Cholangiocarcinoma (CCA) is a hepatobiliary malignancy exhibiting high incidence in countries with endemic liver-fluke infection. We analysed 489 CCAs from 10 countries, combining whole-genome (71 cases), targeted/exome, copy-number, gene expression, and DNA methylation information. Integrative clustering defined four CCA clusters – Fluke-Positive CCAs (Clusters 1/2) are enriched in ERBB2 amplifications and TP53 mutations, conversely Fluke-Negative CCAs (Clusters 3/4) exhibit high copy-number alterations and PD-1/PD-L2 expression, or epigenetic mutations (IDH1/2, BAP1) and FGFR/PRKA-related gene rearrangements. Whole-genome analysis highlighted FGFR2 3′UTR deletion as a mechanism of FGFR2 upregulation. Integration of non-coding promoter mutations with protein-DNA binding profiles demonstrates pervasive modulation of H3K27me3-associated sites in CCA. Clusters 1 and 4 exhibit distinct DNA hypermethylation patterns targeting either CpG islands or shores – mutation signature and subclonality analysis suggests that these reflect different mutational pathways. Our results exemplify how genetics, epigenetics and environmental carcinogens can interplay across different geographies to generate distinct molecular subtypes of cancer.

SummaryBackgroundNeoadjuvant chemotherapy (NACT) for early breast cancer can make breast-conserving surgery more feasible and might be more likely to eradicate micrometastatic disease than might the same chemotherapy given after surgery. We investigated the long-term benefits and risks of NACT and the influence of tumour characteristics on outcome with a collaborative meta-analysis of individual patient data from relevant randomised trials.MethodsWe obtained information about prerandomisation tumour characteristics, clinical tumour response, surgery, recurrence, and mortality for 4756 women in ten randomised trials in early breast cancer that began before 2005 and compared NACT with the same chemotherapy given postoperatively. Primary outcomes were tumour response, extent of local therapy, local and distant recurrence, breast cancer death, and overall mortality. Analyses by intention-to-treat used standard regression (for response and frequency of breast-conserving therapy) and log-rank methods (for recurrence and mortality).FindingsPatients entered the trials from 1983 to 2002 and median follow-up was 9 years (IQR 5–14), with the last follow-up in 2013. Most chemotherapy was anthracycline based (3838 [81%] of 4756 women). More than two thirds (1349 [69%] of 1947) of women allocated NACT had a complete or partial clinical response. Patients allocated NACT had an increased frequency of breast-conserving therapy (1504 [65%] of 2320 treated with NACT vs 1135 [49%] of 2318 treated with adjuvant chemotherapy). NACT was associated with more frequent local recurrence than was adjuvant chemotherapy: the 15 year local recurrence was 21·4% for NACT versus 15·9% for adjuvant chemotherapy (5·5% increase [95% CI 2·4–8·6]; rate ratio 1·37 [95% CI 1·17–1·61]; p=0·0001). No significant difference between NACT and adjuvant chemotherapy was noted for distant recurrence (15 year risk 38·2% for NACT vs 38·0% for adjuvant chemotherapy; rate ratio 1·02 [95% CI 0·92–1·14]; p=0·66), breast cancer mortality (34·4% vs 33·7%; 1·06 [0·95–1·18]; p=0·31), or death from any cause (40·9% vs 41·2%; 1·04 [0·94–1·15]; p=0·45).InterpretationTumours downsized by NACT might have higher local recurrence after breast-conserving therapy than might tumours of the same dimensions in women who have not received NACT. Strategies to mitigate the increased local recurrence after breast-conserving therapy in tumours downsized by NACT should be considered—eg, careful tumour localisation, detailed pathological assessment, and appropriate radiotherapy.FundingCancer Research UK, British Heart Foundation, UK Medical Research Council, and UK Department of Health.

Objectives-To evaluate the eVect of a combination of immunoglobulins (IVIg), cyclophosphamide (CTX), and methylprednisolone (MP) on the clinical course of patients with paraneoplastic neurological syndrome (PNS) and antineuronal antibodies (Abs). Methods-Seventeen patients with paraneoplastic encephalomyelitis/sensory neuropathy (PEM/SN) with anti-Hu Abs (n=10) or cerebellar degeneration (PCD) with anti-Yo Abs (n=7) received one to nine cycles (mean 3.5) of a combination of IVIg (0.5 g/kg/day from days 1 to 5), CTX (600 mg/m2 at day 1) and MP (1g/day from day 1 to 3). The Rankin scale (RS) was used to evaluate the response. A positive response was considered as either improvement or stabilisation in patients who were still ambulatory (RS<3) at the onset of treatment, whereas only improvement, and not stabilisation, was considered a therapeutic benefit in bedridden patients (RS>4). Results-Tolerance was good and no patient experienced grade 3/4 toxicity (World Health Organisation). Sixteen patients were evaluable for response. Of the seven patients with RS>4, none improved. Of the nine patients with RS<3, none improved but three (two SN and one PCD) stabilised for 4, 35, and 16 months. Conclusions-This study suggests that vigorous immunosuppressive treatment is not useful in severely disabled PNS patients with antineuronal Abs. In a minority of patients (mainly with SN) who are not severely disabled at the onset of treatment, a transient stabilisation is possible and deserves further evaluation. (J Neurol Neurosurg Psychiatry 2000;68:479-482)

Previous studies of the HIV-1 disease have shown that HLA and Chemokine receptor genetic variants influence disease progression and early viral load. We performed a Genome Wide Association study in a cohort of 605 HIV-1-infected seroconverters for detection of novel genetic factors that influence plasma HIV-RNA and cellular HIV-DNA levels. Most of the SNPs strongly associated with HIV-RNA levels were localised in the 6p21 major histocompatibility complex (MHC) region and were in the vicinity of class I and III genes. Moreover, protective alleles for four disease-associated SNPs in the MHC locus (rs2395029, rs13199524, rs12198173 and rs3093662) were strikingly over-represented among forty-five Long Term HIV controllers. Furthermore, we show that the HIV-DNA levels (reflecting the HIV reservoir) are associated with the same four SNPs, but also with two additional SNPs on chromosome 17 (rs6503919; intergenic region flanked by the DDX40 and YPEL2 genes) and chromosome 8 (rs2575735; within the Syndecan 2 gene). Our data provide evidence that the MHC controls both HIV replication and HIV reservoir. They also indicate that two additional genomic loci may influence the HIV reservoir.