Clinical Significance of Somatic Mutations in RAS/RAF/MAPK Signaling Pathway in Moroccan and North African Colorectal Cancer Patients

Background: Mutations in RAS (KRAS, NRAS) and BRAF genes are the main biomarker predicting response to anti-EGFR monoclonal antibodies in targeted therapy in colorectal cancer (CRC). Objective: Our study aims to evaluate the frequencies of KRAS, NRAS and BRAF mutations and their possible associations with clinico-pathological features in CRC patients from Morocco. Methods: DNA was extracted from 80 FFPE samples using the QIAamp DNA FFPE-kit. RAS and BRAF mutations were assessed by pyrosequencing assays using Qiagen, KRAS Pyro®kit 24.V1, Ras-Extension Pyro®kit 24.V1 and BRAF Pyro®Kit 24.V1, respectively, and carried out in the PyroMark-Q24. Results: RAS mutations were identified in 57.5% (56.2% in KRAS, 8.8% in NRAS). In KRAS gene, exon 2 mutations accounted for 93.3% (68.9% in codon 12, 24.4% in codon 13). Within codon 12, G12D was the most prevalent mutation (37.7%), followed by G12C (13.4%), G12S (8.9%) and G12V (6.6%). Within codon 13, the most frequently observed mutation was G13D (22.3%). The mutation rates of exon 3 and 4 were 15.6% and 13.3%, respectively. In exon 3 codon 61, 2.3% patients were detected with two concurrent mutations (Q61R, Q61H), and 4.4% with three concurrent mutations (Q61R, Q61H, Q61L). In NRAS gene, the mutation rates of exon 2, 3 and 4 were 57.1%, 28.6%, and 14.3%, respectively. G13A and Q61H were the most common mutations, accounting for 42.9% and 28.5%, respectively. There were 13% patients with concurrent KRAS/NRAS mutation and 4.3% wt KRAS with NRAS mutations. No mutations were identified in BRAF gene. In both sexes, KRAS codon 12 mutations were associated with higher stage III/IV tumors. Moreover, Patients whose tumor is in the proximal colon (56.3%) are more likely to harbor KRAS mutations than those tumor located in rectum (25%). Conclusion: RAS mutations could be useful in future target anti-EGFR therapy and molecular CRC screening strategy in Morocco.     

Thiotepa-based high-dose chemotherapy with autologous stem-cell rescue in patients with recurrent or progressive CNS germ cell tumors.

PURPOSE: To evaluate the efficacy and toxicity of high-dose chemotherapy (HDC) followed by autologous stem-cell rescue (ASCR) in patients with relapsed or progressive CNS germ cell tumors (GCTs). PATIENTS AND METHODS: Twenty-one patients with CNS GCTs who experienced relapse or progression despite having received initial chemotherapy and/or radiotherapy were treated with thiotepa-based HDC regimens followed by ASCR. RESULTS: Estimated overall survival (OS) and event-free survival (EFS) rates for the entire group 4 years after HDC were 57% +/- 12% and 52% +/- 14%, respectively. Seven of nine (78%) patients with germinoma survived disease-free after HDC with a median survival of 48 months. One patient died as a result of progressive disease (PD) 39 months after HDC, and another died as a result of pulmonary fibrosis unrelated to HDC 78 months after ASCR without assessable disease. However, only four of 12 patients (33%) with nongerminomatous germ cell tumors (NGGCTs) survived without evidence of disease, with a median survival of 35 months. Eight patients with NGGCTs died as a result of PD, with a median survival of 4 months after HDC (range, 2 to 17 months). Patients with germinoma fared better than those with NGGCTs (P =.016 and.014 for OS and EFS, respectively). Patients with complete response to HDC also had significantly better outcome (P <.001 for OS and EFS) compared with patients with only a partial response or stable disease. There were no toxic deaths because of HDC. CONCLUSION: Dose escalation of chemotherapy followed by ASCR is effective therapy for patients with recurrent CNS germinomas and might be effective in patients with recurrent NGGCTs with a low tumor burden.     

Impact of epidermal growth factor receptor (EGFR) kinase mutations, EGFR gene amplifications, and KRAS mutations on survival of pancreatic adenocarcinoma

BACKGROUND: Erlotinib, in combination with gemcitabine, has shown clinical benefits in pancreatic adenocarcinoma patients. The presence of EGFR mutations and increased EGFR copy numbers in pancreatic adenocarcinoma was explored. METHODS: Sixty-six pancreatic cancer patients were included in the analysis. The EGFR mutation was analyzed by DNA sequencing of exons 18-21 in the tyrosine kinase domain. KRAS mutation was analyzed by sequencing codons 12, 13, and 61. Quantitative real-time polymerase chain reaction was performed to analyze the copy number of EGFR. RESULTS: In the current study the EGFR mutation was harbored in only 1 (1.5%) of the 66 inoperable or metastatic pancreatic adenocarcinoma patients. Amino acid substitution was detected in exon 20 of the EGFR gene. Increased EGFR copy numbers (> or =3.0 per cell) were detected in 26 (41%) patients. There was only 1 patient, who had a highly increased EGFR copy number (> or =6.0 per cell), who died, 2.1 months from the date of diagnosis. The EGFR amplification did not significantly influence survival in pancreatic adenocarcinoma patients (P = .935). Thirty-two (49%) of the 65 pancreatic adenocarcinomas examined harbored a point mutation in codons 12 (n = 31) and 61 (n = 1) of the KRAS gene. The presence of a point mutation in codon 12 adversely influenced survival of pancreatic cancer patients (P = .030). CONCLUSIONS: The incidence of somatic mutations in the tyrosine kinase domains of EGFR was very low and the increased gene copy number of EGFR did not significantly influence survival.     

Distribution of KRAS and BRAF Mutations in Metastatic Colorectal Cancers in Turkish Patients

The results of this study demonstrate the potential prognostic and predictive values of KRAS and BRAF gene mutations in patients with colorectal cancer (CRC). It has been proven that KRAS and BRAF mutations are predictive biomarkers for resistance to anti-EGFR monoclonal antibody treatment in patients with metastatic CRC (mCRC). We demonstrated the distribution of KRAS (codons 12, 13 and 61) and BRAF (codon 600) gene mutations in 50 mCRCs using direct sequencing and compared the results with clinicopathological data. KRAS and BRAF mutations were identified in 15 (30%) and 1 (2%) patients, respectively. We identified KRAS mutations in codon 12, 13 and 61 in 73.3% (11/15), 20% (3/15) and 6.67% (1/15) of the positive patients, respectively. The KRAS mutation frequency was significantly higher in tumors located in the ascending colon (p=0.043). Thus, we found that approximately 1/3 of the patients with mCRC had KRAS mutations and the only clinicopathological factor related to this mutation was tumor location. Future studies with larger patient groups should yield more accurate data regarding the molecular mechanism of CRC and the association between KRAS and BRAF mutations and clinicopathological features.     

Molecular spectrum of KRAS,BRAF, and PIK3CA gene mutation: determination of frequency,distribution pattern in Indian colorectal carcinoma

Molecular evaluation of KRAS, BRAF, and PIK3CA mutation has become an important part in colorectal carcinoma evaluation, and their alterations may determine the therapeutic response to anti-EGFR therapy. The current study demonstrates the evaluation of KRAS, BRAF, and PIK3CA mutation using direct sequencing in 204 samples. The frequency of KRAS, BRAF, and PIK3CA mutations was 23.5, 9.8, and 5.9 %, respectively. Five different substitution mutations at KRAS codon 12 (G12S, G12D, G12A, G12V, and G12C) and one substitution type at codon 13 (G13D) were observed. KRAS mutations were significantly higher in patients who were >50 years, and were associated with moderate/poorly differentiated tumors and adenocarcinomas. All mutations in BRAF gene were of V600E type, which were frequent in patients who were ≤50 years. Unlike KRAS mutations, BRAF mutations were more frequent in well-differentiated tumors and right-sided tumors. PIK3CA–E545K was the most recurrent mutation while other mutations detected were T544I, Q546R, H1047R, G1049S, and D1056N. No significant association of PIK3CA mutation with age, tumor differentiation, location, and other parameters was noted. No concomitant mutation of KRAS and BRAF mutations was observed, while, interestingly, five cases showed concurrent mutation of KRAS and PIK3CA mutations. In conclusion, to our knowledge, this is the first study to evaluate the PIK3CA mutation in Indian CRC patients. The frequency of KRAS, BRAF, and PIK3CA was similar to worldwide reports. Furthermore, identification of molecular markers has unique strengths, and can provide insights into the pathogenic process and help optimize personalized prevention and therapy.     

Evaluation of KRAS Gene Mutations in Metastatic Colorectal Cancer Patients in Kermanshah Province

Background: Worldwide, colorectal cancer (CRC) is reported to be the fourth most common cancer in men and the third most common in women. KRAS is a protooncogene located on the short arm of chromosome 12. The aim of this study was to evaluate the KRAS oncogene and its relationship it with clinicopathologic features in 33 Kurdish patients. Materials and Methods: Metastatic CRC between 2012 and 2016 that came to Imam Reza hospital, Kermanshah province, Iran, were analysed for KRAS mutations using allele specific PCR primers and pyrosequencing. Correlations between variables was analyzed in PASW SPSS and overall survival curves were plotted in Graph Pad prism 5. Results: The mean age for them at diagnosis was 51.512.6 years (range, 2276 years). Among the 33 patients that were sequenced, 12 samples in the KRAS gene had a nucleotide change, 11 in codon 12 and 1 in codon 13.There was no significant relationship between the mutation and clinical and pathological aspects of the disease. Conclusions: Knowledge of the KRAS status can help in decisionmaking to treat metastatic colorectal cancer patients more efficiently and increase survival. However, many Kurdish people due to economic problems are not able to do this valuable genetic test. In addition, we need more careful research of KRAS oncogene at the molecular level in young populations with more patients.     

结直肠癌组织中KRAS和BRAF基因突变与临床病理特征及预后的关系

目的:探讨结直肠癌组织中KRAS和BRAF基因突变与临床病理和预后的关系.方法:采用扩增阻滞突变系统(ARMS)方法对134例结直肠癌组织进行回顾性分析.结果:134例CRC组织中KRAS基因突变率49.3％(66/134),第2外显子突变率42.5％(57/134),其中12及13密码子突变率分别为35.1％(47/...     

Impact of the Specific Mutation in KRAS Codon 12 Mutated Tumors on Treatment Efficacy in Patients with Metastatic Colorectal Cancer Receiving Cetuximab-Based First-Line Therapy: A Pooled Analysis of Three Trials

Purpose: This study investigated the impact of specific mutations in codon 12 of the Kirsten-ras (KRAS) gene on treatment efficacy in patients with metastatic colorectal cancer (mCRC). Patients: Overall, 119 patients bearing a KRAS mutation in codon 12 were evaluated. All patients received cetuximab-based first-line chemotherapy within the Central European Cooperative Oncology Group (CECOG), AIO KRK-0104 or AIO KRK-0306 trials. Results: Patients with KRAS codon 12 mutant mCRC showed a broad range of outcome when treated with cetuximab-based first-line regimens. Patients with tumors bearing a KRAS p.G12D mutation showed a strong trend to a more favorable outcome compared to other mutations (overall survival 23.3 vs. 14-18 months; hazard ratio 0.66, range 0.43-1.03). An interaction model illustrated that KRAS p.G12C was associated with unfavorable outcome when treated with oxaliplatin plus cetuximab. Conclusion: The present analysis suggests that KRAS codon 12 mutation may not represent a homogeneous entity in mCRC when treated with cetuximab-based first-line therapy.     

江苏地区肺癌和胃癌患者 KRAS 基因突变状态分析*

目的：检测江苏地区肺癌和胃癌患者KRAS基因突变状态及其与临床病理特征的关系,并比较其在两种癌症间的异同。方法：收集肺癌128 例,胃癌115 例。采用直接测序法检测KRAS基因第2 号外显子突变,分析基因突变状态及其与临床病理特征的相关性。结果：KRAS基因突变率在肺癌和胃癌中无显著性差异（6.3% vs. 4.3% ,P > 0.05）。 两种癌症中,KRAS 基因突变都以第12密码子为主。KRAS 突变与年龄,性别无明显相关。肺腺癌患者KRAS基因突变高于非腺癌包括鳞癌等（10.7% vs. 0 ,P < 0.05）。 结论：江苏地区肺癌和胃癌患者中,KRAS第2 外显子突变率均较低,男性和女性的突变率无明显差异。肺腺癌患者KRAS基因突变率相对较高,因此个体化治疗前应同时检测KRAS 基因,以筛选出对靶向治疗耐药的肺癌患者,从而更好地指导患者的个体化分子靶向治疗。     

The role of chemotherapy in intracranial germinoma: A case report

Background: The case of a 29-year-old man with histologically proven simultaneous germinoma (seminoma) of the pineal gland and a stage I embryonal carcinoma of the testis is reported. An intradural metastatic lesion from the pineal germinoma was diagnosed at the level of the first thoracic vertebra. Treatment, after inguinal orchiectomy, was chemotherapy only, rather than conventional radiotherapy for the pineal germinoma.Methods: Therapy consisted of bleomycin (B), etoposide (E) and cisplatin (P). MRI was used to assess the effectiveness of BEP chemotherapy.Results: A complete remission of the pineal gland germinoma and the epidural metastasis was documented after two cycles of BEP chemotherapy and after 15 months of follow-up the patient remains free of relapse.Discussion: The pathogenesis of simultaneously occurring germinoma of the pineal gland and embryonal cell carcinoma of the testis is discussed.The choice of therapy in these circumstances is a matter of debate and the good result of chemotherapy alone in this patient suggest that primary chemotherapy may be the therapy of choice in patients with pineal germinomas.     

KRAS, BRAF and PIK3CA mutations in human colorectal cancer: relationship with metastatic colorectal cancer

Many abnormal gene expressions and dysregulated signaling pathways have been found in human colorectal cancer. Activating mutations of the KRAS, BRAF or PIK3CA oncogenes are frequently found in colorectal cancer. The aim of the study was to investigate the molecular occurrence of KRAS, BRAF and PIK3CA mutations in the colorectal tumorigenesis and to study the association of these events with clinicopathological parameters. In our study, DNA was extracted from 200 cases of human colorectal cancer tissue samples. KRAS, BRAF and PIK3CA mutation analysis was performed by PCR and pyrosequencing. Using statistical methods, we analyzed the relationships between the gene mutations and clinicopathological parameters. KRAS point mutations were detected in 63/200 patients (31.5%), with codon 12 mutations in 52/200 patients (26%), codon 13 mutations in 10/200 patients (5%) and codon 12.13 bi-mutations in 1/200 patients (0.5%). The V600E mutations of BRAF were detected in 14/200 patients (7%). PIK3CA point mutations (exon 9, exon 20) were detected in 25/200 (12.5%) patients, exon 9 mutatons in 12/200 patients (6%) and exon 20 mutations in 13/200 (6.5%). Our study suggested that both KRAS and BRAF mutations are exclusive, but KRAS and PIK3CA mutations are coexistent. The mutational status of BRAF did not correlate with Dukes' staging, histological type, age and gender. However, strong associations were found between KRAS, PIK3CA mutations and Dukes' staging (staging D, 12/25, 48%). Notably, our data indicated that colorectal cancers with KRAS and PIK3CA bi-mutations are more likely to develop into liver metastasis.     

High Frequency of KRAS Codon 146 and FBXW7 Mutations in Thai Patients with Stage II-III Colon Cancer

Background: KRAS, NRAS, and BRAF gene mutations are the most clinically relevant and frequently reported incolorectal cancer (CRC). Although data on these genes are frequently reported in several counties, data specific to thesegenes among Thai population are scarce. The aim of this study was to investigate and identify molecular alterationsassociated with colon cancer in Thai population, and to determine the impact of these genetic aberrations on clinicaloutcome. Methods: DNA from 108 archived formalin-fixed, paraffin-embedded (FFPE) tissue samples that histologicallyconfirmed adenocarcinoma of stage II-III colon cancer between 2010 and 2012 at Siriraj Hospital (Bangkok, Thailand)were extracted. Gene mutational analysis was performed by next-generation sequencing (NGS) using an OncomineSolid Tumor DNA kit (Thermo Fisher Scientific, Inc., Waltham, MA, USA). Results: A total of 22 somatic genemutations were detected. The mutation frequency observed in KRAS, NRAS, BRAF, PIK3CA, and FBXW7 mutationswas 47.2%, 1.9%, 1.9%, 12%, and 14.8%, respectively. KRAS mutation codon 12, 13, 59, 61, 117, and 146 mutationswere identified in 29.6%, 8.3%, 1.8%, 0.9%, 0.0%, and 8.3%, respectively. KRAS Exon 4 had better DFS comparedwith Exon 2 and 3. Conclusions: This study is the first to comprehensively report hotspot mutations using NGS in Thaicolon cancer patients. The most commonly identified gene mutation frequencies among Thai patients (KRAS, NRAS,BRAF, TP53, and PIK3CA) were similar to the gene mutation frequencies reported in Western population, except forsubgroup of KRAS codon 146 and FBXW7 mutations that had a slightly higher frequency.     

Combined treatment modality for intracranial germinomas: results of a multicentre SFOP experience. Société Française d'Oncologie Pédiatrique

Conventional therapy for intracranial germinomas is craniospinal irradiation. In 1990, the Société Fran?aise d'Oncologie Pédiatrique initiated a study combining chemotherapy (alternating courses of etoposide-carboplatin and etoposide-ifosfamide for a recommended total of four courses) with 40 Gy local irradiation for patients with localized germinomas. Metastatic patients were allocated to receive low-dose craniospinal radiotherapy. Fifty-seven patients were enrolled between 1990 and 1996. Forty-seven had biopsy-proven germinoma. Biopsy was not performed in ten patients (four had diagnostic tumour markers and in six the neurosurgeon felt biopsy was contraindicated). Fifty-one patients had localized disease, and six leptomeningeal dissemination. Seven patients had bifocal tumour. All but one patient received at least four courses of chemotherapy. Toxicity was mainly haematological. Patients with diabetus insipidus (n = 25) commonly developed electrolyte disturbances during chemotherapy. No patient developed tumour progression during chemotherapy. Fifty patients received local radiotherapy with a median dose of 40 Gy to the initial tumour volume. Six metastatic patients, and one patient with localized disease who stopped chemotherapy due to severe toxicity, received craniospinal radiotherapy. The median follow-up for the group was 42 months. Four patients relapsed 9, 10, 38 and 57 months after diagnosis. Three achieved second complete remission following salvage treatment with chemotherapy alone or chemo-radiotherapy. The estimated 3-year survival probability is 98% (CI: 86.6-99.7%) and the estimated 3-year event-free survival is 96.4% (CI: 86.2-99.1%). This study shows that excellent survival rates can be achieved by combining chemotherapy and local radiotherapy in patients with non-metastatic intracranial germinomas.     

Combined chemotherapy and radiotherapy for intracranial germinomas in adultpatients: a single-institution study

We report on our experience in the treatment of intracranial germinomas (18 pure germinomas and two germinomas with syncytiotrophoblastic giant cells) according to a strategy of radiotherapy doses and fields reduction after a neoadjuvant chemotherapy (Cisplatin-vinblastine and bleomycin combination). Radiation therapy was delivered after the completion of the third and last course of chemotherapy. For the solitary germinoma the target volume was the gross tumour volume. In the five multifocal germinoma patients the whole ventricle volume was irradiated. For the single disseminated germinoma patient we treated the whole central nervous system. The cumulative doses were 30 Gy for the pure germinomas. For the STGCs, a cumulative dose of 35 Gy was used. The median follow-up was 55 months (range 12–120). 18 patients were alive without recurrence of disease. In the two patients with STGCs the death took place 16 and 35 months after diagnosis.     

Analysis of the correlation with KRAS gene mutation status and the benefit of cetuximab plus irinotecan as third- line chemotherapy for the Treatment of unresectable metastatic colorectal cancer

Mutation of the KRAS gene in patients with metastatic colorectal cancer(mCRC)has been established as a predictive marker of poor response to anti-EGFR cetuximab. The Japanese Society of Medical Oncology recommends that the KRAS mutation status at codon 12 and codon 13 should be genotyped by direct-sequencing or allele-specific PCR. In this study, we tested the point mutation of codon 12 and 13 in the KRAS gene by Luminex(xMAP)flow cytometry with sequence-specific oligonucleotide probes for 39 out of 64 unresectable mCRC patients enrolled from Sep 2008 to Oct 2009, who were administered cetuximab in combination with irinotecan(CPT-11)as third-line therapy. We retrospectively analyzed the relationship between KRAS mutation status and responses to combination therapy. Mutations in the KRAS gene were detected in 38. 5% of cases(codon12: 73%, codon 13: 27%), and the median follow-up time was 8. 2 months(range, 1. 4-15. 2 months). The response rates for patients with KRAS wild-type and patients with KRAS mutations were 33. 3%(95%CI 14. 5-52. 2%)and 0%(p=0. 015); the disease control rates were 75%(95%CI 57. 7-92. 3%)and 40%(95%CI, 15. 2-64. 8%; p=0. 044); the median TTF was 7 months(95%CI 4. 6-9. 3)and 2. 3 months(95%CI 1. 3-3. 2; p=0. 0007), and the median OS was 12. 9 months(95%CI 6. 7-19. 1)and 10. 8 months(95%CI 5. 0-16. 7; p=0. 15), respectively. Therefore, we concluded that the KRAS mutation in mCRC is a predictive factor for the lack of response to combination therapy with cetuximab plus CPT- 11, as reported in previous clinical studies.     

原发小细胞肺癌中BRAF/KRAS以及PIK3CA突变的基因特征及临床特征

目的 在中国人群小细胞肺癌(SCLC)标本中检测BRAF/KRAS以及PIK3CA基因突变频率,分析这些基因突变的基因特征和临床特征。方法 2009-2014年共收集557例单纯SCLC患者组织样本。利用双脱氧测序法进行BRAF、KRAS、PIK3CA、NRAS、MEK1基因突变检测。χ²检验分析临床因素与基因突变的相关性,Kaplan-Meier法生存分析,Cox模型多因素预后分析。结果 在557例标本中检测到13例BRAF突变,突变类型包括V600E (n=5)、V600A (n=2)、V600M (n=1)、D594G (n=1)、G464E (n=1)、K601R (n=2)、S605N (n=1)。6例KRAS突变,突变类型包括G12C (n=3)、G12A (n=1)、G12D (n=1)、G13D (n=1)。4例PIK3CA突变,突变类型包括E545G (n=2)、H1047R (n=2)。另外1例NRAS突变(Q61R)和1例MEK1突变(D61Y)。这些突变基因与患者年龄、性别、吸烟状态、临床分期均无相关性。单因素生存分析结果显示基因突变组患者的生存时间比无此类突变者生存时间差,中位生存时间分别为(10.30±0.75)个月(95%CI为8.83~11.77个月)和(12.80±0.54)个月(95%CI为11.74~13.86)(P=0.011)。结论 在单纯SCLC中存在小比例的BRAF/KRAS、PIK3CA基因突变群体,这些基因突变与患者的临床特征无明显统计学相关性,但单因素生存分析显示与患者生存预后呈负相关。     

Recurrent KRAS codon 146 mutations in human colorectal cancer

An activating point mutation in codon 12 of the HRAS gene was the first somatic point mutation identified in a human cancer and established the role of somatic mutations as the common driver of oncogenesis. Since then, there have been over 11,000 mutations in the three RAS (HRAS, KRAS and NRAS) genes in codons 12, 13 and 61 reported in the literature. We report here the identification of recurrent somatic missense mutations at alanine 146, a highly conserved residue in the guanine nucleotide binding domain. In two independent series of colorectal cancers from Hong Kong and the United States we detected KRAS A146 mutations in 7/126 and 2/94 cases, respectively, giving a combined frequency of 4%. We also detected KRAS A146 mutations in 2/40 (5%) colorectal cell lines, including the NCI-60 colorectal cancer line HCC2998. Codon 146 mutations thus are likely to make an equal or greater contribution to colorectal cancer than codon 61 mutations (4.2% in our combined series, 1% in the literature). Lung adenocarcinomas and large cell carcinomas did not show codon 146 mutations. We did, however, identify a KRAS A146 mutation in the ML-2 acute myeloid leukemia cell line and an NRAS A146 mutation in the NALM-6 B-cell acute lymphoblastic leukemia line, suggesting that the contribution of codon 146 mutations is not entirely restricted to colorectal cancers or to KRAS.     

肺腺癌患者EGFR和KRAS基因突变与预后的相关性研究

目的 探讨肺腺癌患者表皮生长因子受体(EGFR)和KRAS基因突变与预后的相关性.方法 选取134例肺腺癌患者的肺腺癌组织标本,应用探针扩增阻滞突变系统在PCR仪上进行EGFR和KRAS基因突变检测,分析EGFR和KRAS基因突变与肺腺癌患者临床病理特征及预后的关系.结果 134例患者中,EGFR基因突变53例,突变率为39.55%,KRAS基因突变6例,突变率为4.48%.肺腺癌患者EGFR基因突变率与年龄、吸烟史有关(P﹤0.01).EGFR基因突变型患者的KRAS基因突变率低于EGFR基因野生型患者(P﹤0.05).EGFR基因突变型患者的无进展生存期(PFS)长于EGFR基因野生型患者(P﹤0.05),KRAS基因野生型患者的PFS长于KRAS基因突变型患者(P﹤0.05).结论 EGFR基因突变的肺腺癌患者KRAS基因更倾向于野生型,EGFR基因突变型或KRAS基因野生型的肺腺癌患者PFS更长.     

Impacts of elevated level of hCG in serum on clinical course and radiotherapy results in the histology-confirmed intracranial germinomas

The prognosis of intracranial germinoma producing the human chorionic gonadotropin (hCG) is controversial due to limited information. We undertook a retrospective analysis to determine whether this type of tumor has similar clinical course and prognosis to hCG non-secreting germinoma. Thirty-one histologically confirmed intracranial germinoma patients who had pretreatment hCG examination in serum/CSF were treated with radiotherapy between 1980 and 1996. hCG level was measured by immunoradioassay of beta subunit of hCG. Six patients had elevated serum hCG levels and were defined as having hCG secreting germinoma. All except three patients received craniospinal axis irradiation. The follow-up ranged from 19-175 months with a median of 63 months. hCG secreting germinoma accounted for 19% of intracranial germinoma cases. Elevated hCG levels ranged from 39-260 IU/l in serum. No difference was found between hCG non-secreting germinoma and hCG secreting germinoma in terms of patient or treatment characteristics. There was no recurrence among the six hCG secreting germinoma patients. The 5-year overall and disease-free survival rates were 96% for patients with hCG non-secreting germinomas and 100% for the patients with hCG secreting germinomas. The survival difference was not significant (p = 0.59). Our results suggest that elevated level of hCG did not result in any differences in the clinical characteristics or survival after radical radiotherapy in histologically confirmed intracranial germinoma.     

Radiation therapy for intracranial germ cell tumors

PURPOSE: To review the combined experiences of University of California, San Francisco, and Stanford University Medical Center in the treatment of intracranial germ cell tumors (GCT) and to assess the impact of craniospinal radiation (CSI) on patterns of relapse, progression-free survival (PFS), and overall survival (OS). PATIENTS AND METHODS: Ninety-three patients received radiation for newly diagnosed intracranial GCTs, including 49 germinomas, 16 nongerminomatous GCTs (NGGCT), and 28 with no biopsy. Median follow-up for surviving patients was 4.5 years (range 0.25-34). Tests for variables correlating with OS and PFS were conducted using Cox proportional hazards model. RESULTS: Five-year PFS and OS rates were 60% +/- 15% and 68% +/- 14% for patients with NGGCT and 88% +/- 5% and 93% +/- 4% for those with germinoma. Of 6 patients with localized NGGCT who did not receive CSI, 1 experienced an isolated spinal recurrence but was salvaged. Of 41 patients with localized germinoma, 6 who received CSI and 35 who did not, no isolated spinal cord relapses occurred. Twenty-one patients with localized germinoma received neither CSI nor whole brain radiation. Of these, none of 18 with ventricular radiation relapsed. One of 3 patients with primary tumor radiation relapsed intracranially but had only received 11 Gy at initial treatment. On multivariate analysis, germinoma histology but not CSI correlated with improved PFS and OS. CONCLUSION: CSI is not indicated in the treatment of localized germinomas. For patients with localized germinomas treated with radiation alone, we recommend ventricular irradiation followed by primary tumor boost to a total of 45-50 Gy.