Panitumumab use in metastatic colorectal cancer and patterns of RAS testing: results from a Europe-wide physician survey and medical records review.

BACKGROUND: In Europe, treatment of metastatic colorectal cancer (mCRC) with panitumumab requires prior confirmation of RAS wild-type mutation status. Two studies - a physician survey and a medical records review (MRR) - were conducted to evaluate the use of panitumumab and awareness among prescribing oncologists of the associated RAS testing requirements in clinical practice. METHODS: Both studies enrolled participants from nine European countries and were carried out in three consecutive rounds. Rounds 1 and 2 (2012-2013) examined KRAS (exon 2) testing only; the results have been published in full previously. Round 3 (2014-2015) examined full RAS testing (exons 2, 3, 4 of KRAS and NRAS) and was initiated following a change in prescribing guidelines, from requiring KRAS alone to requiring full RAS testing. For the physician survey, telephone interviews were conducted with oncologists who had prescribed panitumumab to patients with mCRC in the previous 6 months. For the MRR, oncologists were asked to provide anonymised clinical information, extracted from their patients' records. RESULTS: In Round 3, 152 oncologists and 131 patients' records were included in the physician survey and MRR, respectively. In Round 3 of the physician survey, 95.4% (n = 145) of participants correctly identified that panitumumab should only be prescribed in RAS wild-type mCRC compared with 99.0% (n = 298) of 301 participants in Rounds 1 and 2, responding to the same question about KRAS testing. In Round 3 of the MRR, 100% (n = 131) of patients included in the study had confirmed KRAS or RAS wild-type status prior to initiation of panitumumab compared with 97.7% (n = 299) of 306 patients in Rounds 1 and 2 (KRAS only). Of those patients in Round 3, 83.2% (n = 109) had been tested for RAS status and 16.8% (n = 22) had been tested for KRAS status only. CONCLUSIONS: Physicians' adherence to prescribing guidelines has remained high over time in Europe, despite the change in indication for panitumumab treatment, from KRAS to RAS wild-type mCRC. Additionally, this study demonstrates the uptake of full RAS testing among the majority of oncologists and pathologists.

RelA NF-κB subunit activation as a therapeutic target in diffuse large B-cell lymphoma.

It has been well established that nuclear factor kappa-B (NF-κB) activation is important for tumor cell growth and survival. RelA/p65 and p50 are the most common NF-kB subunits and involved in the classical NF-kB pathway. However, the prognostic and biological significance of RelA/p65 is equivocal in the field. In this study, we assessed RelA/p65 nuclear expression by immunohistochemistry in 487 patients with de novo diffuse large B-cell lymphoma (DLBCL), and studied the effects of molecular and pharmacological inhibition of NF-kB on cell viability. We found RelA/p65 nuclear expression, without associations with other apparent genetic or phenotypic abnormalities, had unfavorable prognostic impact in patients with stage I/II DLBCL. Gene expression profiling analysis suggested immune dysregulation and antiapoptosis may be relevant for the poorer prognosis associated with p65 hyperactivation in germinal center B-cell-like (GCB) DLBCL and in activated B-cell-like (ABC) DLBCL, respectively. We knocked down individual NF-κB subunits in representative DLBCL cells in vitro, and found targeting p65 was more effective than targeting other NF-κB subunits in inhibiting cell growth and survival. In summary, RelA/p65 nuclear overexpression correlates with significant poor survival in early-stage DLBCL patients, and therapeutic targeting RelA/p65 is effective in inhibiting proliferation and survival of DLBCL with NF-κB hyperactivation.

Assessment of CD37 B-cell antigen and cell of origin significantly improves risk prediction in diffuse large B-cell lymphoma.

CD37 (tetraspanin TSPAN26) is a B-cell surface antigen widely expressed on mature B cells. CD37 is involved in immune regulation and tumor suppression but its function has not been fully elucidated. We assessed CD37 expression in de novo diffuse large B-cell lymphoma (DLBCL), and investigated its clinical and biologic significance in 773 patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and 231 patients treated with CHOP. We found that CD37 loss (CD37-) in ∼60% of DLBCL patients showed significantly decreased survival after R-CHOP treatment, independent of the International Prognostic Index (IPI), germinal center B-cell-like (GCB)/activated B-cell-like (ABC) cell of origin, nodal/extranodal primary origin, and the prognostic factors associated with CD37-, including TP53 mutation, NF-κBhigh, Mychigh, phosphorylated STAT3high, survivinhigh, p63-, and BCL6 translocation. CD37 positivity predicted superior survival, abolishing the prognostic impact of high IPI and above biomarkers in GCB-DLBCL but not in ABC-DLBCL. Combining risk scores for CD37- status and ABC cell of origin with the IPI, defined as molecularly adjusted IPI for R-CHOP (M-IPI-R), or IPI plus immunohistochemistry (IHC; IPI+IHC) for CD37, Myc, and Bcl-2, significantly improved risk prediction over IPI alone. Gene expression profiling suggested that decreased CD20 and increased PD-1 levels in CD37- DLBCL, ICOSLG upregulation in CD37+ GCB-DLBCL, and CD37 functions during R-CHOP treatment underlie the pivotal role of CD37 status in clinical outcomes. In conclusion, CD37 is a critical determinant of R-CHOP outcome in DLBCL especially in GCB-DLBCL, representing its importance for optimal rituximab action and sustained immune responses. The combined molecular and clinical prognostic indices, M-IPI-R and IPI+IHC, have remarkable predictive values in R-CHOP-treated DLBCL.

External quality assessment unravels interlaboratory differences in quality of RAS testing for anti-EGFR therapy in colorectal cancer.

BACKGROUND: Regulations for the selection of patients with metastatic colorectal cancer for anti-EGFR treatment changed at the end of 2013. The set of mutations to be tested extended from KRAS codons 12 and 13 to KRAS and NRAS exons 2, 3, and 4. A European external quality assessment scheme monitored the performance of laboratories and evaluated the implementation of the new regulations. MATERIALS AND METHODS: The 131 participating laboratories received 10 samples of formalin-fixed paraffin-embedded material, including RAS (exon 2, 3, 4) and BRAF mutations. Mock clinical data were provided for three cases. Using their routine methods, laboratories determined the genotypes and submitted three written reports. Assessors scored the results according to predefined evaluation criteria. RESULTS: Half of the participants (49.3%) had completely implemented the new test requirements (codons 12, 13, 59, 61, 117, and 146 of KRAS and NRAS), and 96 laboratories (73.3%) made no genotype mistakes. Correct nomenclature, according to the Human Genome Variation Society, was used by 82 laboratories (62.6%). CONCLUSION: Although regulations were effective for several months, many laboratories were not ready for full RAS testing in the context of anti-EGFR therapy. Nevertheless, in each participating country, there are laboratories that provide complete and correct testing. External quality assessments can be used to monitor implementation of new test regulations and to stimulate the laboratories to improve their testing procedures. Because the results of this program are available on the website of the European Society of Pathology, patients and clinicians can refer test samples to a reliable laboratory.

Prevalence and clinical implications of cyclin D1 expression in diffuse large B-cell lymphoma (DLBCL) treated with immunochemotherapy: a report from the International DLBCL Rituximab-CHOP Consortium Program.

BACKGROUND: Cyclin D1 expression has been reported in a subset of patients with diffuse large B-cell leukemia (DLBCL), but studies have been few and generally small, and they have demonstrated no obvious clinical implications attributable to cyclin D1 expression. METHODS: The authors reviewed 1435 patients who were diagnosed with DLBCL as part of the International DLBCL rituximab with cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP) Consortium Program and performed clinical, immunohistochemical, and genetic analyses with a focus on cyclin D1. All patients who were cyclin D1-positive according to immunohistochemistry were also assessed for rearrangements of the cyclin D1 gene (CCND1) using fluorescence in situ hybridization. Gene expression profiling was performed to compare patients who had DLBCL with and without cyclin D1 expression. RESULTS: In total, 30 patients (2.1%) who had DLBCL that expressed cyclin D1 and lacked CCND1 gene rearrangements were identified. Patients with cyclin D1-positive DLBCL had a median age of 57 years (range, 16.0-82.6 years). There were 23 males and 7 females. Twelve patients (40%) had bulky disease. None of them expressed CD5. Two patients expressed cyclin D2. Gene expression profiling indicated that 17 tumors were of the germinal center type, and 13 were of the activated B-cell type. Genetic aberrations of B-cell leukemia/lymphoma 2 (BCL2), BCL6, v-myc avian myelocytomatosis viral oncogene homolog (MYC), mouse double minute 2 oncogene E3 ubiquitin protein ligase (MDM2), MDM4, and tumor protein 53 (TP53) were rare or absent. Gene expression profiling did not reveal any striking differences with respect to cyclin D1 in DLBCL. CONCLUSIONS: Compared with patients who had cyclin D1-negative DLBCL, men were more commonly affected with cyclin D1-positive DLBCL, and they were significantly younger. There were no other significant differences in clinical presentation, pathologic features, overall survival, or progression-free survival between these two subgroups of patients with DLBCL.

EURECCA colorectal: multidisciplinary mission statement on better care for patients with colon and rectal cancer in Europe.

BACKGROUND: Care for patients with colon and rectal cancer has improved in the last twenty years however still considerable variation exists in cancer management and outcome between European countries. Therefore, EURECCA, which is the acronym of European Registration of cancer care, is aiming at defining core treatment strategies and developing a European audit structure in order to improve the quality of care for all patients with colon and rectal cancer. In December 2012 the first multidisciplinary consensus conference about colon and rectum was held looking for multidisciplinary consensus. The expert panel consisted of representatives of European scientific organisations involved in cancer care of patients with colon and rectal cancer and representatives of national colorectal registries. METHODS: The expert panel had delegates of the European Society of Surgical Oncology (ESSO), European Society for Radiotherapy & Oncology (ESTRO), European Society of Pathology (ESP), European Society for Medical Oncology (ESMO), European Society of Radiology (ESR), European Society of Coloproctology (ESCP), European CanCer Organisation (ECCO), European Oncology Nursing Society (EONS) and the European Colorectal Cancer Patient Organisation (EuropaColon), as well as delegates from national registries or audits. Experts commented and voted on the two web-based online voting rounds before the meeting (between 4th and 25th October and between the 20th November and 3rd December 2012) as well as one online round after the meeting (4th-20th March 2013) and were invited to lecture on the subjects during the meeting (13th-15th December 2012). The sentences in the consensus document were available during the meeting and a televoting round during the conference by all participants was performed. All sentences that were voted on are available on the EURECCA website www.canceraudit.eu. The consensus document was divided in sections describing evidence based algorithms of diagnostics, pathology, surgery, medical oncology, radiotherapy, and follow-up where applicable for treatment of colon cancer, rectal cancer and stage IV separately. Consensus was achieved using the Delphi method. RESULTS: The total number of the voted sentences was 465. All chapters were voted on by at least 75% of the experts. Of the 465 sentences, 84% achieved large consensus, 6% achieved moderate consensus, and 7% resulted in minimum consensus. Only 3% was disagreed by more than 50% of the members. CONCLUSIONS: It is feasible to achieve European Consensus on key diagnostic and treatment issues using the Delphi method. This consensus embodies the expertise of professionals from all disciplines involved in the care for patients with colon and rectal cancer. Diagnostic and treatment algorithms were developed to implement the current evidence and to define core treatment guidance for multidisciplinary team management of colon and rectal cancer throughout Europe.

CD30 expression defines a novel subgroup of diffuse large B-cell lymphoma with favorable prognosis and distinct gene expression signature: a report from the International DLBCL Rituximab-CHOP Consortium Program Study.

CD30, originally identified as a cell-surface marker of Reed-Sternberg and Hodgkin cells of classical Hodgkin lymphoma, is also expressed by several types of non-Hodgkin lymphoma, including a subset of diffuse large B-cell lymphoma (DLBCL). However, the prognostic and biological importance of CD30 expression in DLBCL is unknown. Here we report that CD30 expression is a favorable prognostic factor in a cohort of 903 de novo DLBCL patients. CD30 was expressed in ∼14% of DLBCL patients. Patients with CD30(+) DLBCL had superior 5-year overall survival (CD30(+), 79% vs CD30(-), 59%; P = .001) and progression-free survival (P = .003). The favorable outcome of CD30 expression was maintained in both the germinal center B-cell and activated B-cell subtypes. Gene expression profiling revealed the upregulation of genes encoding negative regulators of nuclear factor κB activation and lymphocyte survival, and downregulation of genes encoding B-cell receptor signaling and proliferation, as well as prominent cytokine and stromal signatures in CD30(+) DLBCL patients, suggesting a distinct molecular basis for its favorable outcome. Given the superior prognostic value, unique gene expression signature, and significant value of CD30 as a therapeutic target for brentuximab vedotin in ongoing successful clinical trials, it seems appropriate to consider CD30(+) DLBCL as a distinct subgroup of DLBCL.

Inter-observer variation in the histological diagnosis of polyps in colorectal cancer screening.

AIM: To determine the inter-observer variation in the histological diagnosis of colorectal polyps. METHODS AND RESULTS: Four hundred and forty polyps were randomly selected from a colorectal cancer screening programme. Polyps were first evaluated by a general (324 polyps) or expert (116 polyps) pathologist, and subsequently re-evaluated by an expert pathologist. Conditional agreement was reported, and inter-observer agreement was determined using kappa statistics. In 421/440 polyps (96%), agreement for their non-adenomatous or adenomatous nature was obtained, corresponding to a very good kappa value of 0.88. For differentiation of adenomas as non-advanced and advanced, consensus was obtained in 266/322 adenomas (83%), with a moderate kappa value of 0.58. For the non-adenomatous or adenomatous nature, both general and expert pathologists, and expert pathologists between each other, showed very good agreement {kappa values of 0.89 [95% confidence interval (CI) 0.83-0.95] and 0.86 (95% CI 0.73-0.98), respectively}. For categorization of adenomas as non-advanced and advanced, moderate agreement was found between general and expert pathologists, and between expert pathologists [kappa values of 0.56 (95% CI 0.44-0.67) and 0.64 (95% CI 0.43-0.85), respectively]. CONCLUSIONS: General and expert pathologists demonstrate very good inter-observer agreement for differentiating non-adenomas from adenomas, but only moderate agreement for non-advanced and advanced adenomas. The considerable variation in differentiating non-advanced and advanced adenomas suggests that more objective criteria are required for risk stratification in screening and surveillance guidelines.

Reliability of the Roenigk classification of liver damage after methotrexate treatment for psoriasis: a clinicopathologic study of 160 liver biopsy specimens.

OBJECTIVE: To determine the interobserver reliability of the Roenigk score as a classification system of liver damage and its possible consequences for clinical practice. DESIGN: Retrospective study. SETTING: Academic research. Patients One hundred sixty liver biopsy specimens from patients with psoriasis receiving methotrexate treatment were rereviewed and analyzed blindly by an experienced pathologist with an interest in liver pathologic conditions. Main Outcome Measure Interobserver variation was evaluated using kappa statistics. RESULTS: A high concordance was present in the evaluation of the Roenigk grade of fibrosis (weighted kappa = 0.73; 95% confidence interval, 0.63-0.83). Agreement was good regarding the number of biopsy specimens for patients whose clinical management should be changed (kappa = 0.71; 95% confidence interval, 0.56-0.87). Conclusion The Roenigk classification in the assessment of liver fibrosis is a reliable scoring system.