The purpose of this section is to educate the reader on how to successfully manage patients with a hypersensitivity reaction to clopidogrel using desensitization protocol based on various published ...protocols. Additionally, we will define drug desensitization, and describe the possible mechanism of how desensitization may function as alternative medication. The indications/contraindications for desensitization will be reviewed. The different published clopidogrel desensitization protocols will be discussed. Based on those protocols, we recommend a protocol we feel is safe and efficacious. Clopidogrel is a thienopyridine antiplatelet drug widely used for treatment and also employed for secondary prevention regarding a range of cardiovascular diseases. However, it has been reported to cause hypersensitivity reactions. Ticlopidine is an alternative medication that can be considered when patients have an allergic reaction to clopidogrel. Additionally, ticlopidine is associated with increased risk causing potentially life-threatening adverse reactions to include: Aplastic anemia, reversible neutropenia, and thrombotic thrombocytopenia purpura vs. clopidogrel. Thus, clopidogrel desensitization offers an attractive alternative. Drug desensitization is defined as causing a temporary state of tolerance to a specific medication responsible for a hypersensitivity reaction. Furthermore, drug desensitization can only be maintained by continuous administration of this drug. Discussion: The exact immunologically mediated mechanism of how rapid oral desensitization works is not fully understood and yet to be defined. Ultimately desensitization results in causing antigen-specific mast cell tolerance. Various protocols have been published. The length of desensitization ranged from 2 h using 9 doses to 7 h using 15 doses. Recommendations: Taking the above into account, we recommend using a modification to the protocol that has the largest number of patients to undergo a standardized clopidogrel desensitization. This approach is shorter, as time has immense importance for these patients. Dosing starts at 10 mg dose and with 60 min intervals between doses, this now becomes a 4 h desensitization protocol.
RAD51 is the central protein in the homologous recombination pathway and is therefore of great relevance in terms of both therapy resistance as well as genomic stability. By using a tissue microarray ...analysis of 1,213 biopsies taken from colorectal adenocarcinomas (CRCs), we investigated whether RAD51 expression can be used as a prognostic marker as well as potential associations between this and the expression of other proteins known to be related to CRC. Strong RAD51 expression was observed in 1% of CRC, moderate in 11%, weak in 34% and no expression in 44%. No correlation was found between RAD51 expression and clinicopathological parameters. RAD51 expression correlated significantly (p = 0.001) with overall survival, with a median survival of 11 months for patients with strong, 46 with moderate, 76 with weak and 68 with negative expression. Multivariate analyses revealed that in addition to tumor stage (p < 0.0001) and nodal status (p < 0.0001), RAD51 expression is also an independent prognostic parameter (p = 0.011). Strong RAD51 expression was found to be associated with the loss of the two DNA mismatch repair proteins MSH (p = 0.0003), MLH (p = 0.002) and β‐catenin (p = 0.012) as well as with elevated p21 (p = 0.003) and EGFR expression (p = 0.0001). However, a correlation with overall survival could only be found for EGFR expression (p = 0.008), although no added benefit in risk stratification could be determined when evaluated together with RAD51. Overexpression of RAD51 is a predictor of poor outcome in CRC. This finding indicated the promise of future studies using RAD51 as a prognostic marker and therapeutic target.
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RAD51 plays a central role in the repair of DNA double‐strand breaks, and its overexpression has been associated with poor prognosis in several malignancies. In this analysis of 1,210 colorectal cancer biopsies, RAD51 overexpression was significantly correlated with poor prognosis. Its expression was further observed to be associated with that of other proteins, most importantly epidermal growth factor receptor. The results indicate the RAD51 may be an important prognostic marker and therapeutic target for colorectal cancer.
Despite much evidence on epigenetic abnormalities in cancer, it is currently unclear to what extent epigenetic alterations can be associated with tumors’ clonal genetic origins. Here, we show that ...the prostate intratumor heterogeneity in DNA methylation and copy-number patterns can be explained by a unified evolutionary process. By assaying multiple topographically distinct tumor sites, premalignant lesions, and lymph node metastases within five cases of prostate cancer, we demonstrate that both DNA methylation and copy-number heterogeneity consistently reflect the life history of the tumors. Furthermore, we show cases of genetic or epigenetic convergent evolution and highlight the diversity in the evolutionary origins and aberration spectrum between tumor and metastatic subclones. Importantly, DNA methylation can complement genetic data by serving as a proxy for activity at regulatory domains, as we show through identification of high epigenetic heterogeneity at androgen-receptor-bound enhancers. Epigenome variation thereby expands on the current genome-centric view on tumor heterogeneity.
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•Epigenetic intratumor heterogeneity reflects prostate tumors’ clonal genetic origins•Tumor and metastatic subclones exhibit diverse evolutionary origins•Distinct tumor lineages show convergent evolution of methylation patterns•Degree of methylation variability at a locus depends on genetic and epigenetic context
Several recent studies have examined the clonal origins of tumor populations on the basis of genetic variability. Brocks et al. now show that subclonal lineages also differ in their DNA methylation patterns and that methylation heterogeneity is consistent with the tumors’ genetic history. Furthermore, high methylation variability at enhancers bound by androgen receptor, which are known to play a role in prostate tumorigenesis, suggests that DNA methylation data can serve as a proxy for the functional state of tumor subclones.
Nuclear mutations are well known to drive tumor incidence, aggression and response to therapy. By contrast, the frequency and roles of mutations in the maternally inherited mitochondrial genome are ...poorly understood. Here we sequence the mitochondrial genomes of 384 localized prostate cancer patients, and identify a median of one mitochondrial single-nucleotide variant (mtSNV) per patient. Some of these mtSNVs occur in recurrent mutational hotspots and associate with aggressive disease. Younger patients have fewer mtSNVs than those who diagnosed at an older age. We demonstrate strong links between mitochondrial and nuclear mutational profiles, with co-occurrence between specific mutations. For example, certain control region mtSNVs co-occur with gain of the MYC oncogene, and these mutations are jointly associated with patient survival. These data demonstrate frequent mitochondrial mutation in prostate cancer, and suggest interplay between nuclear and mitochondrial mutational profiles in prostate cancer.In prostate cancer, the role of mutations in the maternally-inherited mitochondrial genome are not well known. Here, the authors demonstrate frequent, age-dependent mitochondrial mutation in prostate cancer. Strong links between mitochondrial and nuclear mutational profiles are associated with clinical aggressivity.
About 50% of prostate cancers have TMPRSS2-ERG fusions with concurrent ERG overexpression. The aim of this study was to determine whether clinical differences exist between ERG-positive and ...ERG-negative cancers in surgically treated patients not exposed to antihormonal therapy. A secondary aim was to search for differences between these tumor classes.
A tissue microarray containing samples from more than 2,800 prostate cancers with clinical data was analyzed for ERG alterations by immunohistochemistry and FISH. Results were compared with tumor phenotype, biochemical recurrence, and molecular features considered important for prostate cancer. The effect of ERG on androgen receptor (AR)-dependent transcription was analyzed in cell lines.
ERG expression was found in 52.4% of 2,805 cancers with a 95% concordance between ERG expression and ERG gene rearrangement detected by FISH. ERG expression was unrelated to clinical outcome and tumor phenotype. Differences in AMACR, Annexin A3, Bcl2, CD10, ALCAM, chromogranin A, epidermal growth factor receptor, HER2, mTOR, p53, and synaptophysin status were significant but minimal in absolute numbers. The most striking difference was found for AR expression, which was markedly higher in ERG-positive cancers. In vitro studies showed ERG-dependent impairment of AR-mediated transcriptional activity.
The striking similarities between these two types of prostate cancers rules out a major impact of ERG on tumor aggressiveness in early, not hormonally treated cancer. The marked difference in AR levels between ERG-positive and -negative cancers supports a systematic difference in potential response to hormonal therapy as previously observed in clinical trials.
Summary Her-2 is the molecular target for antibody-based treatment of breast cancer (trastuzumab). The potential benefit of anti–Her-2 therapy is currently investigated in several other ...HER-2–amplified cancers including gastric cancer. Although HER-2 amplification occurs in more than 10% of gastric cancers, potential heterogeneity of HER-2 amplification and overexpression could represent a major drawback for anti–Her-2 therapy. To address the potential applicability of trastuzumab in gastric cancer, tissue microarray sections of 166 gastric adenocarcinomas and 69 lymph node metastases were analyzed for Her-2 overexpression and amplification using Food and Drug Administration–approved reagents for immunohistochemistry and fluorescence in situ hybridization. HER-2 amplification was seen in 27 (16%) of 166 gastric adenocarcinomas. Amplification was typically high level with more than 20 HER-2 copies per tumor cell and a HER-2 /centromere 17 ratio >3. Amplification was associated with intestinal tumor phenotype but unrelated to survival, grading, pT, pN, or pM. Identical HER-2 status was found in primary tumor and their matched lymph node metastases. Moreover, HER-2 and Topoisomerase IIα coamplification analysis of 3 to 16 large sections from 8 Her-2–positive gastric cancers did not reveal any heterogeneity of the amplicon site. The high level of HER-2 amplification in combination with the homogeneity of its expression in primary and metastatic tumors argues for a possible therapeutic utility of trastuzumab in HER-2 –amplified gastric adenocarcinomas.
Background Aspirin desensitization improves clinical outcomes in most patients with aspirin-exacerbated respiratory disease. Most protocols for desensitization are time-consuming. Objective Our ...objective was to use historical information about the course of aspirin desensitization to enhance the efficiency of the desensitization protocol. Methods Four hundred twenty subjects with suspected aspirin-exacerbated respiratory disease underwent oral aspirin challenges. Their clinical characteristics were analyzed in relation to features of reactions during aspirin challenges. Results Large (FEV1 decrease >30%) and moderate (FEV1 decrease 21% to 30%) bronchial reactions occurred in 9% and 20% of subjects, respectively. Multivariate analysis identified risk factors associated with these larger reactions, including lack of leukotriene modifier use, baseline FEV1 of less than 80% of predicted value, and previous asthma-related emergency department visits. Seventy-five percent of patients reacted to a provoking dose of either 45 or 60 mg. Only 3% of initial reactions occurred after 150- or 325-mg provoking doses, and none occurred after the 650-mg dose. Conclusions Most bronchial and naso-ocular reactions during oral aspirin challenges occurred within a narrow dosing range (45-100 mg). Only 1 of 26 patients without risk factors had a moderate reaction.
Nodal metastasis (N1) is a strong prognostic parameter in prostate cancer; however, lymph node evaluation is always incomplete.
To study the prognostic value of lymphatic invasion (L1) and whether it ...might complement or even replace lymph node analysis in clinical practice.
Retrospective analysis of pathological and clinical data from 14 528 consecutive patients.
Radical prostatectomy.
The impact of L1 and N1 on patient prognosis was measured with time to biochemical recurrence as the primary endpoint.
Nodal metastases were found in 1602 (12%) of 13 070 patients with lymph node dissection. L1 was seen in 2027 of 14 528 patients (14%) for whom lymphatic vessels had been visualized by immunohistochemistry. N1 and L1 continuously increased with unfavorable Gleason grade, advanced pT stage, and preoperative prostate-specific antigen (PSA) values (p<0.0001 each). N1 was found in 4.3% of 12 501 L0 and in 41% of 2027 L1 carcinomas (p<0.0001). L1 was seen in 11% of 9868 N0 and in 61% of 1360 N1 carcinomas (p<0.0001). Both N1 and L1 were linked to PSA recurrence (p<0.0001 each). This was also true for 17 patients with isolated tumor cells (ie, <200 unequivocal cancer cells without invasive growth) and 193 metastases ≤1mm. Combined analysis of N and L status showed that L1 had no prognostic effect in N1 patients but L1 was strikingly linked to PSA recurrence in N0 patients. N0L1 patients showed a similar outcome as N1 patients.
Analysis of lymphatic invasion provides comparable prognostic information than lymph node analysis. Even minimal involvement of the lymphatic system has pivotal prognostic impact in prostate cancer. Thus, a thorough search for lymphatic involvement helps to identify more patients with an increased risk for disease recurrence.
Already minimal amounts of tumor cells inside the lymph nodes or intraprostatic lymphatic vessels have a severe impact on patient prognosis.
To replace morbidity-prone lymph node analysis, we tested immunohistochemical analysis of lymphatic vessels to predict prognosis after radical prostatectomy. We found that minimal lymphatic invasion had a pivotal prognostic impact.
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