Standard treatment for osteosarcoma patients consists of a combination of cisplatin, adriamycin, and methotrexate before surgical resection of the primary tumour, followed by postoperative ...chemotherapy including vincristine and cyclophosphamide. Unfortunately, many patients still relapse or suffer adverse events. We examined whether common germline polymorphisms in chemotherapeutic transporter and metabolic pathway genes of the drugs used in standard osteosarcoma treatment may predict treatment response.
In this study we screened 102 osteosarcoma patients for 346 Single Nucleotide Polymorphisms (SNPs) and 2 Copy Number Variants (CNVs) in 24 genes involved in the metabolism or transport of cisplatin, adriamycin, methotrexate, vincristine, and cyclophosphamide. We studied the association of the genotypes with tumour response and overall survival. We found that four SNPs in two ATP-binding cassette genes were significantly associated with overall survival: rs4148416 in ABCC3 (per-allele HR = 8.14, 95%CI = 2.73-20.2, p-value = 5.1×10⁻⁵), and three SNPs in ABCB1, rs4148737 (per-allele HR = 3.66, 95%CI = 1.85-6.11, p-value = 6.9×10⁻⁵), rs1128503 and rs10276036 (r² = 1, per-allele HR = 0.24, 95%CI = 0.11-0.47 p-value = 7.9×10⁻⁵). Associations with these SNPs remained statistically significant after correction for multiple testing (all corrected p-values permutation test ≤ 0.03).
Our findings suggest that these polymorphisms may affect osteosarcoma treatment efficacy. If these associations are independently validated, these variants could be used as genetic predictors of clinical outcome in the treatment of osteosarcoma, helping in the design of individualized therapy.
Vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP) regulate each other, contributing to tumor progression.
We have previously reported that MMP9 induces the release of ...tumor VEGF, promoting ascites formation in human ovarian carcinoma
xenografts. The aim of this study was to investigate whether tumor-derived VEGF regulated the expression of gelatinase by
the stroma, influencing the invasive properties of ovarian tumors. Tumor variants derived from 1A9 human ovarian carcinoma,
stably expressing VEGF 121 in the sense (1A9-VS-1) and antisense orientations (1A9-VAS-3), were used. In vivo , zymographic analysis of tumors from 1A9-VS-1 implanted in the peritoneal cavity of nude mice showed higher levels of gelatinases,
particularly murine MMP9, indicating that VEGF stimulates host expression of the matrix-degrading enzyme. Murine MMP9 expression
was also high in the ovaries of mice bearing 1A9-VS-1 tumors. The effect on host MMP9 activity was organ-specific. The levels
of host pro-MMP9 in ovaries correlated with the plasma levels of tumor VEGF and with the selective invasion of the ovaries.
Induction of host MMP9 expression in tumors and ovaries was independent of the site of tumor growth as it was seen in mice
carrying both intraperitoneal and subcutaneous tumors. The anti-VEGF antibody bevacizumab (Avastin) inhibited MMP9 expression
and tumor invasion in the ovaries of mice bearing 1A9-VS-1 tumors. These findings point to a complex cross-talk between VEGF
and MMPs in the progression of ovarian tumor and suggest the possibility of using VEGF inhibitors to affect MMP-dependent
tumor invasion. (Mol Cancer Res 2008;6(4):525–34)
Hereditary pheochromocytoma (PCC) is often caused by germline mutations in one of nine susceptibility genes described to date, but there are familial cases without mutations in these known genes. We ...sequenced the exomes of three unrelated individuals with hereditary PCC (cases) and identified mutations in MAX, the MYC associated factor X gene. Absence of MAX protein in the tumors and loss of heterozygosity caused by uniparental disomy supported the involvement of MAX alterations in the disease. A follow-up study of a selected series of 59 cases with PCC identified five additional MAX mutations and suggested an association with malignant outcome and preferential paternal transmission of MAX mutations. The involvement of the MYC-MAX-MXD1 network in the development and progression of neural crest cell tumors is further supported by the lack of functional MAX in rat PCC (PC12) cells and by the amplification of MYCN in neuroblastoma and suggests that loss of MAX function is correlated with metastatic potential.
Hand-foot syndrome (HFS) is one of the most relevant dose-limiting adverse effects of capecitabine, an oral prodrug of 5-fluorouracil used in the standard treatment of breast and colorectal cancer. ...We investigated the association between grade 3 HFS and genetic variations in genes involved in capecitabine metabolism.
We genotyped a total of 13 polymorphisms in the carboxylesterase 2 (CES2) gene, the cytidine deaminase (CDD) gene, the thymidine phosphorylase (TP) gene, the thymidylate synthase (TS) gene, and the dihydropyrimidine dehydrogenase (DPD) gene in 130 patients treated with capecitabine. We correlated these polymorphisms with susceptibility to HFS.
We found an association of HFS appearance with rs532545 located in the promoter region of CDD (OR = 2.02, 95% CI = 1.02-3.99, P = 0.039). Because we found no association between the rs532545 genotype and CDD mRNA expression in Epstein-Barr virus lymphoblastoid cells, we explored additional genetic variations across the CDD promoter. We found an insertion, rs3215400, in linkage disequilibrium with rs532545 (D' = 0.92), which was more clearly associated with HFS (OR = 0.51, 95% CI = 0.27-0.95, P = 0.028) in patients and with total CDD gene expression (P = 0.004) in lymphoblastoid cells. In silico analysis suggested that this insertion might create a binding site for the transcriptional regulator E2F. Using a SNaPshot assay in lymphoblastoid cells, we observed a 5.7-fold increased allele-specific mRNA expression from the deleted allele.
The deleted allele of rs3215400 shows an increased allele-specific expression and is significantly associated with an increased risk of capecitabine-induced HFS.
Capecitabine‐induced hand‐foot syndrome (CiHFS) is a common dermatological adverse reaction affecting around 30% of patients with capecitabine‐treated cancer, and the main cause of dose reductions ...and chemotherapy delays. To identify novel genetic factors associated with CiHFS in patients with cancer, we carried out an extreme‐phenotype genomewide association study in 166 patients with breast and colorectal capecitabine‐treated cancer with replication in a second cohort of 85 patients. We discovered and replicated a cluster of four highly correlated single‐nucleotide polymorphisms associated with susceptibility to CiHFS at 20q13.33 locus (top hit = rs6129058, hazard ratio = 2.40, 95% confidence interval = 1.78–3.20; P = 1.2 × 10−8). Using circular chromosome conformation capture sequencing, we identified a chromatin contact between the locus containing the risk alleles and the promoter of CDH4, located 90 kilobases away. The risk haplotype was associated with decreased levels of CDH4 mRNA and the protein it encodes, R‐cadherin (RCAD), which mainly localizes in the granular layer of the epidermis. In human keratinocytes, CDH4 downregulation resulted in reduced expression of involucrin, a protein of the cornified envelope, an essential structure for skin barrier function. Immunohistochemical analyses revealed that skin from patients with severe CiHFS exhibited low levels of RCAD and involucrin before capecitabine treatment. Our results uncover a novel mechanism underlying individual genetic susceptibility to CiHFS with implications for clinically relevant risk prediction.
OBJECTIVESTaxanes and anthracyclines are widely used in the treatment of breast cancer, although the benefit is limited to a proportion of patients and predictive biomarkers for clinical outcome ...remain elusive.
PATIENTS AND METHODSWe carried out a pharmacogenetic study in 181 patients with locally advanced breast cancer enrolled in a phase 2 randomized clinical trial (NCT00123929), where patients were randomly assigned to receive neoadjuvant single-agent docetaxel 100 mg/m (n=84) or doxorubicin 75 mg/m (n=97). We studied the association of 226 single nucleotide polymorphisms (SNPs) in 15 key drug biotransformation genes with neoadjuvant pathological tumor response residual cancer burden index to docetaxel and to doxorubicin.
RESULTSWe identified a significant association for rs162561, an intronic SNP located in the cytochrome P450 family 1 subfamily B member 1 (CYP1B1) gene, with tumor response in patients treated with single-agent docetaxel (dominant modelβ=1.02, 95% confidence interval=0.49–1.55; P=1.77×10), and for rs717620, an SNP located in the promoter of the ATP-binding cassette subfamily C member 2 (ABCC2) gene, in patients treated with neoadjuvant doxorubicin (recessive modelβ=1.67; 95% confidence interval=0.26–3.11; P=0.02).
CONCLUSIONWe identified two polymorphisms in CYP1B1 and ABCC2 associated with tumor pathological response following docetaxel or doxorubicin neoadjuvant monotherapy, respectively. Although further validation is required, these variants could be potential predictive genetic markers for treatment outcome in breast cancer patients.
Background.
The approved capecitabine regimen as monotherapy in metastatic breast cancer (MBC) is 1,250 mg/m2 twice daily for 2 weeks on and 1 week off (Cint). Dose modifications are often required ...because of severe hand‐foot syndrome (HFS). We tested a continuous regimen with a lower daily dose but a similar cumulative dose in an attempt to reduce the severity of adverse events (AEs) while maintaining efficacy.
Methods.
We randomized 195 patients with HER‐2/neu‐negative MBC to capecitabine 800 mg/m2 twice daily throughout the 21‐day cycle (Ccont) or to Cint to assess noninferiority in the percentage of patients free of progression at 1 year. Secondary endpoints included efficacy and safety. Associations between polymorphisms in capecitabine metabolism‐related genes and drug response were assessed.
Results.
The percentage of patients free of progression at 1 year was 27.3% with Cint versus 25.3% with Ccont (difference of −2.0%; 95% confidence interval: −15.5% to 11.5%, exceeding the 15% deemed noninferior). Differences regarding other efficacy variables were also not found. Grade 3–4 HFS was the most frequent AE (41.1% in Cint vs. 42.3% in Ccont). Grade 3–4 neutropenia, thrombocytopenia, diarrhea, and stomatitis were more frequent with Cint. A 5′ untranslated region polymorphism in the carboxylesterase 2 gene was associated with HFS. One polymorphism in cytidine deaminase and two in thymidine phosphorylase were associated with survival.
Conclusion.
Our study was unable to show noninferiority with the continuous capecitabine regimen (Ccont) compared with the approved intermittent regimen (Cint). Further investigation is required to improve HFS. Polymorphisms in several genes might contribute to interindividual differences in response to capecitabine.
摘要
研究背景. 卡培他滨获批的用于转移性乳腺癌（MBC）的单药治疗方案已被证明有效，其单药治疗方案为 1250 mg/m2，每日 2 次，使用 2 周后休息一周（Cint方案）。由于可能发生严重的手‐足综合征（HFS），因而常常需要调整剂量。研究者设计了一个新的连续给药方案，日剂量较低而累积剂量相当，试图在维持疗效的同时减轻不良反应事件（AE）。
研究方法. 将 195 例 HER‐2/neu 阴性的 MBC 患者随机分为 Ccont 组（卡培他滨 800 mg/m2，每日 2 次，连用 21 天）或 Cint 组。评价两组患者在 1 年无进展率方面是否具有非劣效性。次要终点包括有效性和安全性。并评估卡培他滨代谢相关的基因多态性与药物反应之间的相关性。
研究结果. Cint 组与 Ccont 组的 1 年无进展率分别为 27.3% 和 25.3%率差为‐2.0%，95% 可信区间（CI）：‐15.5% ∼ 11.5%，超出 15% 的预设非劣效范围。其他有效性指标也未发现显著差异。最常见的 AE 是 3 ∼ 4 级 HFS（Cint组 41.1% vs. Ccont 组 42.3%）。3∼4 级中性细胞减少、血小板减少、腹泻以及口腔炎在 Cint 组较多见。羧酸酯酶 2 基因 5’ 非翻译区的多态性与 HFS 相关。 1 个胞苷脱氨酶多态性和 2 个胸苷磷酸化酶多态性与生存相关。
研究结论. 卡培他滨连续方案（Ccont）与标准间歇给药方案（Cint）相比的非劣效性在该研究中未能得到证实。需要开展进一步研究以改善 HFS。某些基因的多态性可能是导致卡培他滨药物反应个体差异的原因。The Oncologist 2015;20:111–112
Purpose
Multiple sclerosis (MS) has been proposed as a possible differential diagnosis for Fabry disease (FD). The aim of this work was to evaluate the involvement of corpus callosum (CC) on MR ...images and its possible role as a radiological sign to differentiate between FD and MS.
Methods
In this multicentric study, we retrospectively evaluated the presence of white matter lesions (WMLs) on the FLAIR images of 104 patients with FD and 117 patients with MS. The incidence of CC-WML was assessed in the two groups and also in a subgroup of 37 FD patients showing neurological symptoms.
Results
WMLs were detected in 50 of 104 FD patients (48.1%) and in all MS patients. However, a lesion in the CC was detected in only 3 FD patients (2.9%) and in 106 MS patients (90.6%). In the FD subgroup with neurological symptoms, WMLs were present in 26 of 37 patients (70.3%), with two subjects (5.4%) showing a definite callosal lesion.
Conclusion
FD patients have a very low incidence of CC involvement on conventional MR images compared to MS, independently from the clinical presentation and the overall degree of WM involvement. Evaluating the presence of CC lesions on brain MR scans can be used as a radiological sign for a differential diagnosis between MS and FD, rapidly addressing the physician toward a correct diagnosis and subsequent treatment options.
Plasmoblastic lymphoma is a rare and aggressive subtype of diffuse large B cell lymphoma, which occurs usually in the jaw of immunocompromised subjects.
We describe the occurrence of plasmoblastic ...lymphoma in the mediastinum and chest wall skin of an human immunodeficiency virus-negative 63-year-old Caucasian man who had had polycytemia vera 7 years before. At admission, the patient showed a superior vena cava syndrome, with persistent dyspnoea, cough, and distension of the jugular veins. Imaging findings showed a 9.7 × 8 × 5.7 cm mediastinal mass. A chest wall neoformation biopsy and ultrasound-guided fine-needle aspiration biopsy of the mediastinal mass allowed diagnosis of plasmoblastic lymphoma and establishment of an immediate chemotherapeutic regimen, with rapid remission of compression symptoms.
Plasmoblastic lymphoma is a very uncommon, difficult to diagnose, and aggressive disease. The presented case represents the first rare mediastinal plasmoblastic lymphoma in a human immunodeficiency virus-/human herpesvirus-8-negative patient. Pathologists should be aware that this tumor does appear in sites other than the oral cavity. Fine-needle aspiration biopsy is a low-cost, repeatable, easy-to-perform technique, with a high diagnostic accuracy and with very low complication and mortality rates. Fine-needle aspiration biopsy could represent the right alternative to surgery in those patients affected by plasmoblastic lymphoma, being rapid and minimally invasive. It allowed establishment of prompt medical treatment with subsequent considerable reduction of the neoplastic tissue and resolution of the mediastinal syndrome.
Characterisation of a sea urchin (
P.
lividus) homeobox gene PIHbox 9 is reported. The homeodomain of PIHbox9 is 95% identical to the homeodomain of the human HB9 gene, indicating that the two genes ...are highly related. Temporal expression analysis during sea urchin embryogenesis showed an absence of transcripts at early cleavage stages. At late gastrula stage, transcripts were barely detectable and reached the highest abundance at prism/early pluteus stages. By whole mount in situ hybridisation we observed a highly restricted expression in a few cells of the ectoderm–endoderm boundary of embryos at the prism stage. At pluteus stages, expression of PIHbox 9 was confined around the anus.
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