PKM2 Expression as Biomarker for Resistance to Oxaliplatin-Based Chemotherapy in Colorectal Cancer.

The purpose of the current study is to investigate the prognostic significance of M2 isoform of pyruvate kinase (PKM2) mRNA expression loss in patients with operable colon cancer (CC). Two hundred sixty-two specimens from patients with stage-III or high-risk stage-II CC (group-A) treated with adjuvant fluoropyrimidine and oxaliplatin chemotherapy (FOLFOX), 118 specimens from metastatic CC patients (group-B) treated with FOLFOX, and 104 metastatic CC patients (group-C) treated with irinotecan-based chemotherapy were analyzed for PKM2, TS, ERCC1, MYC, and NEDD9 mRNA expression, as well as KRAS exon2 and BRAFV600E mutations. High PKM2 mRNA expression was correlated with left-sided located primaries (p = 0.001, group-A; p = 0.003, group-B; p = 0.001, group-C), high-grade tumors (p = 0.001, group-A; p = 0.017, group-B; p = 0.021, group-C), microsatellite-stable tumors (p < 0.001, group-A), pericolic lymph nodes involvement (p = 0.018, group-A), and cMYC mRNA expression (p = 0.002, group-A; p = 0.008, group-B; p = 0.006, group-C). High PKM2 mRNA expression was correlated with significantly lower disease free survival (DFS) (p = 0.002) and overall survival (OS) (p = 0.001) in the group-A. Similarly, PKM2 mRNA expression was associated with significantly decreased progression free survival (PFS) (p = 0.001) and OS (p = 0.001) in group-B. On the contrary, no significant association for the PKM2 mRNA expression has been observed with either PFS (p = 0.612) or OS (p = 0.517) in group-C. To conclude, the current study provides evidence for the prediction of PKM2 mRNA expression oxaliplatin-based treatment resistance.

Association of Notch and Hedgehog Pathway Activation With Prognosis in Early-stage Colorectal Cancer.

BACKGROUND/AIM: Early-stage colorectal cancer (CRC) carries a wide range of survival probabilities. Novel biomarkers in this setting are eagerly awaited. Cancer stem cells (CSCs) are considered one of the reasons for treatment failure. This study sought to determine whether activation of pathways governing the function of CSC's could correlate with treatment outcomes. MATERIALS AND METHODS: Tumor specimens from 325 patients were analyzed with immunohistochemistry (IHC) for Hedgehog and Notch pathway activation and results were correlated with prognosis. RESULTS: Positive Notch3 protein expression was an unfavorable prognostic factor for disease-free survival (DFS) and overall survival (OS) (HR=2.43, p=0.024 and HR=2.56, p=0.028, respectively). Activation of the Shh pathway showed univariately longer DFS (HR=0.49, p=0.032). Possible crosstalk between the two pathways was indicated. No further associations between pathway activation and outcome were evident. CONCLUSION: Apart from Notch 3, activation of the pathways, as indicated by IHC expression of their components, did not result in differences in terms of DFS or OS.

Colchicum Genus in the Writings of Ancient Greek and Byzantine Physicians.

The plants of the Colchicum family were known during the archaic period in Greece for their deleterious properties. Later on, they were used for the treatment of podagra. The treatment was introduced by the ancient Greek physicians and passed on to the Byzantine and Arabian physicians to endure until nowadays. The first plant was most probably named "Medea" from the notorious Colchican witch. As the most common member of the family blossoms in autumn, the plant was named Colchicum autumnale. Various nominations were also used, such as Ephemeron, Hermodactyl, Anima articulorum and Surugen. Our article discusses them, while at the same time presents the most notable authorities who have used Colchicum plants in herbal medicine and toxicology.

Reduced Expression of SMAD4 Is Associated with Poor Survival in Colon Cancer.

PURPOSE: SMAD4 loss is associated with the development of metastases and poor prognosis. We evaluated expression of SMAD4 protein and its association with tumor characteristics, including biomarkers and outcome in terms of relapse-free survival and overall survival. EXPERIMENTAL DESIGN: We used 1,564 stage II/III colon cancer samples from PETACC-3 to evaluate SMAD4 expression by immunohistochemistry. SMAD4 protein expression was validated by assessing mRNA expression using available expression array data. SMAD4 expression was also studied on 34 adenomas and 10 colon cancer liver metastases with their primaries. Loss of SMAD4 immunoreactivity was defined as focal or diffuse. Cases without SMAD4 loss were subdivided into those with strong and weak expression. RESULTS: SMAD4 protein expression was informative in 1,381/1,564 cases. SMAD4 loss was found in 293/1,381 (21%) cases. Of 1,088 cases without SMAD4 loss (79%), 530 showed weak and 558 strong expression. SMAD4 loss occurred also in adenomas, but less extensively than in carcinomas. Liver metastases followed mostly the expression pattern of the primary tumor. SMAD4 loss, including weak expression, identified patients with poor survival in stage II as well as III and in both treatment arms. SMAD4 loss was less frequent in tumors with microsatellite instability and more frequent in those with loss of heterozygosity of 18q. CONCLUSIONS: We conclude that clonal loss of SMAD4 expression in adenomas, carcinomas, and liver metastases increases with disease progression. SMAD4 loss, and to a lesser extent weak expression, is strongly associated with poor survival regardless of stage. Clin Cancer Res; 22(12); 3037-47. ©2016 AACR.

Avenzoar's (1091-1162) clinical description of cancer.

In the 11(th) and 12(th) century the Western caliphate flourished, making Cordoba the capital of physicians and philosophers. During that period lived and practised the famous physician Ibn Zuhr or Avenzoar. In his monumental treatise Al Taysir, Avenzoar provided the first clinical description of a polypoid colorectal tumour as well as the case of a uterine cancer and a basal cell carcinoma. His medical work remained popular through middle ages, influencing the development of western medicine.

René-Théophile-Hyacinthe Laennec (1781-1826) and the description of metastatic pulmonary melanoma.

In 19th century, the anatomo-clinical school of Paris linked clinical signs with anatomical lesions establishing clinical medicine. One of the most enlightened promoters of this method was the French physician René-Théophile-Hyacinthe Laennec, known as the inventor of stethoscope. In our article, we reveal his work on pulmonary melanoma.

A let-7 microRNA-binding site polymorphism in KRAS predicts improved outcome in patients with metastatic colorectal cancer treated with salvage cetuximab/panitumumab monotherapy.

PURPOSE: An inherited mutation in KRAS (LCS6-variant or rs61764370) results in altered control of the KRAS oncogene. We studied this biomarker's correlation to anti-EGFR monoclonal antibody (mAb) therapy response in patients with metastatic colorectal cancer. EXPERIMENTAL DESIGN: LCS6-variant and KRAS/BRAF mutational status was determined in 512 patients with metastatic colorectal cancer treated with salvage anti-EGFR mAb therapy, and findings correlated with outcome. Reporters were tested in colon cancer cell lines to evaluate the differential response of the LCS6-variant allele to therapy exposure. RESULTS: In this study, 21.2% (109 of 512) of patients with metastatic colorectal cancer had the LCS6-variant (TG/GG), which was found twice as frequently in the BRAF-mutated versus the wild-type (WT) group (P=0.03). LCS6-variant patients had significantly longer progression-free survival (PFS) with anti-EGFR mAb monotherapy treatment in the whole cohort (16.85 vs. 7.85 weeks; P=0.019) and in the double WT (KRAS and BRAF) patient population (18 vs. 10.4 weeks; P=0.039). Combination therapy (mAbs plus chemotherapy) led to improved PFS and overall survival (OS) for nonvariant patients, and brought their outcome to levels comparable with LCS6-variant patients receiving anti-EGFR mAb monotherapy. Combination therapy did not lead to improved PFS or OS for LCS6-variant patients. Cell line studies confirmed a unique response of the LCS6-variant allele to both anti-EGFR mAb monotherapy and chemotherapy. CONCLUSIONS: LCS6-variant patients with metastatic colorectal cancer have an excellent response to anti-EGFR mAb monotherapy, without any benefit from the addition of chemotherapy. These findings further confirm the importance of this mutation as a biomarker of anti-EGFR mAb response in patients with metastatic colorectal cancer, and warrant further prospective confirmation.

Aretaeus of Cappadocia and the first description of diabetes.

The name Aretaeus of Cappadocia has been linked with diabetes more than that of any other physician of antiquity, his texts forming a sophisticated synthesis of the previous knowledge on this disease copiously supplemented by his own observations. Gifted with a unique faculty for observing pathologic phenomena, he was able to elaborate upon earlier texts enriching them with his own original findings and numerous thoughtful reflections. Among the many diseases he dealt with, Aretaeus has bequeathed to us an outstandingly vivid and accurate description of diabetes.

Intestinal ischemia as the first manifestation of vasculitis.

OBJECTIVE: To summarize current knowledge regarding the diagnosis and management of gastrointestinal vasculitis. METHODS: Three cases of gastrointestinal vasculitis with acute abdominal ischemia as their first manifestation are presented. Underlying diseases were microscopic polyangiitis, systemic lupus erythematosus (SLE), and polyarteritis nodosa (PAN). Relevant English-language articles collected from the PubMed database were reviewed. RESULTS: Among the angiitides, PAN, SLE, and Henoch-Schönlein are those most commonly accompanied by gastrointestinal complications. Intestinal vasculitis usually occurs when there is evidence of generalized disease activity. Abdominal computerized tomography is a valuable tool for diagnosing intestinal ischemia and suspected vasculitis. CONCLUSIONS: In young patients presenting with intestinal ischemia, it is essential to assess the possibility of an underlying systemic disease. With prompt initiation of immunosuppressive treatment, surgery may be avoided. Prognosis is improved when there is minimal delay in surgical intervention.