with sarcoma and metastatic colorectal cancer receiving chemotherapy. The impact of palifermin on the incidence of mucositis in nonhematopoietic stem cell transplantation (HSCT) pediatric population receiving chemotherapy has never been reported to date. PATIENTS AND METHODS: This is a retrospective analysis of pediatric patients who received palifermin as secondary prophylaxis to prevent chemotherapy-induced mucositis at Memorial Sloan Kettering Cancer Center from January 1, 2008 to 2014. Data from electronic medical records on days to mucositis resolution, use of opioids, use of total parenteral nutrition, duration of hospitalization, and antibiotics are collected and presented here. RESULTS: A total of 18 patients received palifermin for secondary prophylaxis after developing mucositis from the prior chemotherapy cycle. Mucositis did not reoccur in the subsequent cycle for 13 of the 18 patients. The majority of patients who received palifermin prophylaxis had decreased opioids and antibiotics use and decreased duration of hospitalization. Six of the 7 patients previously requiring total parenteral nutrition due to mucositis had decreased supplemental nutritional needs following the use of palifermin. CONCLUSION: Palifermin may provide benefit as secondary prophylaxis in pediatric patients to prevent chemotherapy-induced mucositis.

FGF5 is a crucial regulator of hair length in humans.

Mechanisms that regulate the growth of eyelashes have remained obscure. We ascertained two families from Pakistan who presented with familial trichomegaly, or extreme eyelash growth. Using a combination of whole exome sequencing and homozygosity mapping, we identified distinct pathogenic mutations within fibroblast growth factor 5 (FGF5) that underlie the disorder. Subsequent sequencing of this gene in several additional trichomegaly families identified an additional mutation in FGF5. We further demonstrated that hair fibers from forearms of these patients were significantly longer than hairs from control individuals, with an increased proportion in the growth phase, anagen. Using hair follicle organ cultures, we show that FGF5 induces regression of the human hair follicle. We have identified FGF5 as a crucial regulator of hair growth in humans for the first time, to our knowledge, and uncovered a therapeutic target to selectively regulate eyelash growth.

Definition of bulky disease in early stage Hodgkin lymphoma in computed tomography era: prognostic significance of measurements in the coronal and transverse planes.

Disease bulk is an important prognostic factor in early stage Hodgkin lymphoma, but its definition is unclear in the computed tomography era. This retrospective analysis investigated the prognostic significance of bulky disease measured in transverse and coronal planes on computed tomography imaging. Early stage Hodgkin lymphoma patients (n=185) treated with chemotherapy with or without radiotherapy from 2000-2010 were included. The longest diameter of the largest lymph node mass was measured in transverse and coronal axes on pre-treatment imaging. The optimal cut off for disease bulk was maximal diameter greater than 7 cm measured in either the transverse or coronal plane. Thirty patients with maximal transverse diameter of 7 cm or under were found to have bulk in coronal axis. The 4-year overall survival was 96.5% (CI: 93.3%, 100%) and 4-year relapse-free survival was 86.8% (CI: 81.9%, 92.1%) for all patients. Relapse-free survival at four years for bulky patients was 80.5% (CI: 73%, 88.9%) compared to 94.4% (CI: 89.1%, 100%) for non-bulky; Cox HR 4.21 (CI: 1.43, 12.38) (P=0.004). In bulky patients, relapse-free survival was not impacted in patients treated with chemoradiotherapy; however, it was significantly lower in patients treated with chemotherapy alone. In an independent validation cohort of 38 patients treated with chemotherapy alone, patients with bulky disease had an inferior relapse-free survival [at 4 years, 71.1% (CI: 52.1%, 97%) vs 94.1% (CI: 83.6%, 100%), Cox HR 5.27 (CI: 0.62, 45.16); P=0.09]. Presence of bulky disease on multidimensional computed tomography imaging is a significant prognostic factor in early stage Hodgkin lymphoma. Coronal reformations may be included for routine Hodgkin lymphoma staging evaluation. In future, our definition of disease bulk may be useful in identifying patients who are most appropriate for chemotherapy alone.

Baseline characteristics of patients predicting suitability for rapid naltrexone induction.

BACKGROUND AND OBJECTIVES: Extended-release (XR) injection naltrexone has proved promising in the treatment of opioid dependence. Induction onto naltrexone is often accomplished with a procedure known as rapid naltrexone induction. The purpose of this study was to evaluate pre-treatment patient characteristics as predictors of successful completion of a rapid naltrexone induction procedure prior to XR naltrexone treatment. METHODS: A chart review of 150 consecutive research participants (N = 84 completers and N = 66 non-completers) undergoing a rapid naltrexone induction with the buprenorphone-clonidine procedure were compared on a number of baseline demographic, clinical and psychosocial factors. Logistic regression was used to identify client characteristics that may predict successful initiation of naltrexone after a rapid induction-detoxification. RESULTS: Patients who failed to successfully initiate naltrexone were younger (AOR: 1.040, CI: 1.006, 1.075), and using 10 or more bags of heroin (or equivalent) per day (AOR: 0.881, CI: 0.820, 0.946). Drug use other than opioids was also predictive of failure to initiate naltrexone in simple bivariate analyses, but was no longer significant when controlling for age and opioid use level. CONCLUSIONS: Younger age, and indicators of greater substance dependence severity (more current opioid use, other substance use) predict difficulty completing a rapid naltrexone induction procedure. Such patients might require a longer period of stabilization and/or more gradual detoxification prior to initiating naltrexone. SCIENTIFIC SIGNIFICANCE: Our study findings identify specific characteristics of patients who responded positively to rapid naltrexone induction.

Aggregation of melanoma tumour site within Western Australian families.

BACKGROUND: Evidence is emerging that melanoma has distinct aetiologic pathways and subtypes, characterized by factors like anatomic site of the tumour. To explore genetic influences on anatomic subtypes, we examined the extent to which melanomas in first-degree relatives shared the same body site of occurrence. METHODS: Population-level linked data was used to identify the study population of over 1.5 million individuals born in Western Australia between 1945 and 2014, and their first-degree relatives. There were 1009 pairs of invasive tumours from 677 family pairs, each categorised by anatomic site. Greater than expected representation of site-concordant pairs would suggest the presence of genetic factors that predispose individuals to site-specific melanoma. RESULTS: Comparing observed versus expected totals, we observed a modest increase in site concordance for invasive head/neck and truncal tumours (P=0.02). A corresponding analysis including in situ tumours showed a similar concordance (P=0.05). No further evidence of concordance was observed when stratified by sex. CONCLUSION: In conclusion, modest evidence of aggregation was observed but with inconsistent patterns between sites. Results suggest that further investigation into the familial aggregation of melanoma by tumour site is warranted, with the inclusion of genetic data in order to disentangle the relative contributions of genetic and environmental factors.