John Wen-Cheng Chang

Reversed mutation rates of KRAS and EGFR genes in adenocarcinoma of the lung in Taiwan and their implications.

In western countries, the Kirsten ras oncogene homolog gene (KRAS) mutation rate is high in patients with nonsmall cell lung cancer (NSCLC), especially in those with adenocarcinoma (30%‐50%), but the epidermal growth factor receptor gene (EGFR) mutation rate is very low (3%‐8%). In addition, KRAS mutations reportedly were associated with EGFR tyrosine kinase inhibitor (EGFR‐TKI) resistance. In Taiwan, high EGFR mutation rates associated with high EGFR‐TKI response rates in patients with NSCLC have been reported; however, KRAS mutation data are limited and have not been correlated with TKI response.

Adequacy and complications of computed tomography-guided core needle biopsy on non-small cell lung cancers for epidermal growth factor receptor mutations demonstration: 18-gauge or 20-gauge biopsy needle

INTRODUCTION To compare adequacy of tissue acquisition for EGFR DNA mutation analysis and the resulting complications in CT-guided lung biopsy cases with either 18-gauge or 20-gauge core biopsy needle. METHODS Forty-seven patients with advanced staged non-small cell lung cancers who were failure-treated by conventional chemotherapy were retrospectively reviewed. All had received CT-guided core needle lung biopsy for histology diagnosis and freshly frozen for EGFR mutation analysis before targeted therapy. We compared the complications resulting from these CT-guided lung biopsies and the specimen assessment using 18-gauge (32 patients) or 20-gauge (15 patients) biopsy needle via 17-gauge or 19-gauge coaxial needle. RESULTS With an overall pneumothorax rate of 12.8%, pneumothorax occurred in 12.5% and 13.3% of patients by 17-gauge and 19-gauge coaxial needles respectively. The overall rate of hemoptysis was 6.4%, with 6.3% by 18-gauge biopsy needle and 6.6% by 20-gauge biopsy needle. Large peritumoral hemorrhage revealed only in 2 cases of those completed with 18-gauge biopsy needles. 18-gauge biopsy needle obtained larger specimens with heavier weight (average 10.15mg vs 9mg) and higher DNA concentration (average 47.13ng/ul vs 35.92ng/ul) than 20-gauge biopsy needle. Otherwise, the range of optical density (1.67-2.09) was more constant in the specimens by 20-gauge biopsy needles. Mutation demonstration was achieved for all samples. CONCLUSION CT-guided core needle biopsy is a feasible technique in acquisition of fresh cancer tissues for EGFR gene mutation analysis. The specimen is adequate for gene demonstration either using 18-gauge or 20-gauge tru-cut biopsy needles via 17-gauge or 19-gauge coaxial needles.

Prognostic Implications of Epidermal Growth Factor Receptor and KRAS Gene Mutations and Epidermal Growth Factor Receptor Gene Copy Numbers in Patients with Surgically Resectable Non-small Cell Lung Cancer in Taiwan

Introduction: The prognostic role of epidermal growth factor receptor (EGFR) mutations in patients with surgically resectable non-small cell lung cancer (NSCLC) without EGFR tyrosine kinase inhibitor treatment has not been well established, because the reports are still few. Materials and Methods: We analyzed the survival data of 164 patients with surgically resectable (stages I to IIIA) NSCLC of two year groups (1996–1998 and 2002–2004), and compared with EGFR mutations, KRAS mutations, and EGFR gene copy numbers. Results: Comparing the survival of wild-type patients and patients having L858R mutations or exon 19 deletion, the median survival was much longer for patient with EGFR mutations (54.7 months) than wild type (34.9 months). The difference was not statistically significant by univariate analysis (p = 0.1981) but had borderline significance by multivariate analyses (p = 0.0506). In addition, the 3-year survival rates of patients with EGFR mutations were also significantly higher than wild type (p = 0.0232). After exclusion of 18 patients treated by EGFR-tyrosine kinase inhibitor for tumor recurrence, the trends were still the same. Patients with KRAS mutations had shorter median survival (21 months) than wild type (44.4 months). Patients with EGFR polysomy (≧copies) also had longer median survival (56.2 months) than wild type (53.4 months). But the survival differences of these two genetic markers were all not significant statistically. Conclusion: It is intriguing that patients with NSCLC with EGFR mutations had better survival than wild type. Such a tumor biology may confound the survival data in a study without the stratification by EGFR mutation.

Increased epidermal growth factor receptor (EGFR) gene copy number is strongly associated with EGFR mutations and adenocarcinoma in non-small cell lung cancers: A chromogenic in situ hybridization study of 182 patients

SUMMARY To evaluate the association of epidermal growth factor receptor (EGFR) gene copy number with EGFR and k-ras mutation status and tyrosine kinase inhibitor (TKI) sensitivity in non-small cell lung cancer (NSCLC), EGFR gene copy number of 182 NSCLC tumor specimens were analyzed by chromogenic in situ hybridization (CISH). EGFR and k-ras mutation analyses were also performed for, respectively, 176 and 157 of the 182 patients. Additionally, 36 patients in this study had received TKI monotherapy. The tumor was considered to be CISH positive if the gene copy number was >or=5 signals per nucleus in >or=40% of tumor cells. CISH-positive tumors were strongly associated with adenocarcinoma (56.8%) compared with squamous cell carcinoma (15.9%) (p<0.0001). The CISH-positive tumors were also strongly associated with EGFR mutations (78%) compared with wild type (20.2%) (p<0.0001). Only six tumors had k-ras mutations. None had EGFR mutation and only one was CISH positive. In the patients treated with TKI, EGFR mutation was strongly associated with TKI responsiveness (22/25 responders) (p<0.0001), but the CISH-positive tumors were only marginally significant (18/25 responders) (p=0.0665). Patients with EGFR mutations or CISH-positive tumors were all associated with longer median survival, although not statistically significant. Our results suggest Increased EGFR copy number was highly correlated with EGFR mutation in adenocarcinoma. Although it is less correlated with TKI responsiveness when compared with EGFR mutations, it still could be a good alternative molecular predictive marker for TKI responsiveness, since CISH can be done on paraffin section and is much quicker than DNA sequencing.

Computed Tomography-Guided Core-Needle Biopsy Specimens Demonstrate Epidermal Growth Factor Receptor Mutations in Patients with Non-Small-Cell Lung Cancer

Background: Target therapy with a new class of epidermal growth factor receptor (EGFR) inhibitors shows improved clinical response in EGFR gene-mutated lung cancers. Purpose: To evaluate the use of computed tomography (CT)-guided core-needle biopsy specimens for the assessment of EGFR gene mutation in non-small-cell lung cancer (NSCLC). Material and Methods: Seventeen (nine males, eight females) patients with advanced NSCLC were enrolled in this study. All patients underwent CT-guided core-needle biopsy of the lung tumor prior to treatment with the EGFR inhibitor gefitinib. There were no life-threatening complications of biopsy. The specimens were sent fresh-frozen for EGFR mutation analysis and histopathological study. Results: There were 12 (70.6%) EGFR gene mutants and five (29.4%) nonmutants. The objective response rate to gefitinib therapy was 73.3% (11 of 15 patients), with 91.7% (11 of 12 mutants) for the mutant group and 0% for the nonmutant group. Conclusion: CT-guided core-needle biopsy of advanced NSCLC enables the acquisition of sufficient tissue for EGFR gene mutation analysis.

Histopathological and CT Features of Pulmonary Sclerosing Haemangiomas

AIM To demonstrate the computed tomography (CT) features of pulmonary sclerosing haemangiomas. MATERIALS AND METHODS Six pathologically proven sclerosing haemangiomas were included in this retrospective review. Patients consisted of five women and one man aged 20-54 years (mean, 34.5 years). Their CT features were recorded according to enhancement patterns and the presence of a tail sign, prominent pulmonary artery sign, air-trapping sign, presence of calcification or cystic spaces, consolidation, and interstitial infiltration. The predominant composition of an individual sclerosing haemangioma was documented by means of microscopy. RESULTS Inhomogeneous enhancement was frequently present and depended on the various compositions of the tumours, especially those in sclerotic and predominantly papillary predominant types. The presence of a tail sign, intra-tumoural cystic areas, and a prominent artery sign were the frequent features in our cases. CONCLUSION Sclerosing haemangioma should be considered in young or middle-aged female patients whose CT images show them having an inhomogeneous enhancing soft tissue mass with a smooth outline and with above the aforementioned features.

Omega-3 fatty acid-, micronutrient-, and probiotic-enriched nutrition helps body weight stabilization in head and neck cancer cachexia

OBJECTIVE To evaluate whether an oral nutritional supplement enriched with omega-3 fatty acids, micronutrients, and probiotics affected body weight (BW) changes, serum albumin and prealbumin levels in patients with head and neck cancer (HNC) cachexia. STUDY DESIGN Sixty-eight HNC patients were randomly assigned to receive either an Ethanwell/Ethanzyme (EE) regimen enriched with omega-3 fatty acids, micronutrients, and probiotics, or control (Isocal) for a 3-month period. Analysis of covariance was used to examine the association between BW change and variables. RESULTS Patients with body mass index (BMI) <19 and those receiving the EE regimen consumed fewer daily calories but showed significantly increased BW and maintained higher serum albumin and prealbumin levels than other patients (P<.05). Their BW changes were significantly associated with changes in serum albumin and prealbumin levels. CONCLUSIONS EE regimen improved BW as well as serum albumin and prealbumin levels in HNC patients with BMI <19.

Sunitinib in metastatic renal cell carcinoma: An ethnic Asian subpopulation analysis for safety and efficacy

We evaluated and compared the safety and efficacy of sunitinib in Asian and non‐Asian patients with metastatic renal cell carcinoma enrolled in a previously reported global expanded access program.

Clinical Implications of High MET Gene Dosage in Non-Small Cell Lung Cancer Patients without Previous Tyrosine Kinase Inhibitor Treatment

Introduction: Recently, two studies revealed that MET amplification was associated with secondary epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC) patients. But it remains uncertain whether MET amplification could be related to primary TKI resistance in NSCLC because of limited data. Materials and Methods: MET gene dosage of the tumor tissues from 208 NSCLC patients was investigated by real time quantitative polymerase chain reaction and compared with molecular and clinical features, including EGFR mutations, KRAS mutations, EGFR gene copy numbers, and patient survivals. Three copies were used as the cutoff. Among them, 25 patients were also evaluable for EGFR TKI responsiveness. Results: The proportion of high MET gene dosage was 10.58% (22/208) with higher incidence in squamous cell carcinoma (11.86%) and smokers (16.18%), although the differences with adenocarcinoma and nonsmokers were nonsignificant. Coexisting EGFR mutations were identified, and the incidence (8.54%) was similar to wild type (12.0%). High MET gene dosage was significantly associated with higher tumor stage (stage I + II versus stage III + IV; p = 0.0254) and prior chemotherapy for stage III + IV adenocarcinoma patients (35.71% versus 7.41%; p = 0.0145) but not correlated with primary TKI resistance. Among the 155 surgically resectable patients (stage I to IIIA), high MET gene dosage was significantly associated with shorter median survival (21.0 months versus 47.1 months; p = 0.042) by univariate analysis. Conclusions: High MET gene dosage was not related to primary TKI resistance and the incidence was increased after chemotherapy, suggesting high MET gene dosage may also be related to chemotherapy resistance.

Acral Melanoma: A Unique Disease in Asia

Compared with the US melanoma incidence rate of 21.1 per 100 000 population from2006 through 2010, a low incidence rateofmelanoma(≤1/100 000)wasreported inEastAsiancountries includingTaiwan,China, Japan,Korea,HongKong,and Singapore. The most common subtype in these countries was acral lentiginous melanoma, which comprised approximately50%to58%ofcutaneousmelanoma.1-6 Incontrast, acral lentiginousmelanoma represented 2% to 3%of allmelanoma among Western populations. Cutaneous acral lentiginousmelanomausually presents in areaswith little to no sun exposure (such as palms, soles, and nail apparatus). Another sun exposure–independent melanoma is mucosal melanoma, which comprised 22% of melanoma in China in 2011.3 ComparedwithWestern countries, where superficial spreadingmelanomacomprisedapproximately 50%to70%,only approximately 5% to 37% of cutaneous melanoma was superficial spreading melanoma in East Asia, where sun-seeking behavior is not as popular as in Western countries. In Asian countries, cutaneous melanoma tends to be diagnosed at an advanced stageand results in low5-year survival rates (Table). UV light exposure has been implicated as a major etiology in the development of melanoma. The defense mechanisms that protect human skin against UV radiation involve melanin synthesis and active repair mechanisms. DNA is the major target of direct or indirect UV-induced cellular damage. UV-induced DNA photoproducts are able to cause specific mutations in genes susceptible to developing skin cancers. Recent molecular genetic investigations have revealed thatmelanomas fromsun-exposedareas showedfrequentmutations in either theBRAF orNRAS gene. In contrast,BRAF or NRASmutations were infrequent in melanomas arising from non–sun-exposedareas, suchas acral skin,nail apparatus, and mucosa. Instead, these types of melanomas showed a higher degreeof chromosomal aberrations; specifically, genomic amplifications involving small portionsof chromosomearms.7 In acral melanoma, the most frequently amplified region was chromosome 11q13, which contains the CCND1 gene. This region has not been well studied in Asian melanoma. The etiology of acral melanoma in Asia remains to be determined. Inanetiological studyofacralmelanomas fromAustralia, an increased risk was associated with penetrating injuryof the feet orhands (relative risk [RR], 5.0) andwithheavy exposure to agricultural chemicals (RR, 3.6).8 These risk factors could be also true in other Asian countries. In this issue, Jung and coauthors4 reported the characteristics of 177 acral melanomas in Korea. This is an important article that explores thepossiblecausesofacralmelanomainEastAsia.Based on theobservational study, theauthorsdemonstratedahigher incidenceofacralmelanomaatmorephysicallypressuredsites (such as the center area of the heels and inner forefoot) than non–physically pressured areas in the acral skin. The authors also observed that acral melanoma tended to spread along naturally occurring creases of the skin. They concluded that chronic physical pressure could influence the incidence and spreading pattern of acral melanoma. Among the 52 patients that provided their trauma history, 15 (29%) patients had evident histories of previous trauma on their sites ofmelanoma. Thisobservationseemstobeconsistentwith theworkofGreen andcoauthors8 suggesting traumaasa risk factorof acralmelanoma. It should be noted that the study by Jung et al4 is observational. Further research with a case-control study is needed to determine the extent and impact of trauma on the developmentofacralmelanoma.Nonetheless, thestudysheds light on the possible etiology of acral melanoma in East Asia. Related article page 1281