Colorectal Cancer: An Update on Treatment Options and Future Perspectives.

Throughout the years, colorectal cancer has steadily become a global health problem. While other types of cancers have seen a decline in cases because of screening and vaccination programs, colorectal cancer has risen become the third most diagnosed cancer worldwide and, more worryingly, the second leading cancer-related cause of death. The introduction of targeted therapy has been widely considered a major paradigm shift in the treatment of colorectal cancer, which agents such as bevacizumab and cetuximab quickly becoming mainstay options in the treatment of locally advanced or metastatic disease. However, this type of treatment has also shown its limitations, with limited or no benefit for a large portion of the patients. With more and more knowledge being gathered on the molecular mechanisms which govern the malignant phenotype presented by colorectal cancer, scientists are engaged in a continuous effort to develop new therapies based on these discoveries.

A Statistical Analysis of Risk Groups in Colorectal Cancer Patients.

Colorectal cancer (CRC) is considered a major global health concern due to an increasing number of new cases and cancer-related deaths each year, strong link to dietary habits prevalent in middle and high-income countries and limited therapeutic options especially in locally-advanced and metastatic settings. To counter this growing problem, the scientific community has strived to underpin the major molecular mechanisms behind the aggressive phenotype displayed by CRC and also develop new agents to selectively target and inhibit these core drivers. This evolution has allowed the separation of patients according to different risk groups in concordance with epidemiological parameters alongside novel biomarkers such as gene alterations, protein overexpression and aberrant signaling pathways. In this study we included 20 patients who underwent colonoscopy and were later received histopathologic confirmation of CRC. The statistical anamnestic data obtained from the patients (age, gender, home distribution, signs and symptoms) was corroborated with the results obtained from the histopathologic and immunohistochemical analysis of the samples obtained via colonoscopy. The average age was 63.8 years, the male: female ratio was 2.33 and the origin of 2/3 of the patients was urban and the most encountered symptoms were transit disorders (75%). In terms of colonoscopy results, the majority of tumors were found on the rectum (85%), 90% of tumors were adenocarcinomas, having a vegetant aspect in 60% of the cases and a moderate degree of differentiation in 50% of situations.

Committing to quantum resistance: a slow defence for Bitcoin against a fast quantum computing attack.

Quantum computers are expected to have a dramatic impact on numerous fields due to their anticipated ability to solve classes of mathematical problems much more efficiently than their classical counterparts. This particularly applies to domains involving integer factorization and discrete logarithms, such as public key cryptography. In this paper, we consider the threats a quantum-capable adversary could impose on Bitcoin, which currently uses the Elliptic Curve Digital Signature Algorithm (ECDSA) to sign transactions. We then propose a simple but slow commit-delay-reveal protocol, which allows users to securely move their funds from old (non-quantum-resistant) outputs to those adhering to a quantum-resistant digital signature scheme. The transition protocol functions even if ECDSA has already been compromised. While our scheme requires modifications to the Bitcoin protocol, these can be implemented as a soft fork.

Histopathological Study on Conservatively Operated Breast Carcinomas.

In this histopathological study we looked at 303 cases of breast carcinomas, managed though conservative breast surgery and later analysed with the help of a classical histopathological technique, paraffin embedding. The carcinomas were assessed in terms of tumor size, lymph node status, histological type, correlation between invasive tumors and an situ carcinoma component, resection margins, grading and patients age. Following assessment, we looked at associations between above morphological and clinical parameters and ipsilateral local recurrences. We concluded that more than half of our cases were carcinomas, measuring between 2 cm and 5 cm, with no associated lymph node involvement, in keeping with pTNM criteria for stage II. By far, in our study, the most frequent histopathological type was type NOS (63.37%) followed by invasive lobular carcinoma (10.56%) and mixed ducto-lobular invasive carcinoma (6.27%). Other types of invasive carcinoma were rarer, each representing less than 4% of cases. In regards to in situ carcinomas we noted the most common histological types to be both cribriform intraductal carcinoma and comedocarcinoma, each identified in 1.65% of cases. Amongst invasive breast carcinomas, infiltrating ductal carcinoma not otherwise specified (NOS) was found to be most commonly associated with in situ ductal carcinoma lesions. This was seen in 34.9% of cases, and was the only type associated with an extensive in situ component. Analysing the grading of mammary carcinomas in our study showed that the vast majority of cases (63.04%) were grade 3 tumors. In regards to surgical resection margins, ¾ of cases were noted to have negative margins. Tumor recurrences were noted in 12 cases. These cases were most commonly noted to reoccur following initial poorly differentiated, infiltrating ductal carcinomas, not otherwise specified (NOS), with positive resection margins, measuring less than 2 cm. Patiens tended to be under the age of 40 and had positive lymph nodes. The emergence of local recurrences after conservative surgery for early breast cancer is singnificantly linked to poorly differentiated primary tumors (p <0.05) but not correlated with histological type, presence of extensive intraductal carcinoma component, size of primary breast tumor or lymph node status ( p> 0.05). In terms of increasing the risk of ipsilateral recurrence the most important aspect highlighted in our sudy was the status of the resection margins. Patients with positive resection margins had a significantly high risk to develop recurrences after the conservative surgery, compared to those with negative margins (p <0.001).

Coordination of centrosome homeostasis and DNA repair is intact in MCF-7 and disrupted in MDA-MB 231 breast cancer cells.

When cells encounter substantial DNA damage, critical cell cycle events are halted while DNA repair mechanisms are activated to restore genome integrity. Genomic integrity also depends on proper assembly and function of the bipolar mitotic spindle, which is required for equal chromosome segregation. Failure to execute either of these processes leads to genomic instability, aging, and cancer. Here, we show that following DNA damage in the breast cancer cell line MCF-7, the centrosome protein centrin2 moves from the cytoplasm and accumulates in the nucleus in a xeroderma pigmentosum complementation group C protein (XPC)-dependent manner, reducing the available cytoplasmic pool of this key centriole protein and preventing centrosome amplification. MDA-MB 231 cells do not express XPC and fail to move centrin into the nucleus following DNA damage. Reintroduction of XPC expression in MDA-MB 231 cells rescues nuclear centrin2 sequestration and reestablishes control against centrosome amplification, regardless of mutant p53 status. Importantly, the capacity to repair DNA damage was also dependent on the availability of centrin2 in the nucleus. These observations show that centrin and XPC cooperate in a reciprocal mechanism to coordinate centrosome homeostasis and DNA repair and suggest that this process may provide a tractable target to develop treatments to slow progression of cancer and aging.

Impact of pain in health related quality of life of patients with systemic sclerosis.

OBJECTIVES: Systemic sclerosis (SSc) has an heterogenous clinical pattern, with variable organ involvement and degrees of severity. Like in other rheumatic diseases, the self-questionnaires have been used to evaluate SSc globally. The aim of the study is as to evaluate the quality of life (QoL) in patients with either diffuse or limited SSc, and to examine the impact of pain on the QoL scores. METHODS: Patients with SSc, either diffuse or limited SSc, were included in a cross-sectional study. The QoL was evaluated with the short-form 36 (SF-36) and the functional repercussion with the SSc-modified Health Assessment Questionnaire (S-HAQ). RESULTS: A total of 89 patients (67 with diffuse and 22 with limited SSc) were included. The SF-36 score values were lower in SSc patients than those reported in the general population. The physical component scores (PCS) of the SF-36 was significantly worse in diffuse compared with limited SSc (P < 0.05). The PCS was significantly negatively related to the number of clinical manifestations (ANOVA, P < 0.0001). The mental component score (MCS) was not influenced by the type of SSc or the number of clinical manifestations presented by the patient. The QoL of SSc patients was highly correlated with pain (R = 0.69) and disability (R = 0.70). Interestingly, the QoL of SSc patients was only slightly correlated with cutaneous (R = 0.42) and pulmonary involvement (R = 0.57). CONCLUSION: The QoL of patients with SSc is strongly influenced by the type of SSc, the burden of clinical manifestations, the functional disability and by the pain, whatever its cause. The treatment of pain should be considered as priority to improve the QoL of SSc patients.

[Disseminated tuberculosis and profound thrombopenia]. / Tuberculose disséminée et thrombopénie profonde.

Thrombocytopenia within the context of disseminated tuberculosis can lead to complications requiring rapid treatment. Although the origin is generally central, thrombocytopenia can arise from an immune disorder. We hereby report a case of disseminated tuberculosis associated with thrombocytopenia, which required, in addition to antituberculosis therapy initiated before bacteriological proof, corticosteroid treatment and multiple platelet transfusions. The discovery of anti-platelet antibodies along with the success of immunomodulator therapy confirmed the auto-immune origin of this thrombocytopenia.

[Cardiopulmonary function before and after cyclophosphamide treatment in severe systemic sclerosis: comparison of monthly intravenous bolus and autologous haematopoietic stem cell transplantation]. / Etude de la fonction cardiopulmonaire avant et après traitement par cyclophosphamide dans la sclérodermie systémique sévère: comparaison de deux modes d'administration (Intensification thérapeutique suivie d'autogreffe de cellules souches hématopoïétiques périphériques ou bolus mensuels intraveineux).

PURPOSE: Cyclophosphamide in monthly intravenous bolus is used to treat severe forms of systemic sclerosis with pulmonary involvement. Since 1996, cyclophosphamide therapeutic intensification with autologous haematopoietic stem cells transplantation allowed significant improvement in skin and functional scores in severe systemic sclerosis. Cyclophosphamide potential cardiotoxicity in this setting has been questioned. METHODS: To analyse cyclophosphamide potential cardiopulmonary toxicity (as graded with WHO classification), we retrospectively studied all severe systemic sclerosis patients treated with cyclophosphamide either during autologous haematopoietic stem cells transplantation procedure (group A) or intravenous cyclophosphamide (group B) recruited in 7 French centers volunteers for the study. Parameters to evaluate heart and lung functions at inclusion, then at last follow-up between 6 and 12 months after start of treatment, were compared using the Mann-Whitney test. RESULTS: (Mean+/-standard deviation): Groups A (N=14) and B (N=13) were similar at the beginning of the study in terms of skin, renal, heart and lung involvement. Cyclophosphamide total dose (/m(2)) received in group A was superior (P=0.02) to the one in group B. After respective follow-up of 10+/-2.8 (group A) and 9.9+/-2.7 (group B) months, cyclophosphamide cardio toxicity (group A: N=3; group B: N=2), evolution of the left ventricular ejection fraction and arterial and pulmonary pressures did not differ in the two groups. CONCLUSION: In spite of higher cyclophosphamide doses during autologous haematopoietic stem cells transplantation than bolus treatment, cardiopulmonary toxicity appeared not increased. The ongoing European ASTIS trial will compare the respective benefits of these 2 cyclophosphamide regimens in severe Systemic sclerosis.

[Therapeutic intensification and autologous stem cell transplantation in autoimmune diseases]. / Intensification thérapeutique et autogreffe de cellules souches hématopoïétiques pour le traitement des maladies auto-immunes.

THE PATHOPHYSIOLOGY of most autoimmune diseases is often poorly understood. EXPERIMENTAL CONSIDERATIONS and clinical experience suggest that high doses immunoablation followed by stem cell transplantation is a therapeutic option to consider for certain severe autoimmune disorders. THE CONCEPT OF RESTORING NORMAL IMMUNE REACTIVITY must in part br true since current results of 466 transplants (445 autologous, 21 allogeneic) patients suffering from various autoimmune diseases show a beneficial outcome in approximately 2/3 of the patients. TO IMPROVE THE EFFICACY AND SAFETY OF SUCH AN AGGRESSIVE PROCEDURE in patients with potentially affected vital organs by the underlying autoimmune disease, it is especially important to follow international consensus guidelines and to centrally collect clinical data for in depth analysis in the EBMT International Stem Cell Project for Autoimmune Disease in Basel, Switzerland. PHASE III STUDIES ARE RUNNING FOR SYSTEMIC SCLEROSIS (Astis, Autologous Stem cell Transplantation International Rheumatoid Arthritis Trial) started in 2003. A STUDY PROJECT IS PLANNED FOR MULTIPLE SCLEROSIS (Astims, Autologous Stem cell Transplantation International Multiple Sclerosis).

[Quality of life assessment with the MOS-SF36 in patients with systemic sclerosis]. / Evaluation de la qualité de vie par le MOS-SF36 dans la sclérodermie systémique.

OBJECTIVE: To investigate the metric properties and the validity of the Medical Outcome Study Short Form 36 (SF-36), a questionnaire to assess the quality of life, in patients with either diffuse or limited systemic sclerosis (SS), and to examine the effect of the disease on quality of life. METHODS: Cross sectional study of 86 patients with a SS (64 diffuse SS, 22 limited SS). Disease severity was assessed by clinical examination, pulmonary functional tests and Health Assessment Questionnaire (HAQ) modified for scleroderma. RESULTS: The SF-36 scores values were lower in diffuse than in limited sclérodermie systémique. The Physical Component Score was worse in patients with than without any clinical involvement. This score increased in relation with the number of clinical involvements. The quality of life of patients with SS was correlated to its functional repercussion. CONCLUSION: The quality of life in SS patients is correlated with the clinical severity of the disease. The use of SF-36 to measure the quality of life is useful for the clinical evaluation of patients with SS.