Better survival of renal cell carcinoma in patients with inflammatory bowel disease

Background

Immunosuppressive therapy may impact cancer risk in inflammatory bowel disease (IBD). Cancer specific data regarding risk and outcome are scarce and data for renal cell carcinoma (RCC) are lacking. We aimed(1) to identify risk factors for RCC development in IBD patients (2) to compare RCC characteristics, outcome and survival between IBD patients and the general population.

Methods

A PALGA (Dutch Pathology Registry) search was performed to establish a case group consisting of all IBD patients with incident RCC in The Netherlands (1991–2013). Cases were compared with two separate control groups: (A) with a population-based IBD cohort for identification of risk factors (B) with a RCC cohort from the general population to compare RCC characteristics and outcomes.

Results

180 IBD patients with RCC were identified. Pancolitis (OR 1.8–2.5), penetrating Crohn''s disease (OR 2.8), IBD related surgery (OR 3.7–4.5), male gender (OR 3.2–5.0) and older age at IBD onset (OR 1.0–1.1) were identified as independent risk factors for RCC development. IBD patients had a significantly lower age at RCC diagnosis (p < 0.001), lower N-stage (p = 0.025), lower M-stage (p = 0.020) and underwent more frequently surgical treatment for RCC (p < 0.001) compared to the general population. This translated into a better survival (p = 0.026; HR 0.7) independent of immunosuppression.

Conclusions

IBD patients with a complex phenotype are at increased risk to develop RCC. They are diagnosed with RCC at a younger age and at an earlier disease stage compared to the general population. This translates into a better survival independent of immunosuppressive or anti-TNFα therapy.     

Selective resistance to the PARP inhibitor olaparib in a mouse model for BRCA1-deficient metaplastic breast cancer

Metaplastic breast carcinoma (MBC) is a rare histological breast cancer subtype characterized by mesenchymal elements and poor clinical outcome. A large fraction of MBCs harbor defects in breast cancer 1 (BRCA1). As BRCA1 deficiency sensitizes tumors to DNA cross-linking agents and poly(ADP-ribose) polymerase (PARP) inhibitors, we sought to investigate the response of BRCA1-deficient MBCs to the PARP inhibitor olaparib. To this end, we established a genetically engineered mouse model (GEMM) for BRCA1-deficient MBC by introducing the MET proto-oncogene into a BRCA1-associated breast cancer model, using our novel female GEMM ES cell (ESC) pipeline. In contrast to carcinomas, BRCA1-deficient mouse carcinosarcomas resembling MBC show intrinsic resistance to olaparib caused by increased P-glycoprotein (Pgp) drug efflux transporter expression. Indeed, resistance could be circumvented by using another PARP inhibitor, AZD2461, which is a poor Pgp substrate. These preclinical findings suggest that patients with BRCA1-associated MBC may show poor response to olaparib and illustrate the value of GEMM-ESC models of human cancer for evaluation of novel therapeutics.Poly(ADP-ribose) polymerase (PARP) inhibition provides a promising therapeutic strategy for targeting homologous recombination (HR)-deficient tumors, such as breast cancer 1 (BRCA1)-mutated cancers (1). Indeed, clinical phase I and phase II trials have shown potent anticancer activity of small molecule inhibitors of PARP, such as olaparib, in patients with BRCA1-associated breast cancer (2, 3). However, it remains to be established whether different breast cancer subtypes in BRCA1 mutation carriers respond equally to PARP inhibition. Reduced sensitivity of breast cancers to anticancer drugs has frequently been associated with an epithelial-to-mesenchymal transition (EMT) (4–7). Metaplastic breast carcinomas (MBCs) are a subset of triple-negative breast cancers (TNBCs) characterized by a claudin-low and EMT-like phenotype (8) and a poor prognosis compared with other TNBCs (9). More than 60% of MBCs have BRCA1 promoter methylation, raising the question whether these tumors can be effectively targeted by using PARP inhibitors (10). To address this issue in an experimentally controlled setting, we set out to generate a genetically engineered mouse model (GEMM) of BRCA1-deficient MBC by inducing EMT via MET overexpression in a previously established GEMM of BRCA1-mutated breast cancer. We report that EMT is associated with olaparib resistance and can be effectively bypassed by administration of AZD2461, a PARP inhibitor with low affinity for the P-glycoprotein (Pgp) drug efflux transporter.     

Association between Toll-like receptor 4 and inflammatory bowel disease

BACKGROUND: The human Toll-like receptor 4 (TLR4) participates in the innate response. Recently, the TLR4 variant Asp299Gly has been described to affect the response of this receptor to lipopolysaccharide. As such, there is a potentially important role of TLR4 in the pathogenesis of inflammatory bowel disease (IBD). We studied the involvement of TLR4 in IBD in a large population of Dutch patients with IBD and in family-based controls. METHODS: In 781 IBD cases and 315 controls, genotyping was performed forAsp299Gly and Thr399Ile variants and for 4 microsatellite markers flanking TLR4. Association analysis and the were applied. In addition, interaction of TLR4 with the caspase recruitment domain containing protein 15 gene (CARD15) was studied in patients with Crohn's disease (CD). RESULTS: The haplotype sharing statistic showed association at microsatellite marker D9S1864 with IBD (P = 0.0019), and in particular with CD (P = 0.0025) and at TLR406 with ulcerative colitis (UC; P = 0.027). No association was found for Asp299Gly and Thr399Ile. However, the frequencies of both variant allele carriers were higher among CD cases with a disease onset > or = 40 years than among controls. No evidence for interaction between TLR4 and CARD15 was found. CONCLUSIONS: Haplotype analysis shows that TLR4 is associated with both CD and UC. The Asp299Gly and Thr399Ile variants do not show an association with CD, UC, or IBD as a group, indicating that these polymorphisms are likely not the causal ones. We propose that the 2 polymorphisms are in linkage with (the) disease susceptibility variant(s) located elsewhere on TLR4.     

Pharmacological management of pain in chronic pancreatitis

Pain is the major presenting symptom of chronic pancreatitis. Patients with chronic pancreatitis experience substantial impairments in health-related quality of life. Pain may be considered as the most important factor affecting the quality of life. The pathogenesis of pancreatic pain is poorly understood. The cause of pain in chronic pancreatitis is probably multifactorial. This article discusses the various hypotheses that have been suggested to underlie pain. Special attention is paid to the concept of autonomous central sensitisation and hyperalgesia as a cause of pain. Strict abstinence from alcohol is the first step of chronic pancreatic pain management. As a second step, it is important to exclude treatable complications of chronic pancreatitis, such as pseudocysts. Symptomatic treatment with analgesics is often unavoidable in patients with chronic pancreatitis. Acetaminophen, non-steroidal anti-inflammatory drugs and eventually opioids are suitable. Several trials have been performed with pancreatic enzymes, but a meta-analysis demonstrated no significant benefit in terms of pain relief. The treatment of chronic pancreatic pain requires a multidisciplinary approach that tailors the various therapeutic options to meet the need of the individual patient.     

Boy with autosomal recessive polycystic kidney and autosomal dominant polycystic liver disease

BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) shows a great phenotypic variability between patients, ranging from perinatal demise to mildly affected adults. Autosomal dominant polycystic liver disease (PCLD) does not manifest in childhood. CASE-DIAGNOSIS/TREATMENT: A boy was reported with the co-occurrence of ARPKD and PCLD. He presented at the age of 16 days with pyelonephritis and urosepsis. Subsequent investigations showed enlarged kidneys and hyperechogenic renal medulla and liver parenchyma. Genetic analysis revealed compound heterozygous mutations in the PKHD1 gene (p.Arg496X and p.Ser1862Leu). After his mother was diagnosed with PCLD, the finding of a liver cyst on ultrasound prompted analysis of the PRKCSH gene, revealing a missense mutation (p.Arg139His). At the most recent follow-up at 13 years of age, the patient's course and clinical examination was uneventful with normal renal and liver function without evidence of portal hypertension. CONCLUSIONS: The patient with ARPKD and PCLD has so far demonstrated a benign clinical outcome, consistent with the great phenotypic variability of ARPKD and, apart from the liver cyst, asymptomatic manifestation of PCLD in childhood. However, close long-term follow-up is mandatory.