Screening of ROS1 Rearrangements in Lung Adenocarcinoma by Immunohistochemistry and Comparison with ALK Rearrangements

ROS1 rearrangement is a predictive biomarker for response to the tyrosine kinase inhibitor, crizotinib. We investigated the usefulness of ROS1 immunohistochemistry (IHC) for the detection of patients who harbor ROS1 rearrangements in two separate cohorts. We also compared ROS1 IHC with ALK IHC in terms of diagnostic performance to predict each gene rearrangement. In a retrospective cohort, IHC was performed in 219 cases of lung adenocarcinoma with already known genetic alterations. In a prospective cohort, we performed IHC for 111 consecutive cases of lung adenocarcinoma and confirmed the results by subsequent FISH. In the retrospective cohort, all 8 ROS1-rearranged tumors were immunoreactive, and 14 of 211 ROS1-wild cases were immunoreactive (sensitivity 100% and specificity 93.4%). In the prospective cohort, all IHC-negative cases were FISH-negative, and 5 of 34 ROS1 immunoreactive cases were ROS1-rearranged (sensitivity 100% and specificity 72.6%). In ROS1-wild tumors, ROS1 protein was more expressed in the tumors of ever-smokers than in those of never-smokers (p = 0.003). ALK IHC showed 100% sensitivity and 98.1 to 100% specificity in both patient cohorts. In conclusion, ROS1 IHC is highly sensitive, but less specific compared with ALK IHC for detection of the corresponding rearrangement. ROS1 IHC-reactive tumors, especially when the tumor is stained with moderate to strong intensity or a diffuse pattern, are recommended to undergo FISH to confirm the gene rearrangement.     

Clinical Characteristics and Outcomes in Patients with Pulmonary Blastomycosis

Background  Blastomycosis is an uncommon granulomatous infection caused by the thermally dimorphic fungus Blastomyces dermatitidis. The most frequent clinical infections involve the lung, skin, and bone. Pulmonary manifestations range from asymptomatic self-limited infection to severe diffuse pneumonia causing respiratory failure. Objectives  To establish the clinical characteristics and outcomes of patients with pulmonary blastomycosis diagnosed at hospitals in Manitoba and northwestern Ontario, Canada. Methods  A retrospective review of medical records was done for 318 patients with blastomycosis in these regions. Results  The majority of patients were Caucasian (198 (62.5%) patients), male (193 (61%) patients), and residents of Ontario (209 (65.7%) patients). Most patients were treated in an inpatient hospital ward (266 (84%) patients) and survived (294 (92%) patients). Pulmonary involvement, either alone or associated with other sites, was present in 296 (93%) of the 318 patients; 22 (7%) patients had no evidence of pulmonary blastomycosis. The majority of patients had localized lung disease (1–3 quadrants on chest radiograph involved; 225 (82%) patients). Of 294 (92%) patients requiring hospitalization, 266 (90%) patients received all inpatient care on a general medical ward; 28 (10%) patients received some care in the intensive care unit (ICU). Factors associated with ICU admission included diffuse pulmonary disease (four quadrants involved on chest radiograph), diabetes, and prior use of antimicrobial therapy. Twenty-four (8%) patients died, and multivariate analysis showed that older age and Aboriginal ethnicity were the significant risk factors for death from blastomycosis. Conclusion  Blastomycosis is a cause of serious, potentially life-threatening pulmonary infection in this geographic region. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Prevalence and Clinicopathological Characteristics of HER2 and BRAF Mutation in Chinese Patients with Lung Adenocarcinoma

Aims

To determine the prevalence and clinicopathological characteristics of BRAF V600E mutation and HER2 exon 20 insertions in Chinese lung adenocarcinoma (ADC) patients.

Methods

Given the fact that the driver mutations are mutually exclusive in lung ADCs, 204 EGFR/KRAS wild-type cases were enrolled in this study. Direct Sanger sequencing was performed to examine BRAF V600E and HER2 exon 20 mutations. The association of BRAF and HER2 mutations with clinicopathological characteristics was statistically analyzed.

Results

Among the 204 lung ADCs tested, 11 cases (5.4%) carried HER2 exon 20 insertions and 4 cases (2.0%) had BRAF V600E mutation. HER2 mutation status was identified to be associated with a non-smoking history (p<0.05). HER2 mutation occurs in 9.4% of never smokers (10/106), 8.7% of female (8/92) and 2.7% of male (3/112) in this selected cohort. All four BRAF mutated patients were women and three of them were never-smokers. No HER2 mutant patients harbor BRAF mutation.

Conclusions

HER2 and BRAF mutations identify a distinct subset of lung ADCs. Given the high prevalence of lung cancer and the availability of targeted therapy, Chinese lung ADC patients without EGFR and KRAS mutations are recommended for HER2 and BRAF mutations detection, especially for those never smokers.     

Clinical Characteristics and Treatment Outcomes of Patients with Low- and High-Concentration Isoniazid-Monoresistant Tuberculosis

Background

Isoniazid (INH) resistance is now the most common type of tuberculosis (TB) infection resistance worldwide. The aim of this study was to evaluate the clinical characteristics and treatment outcomes of patients with low- and high-concentration INH-monoresistant TB.

Methods

One hundred and thirty-four patients with culture-confirmed INH-monoresistant TB during 2006 January to 2007 December were retrospectively enrolled. INH resistance was classified as either low-concentration or high-concentration resistance according to the critical concentrations of 0.2 µg/mL or 1 µg/mL of INH, respectively. The patients’ clinical outcomes, treatment regimens, and treatment duration were analyzed.

Results

The treatment success rates between low- and high-concentration INH-resistant TB were similar (81.8% vs. 86.7%). The treatment regimens and treatment duration were similar between both groups. Only a minor percentage of the patients in both groups received 6-month treatment regimens (low vs. high concentration resistance, 9.1% vs. 13.3%; respectively, p = 0.447) The most common reason for treatment duration longer than 6 months was pyrazinamide given for less than 6 months, followed by a delay in clinical response to treatment. Multivariable analysis showed that prior tuberculosis treatment (Odds ratio, 2.82, 95% C.I., 1.02–7.77, p = 0.045) was the only independent risk factor for unsuccessful treatment outcome.

Conclusion

Different levels of INH resistance did not affect the treatment outcomes of patients with INH-monoresistant tuberculosis. Prolonged Rifampin-containing regimens may achieve those good outcomes in patients with low- and high-concentration INH-monoresistant TB.     

Clinical Outcomes of Patients with Resected Oral Cavity Cancer and Simultaneous Second Primary Malignancies

Objectives

Simultaneous second primary tumors (SSPT) are not uncommon in patients with oral cavity squamous cell carcinoma (OSCC) living in areas where the habit of betel quid chewing is widespread. We sought to identify the main prognostic factors in OSCC patients with SSPT and incorporate them into a risk stratification scheme.

Methods

A total of 1822 consecutive patients with primary OSCC treated between January 1996 and February 2014 were analyzed for the presence of SSPT. The 18-month and 5-year overall survival (OS) rates served as the main outcome measures.

Results

Of the 1822 patients, 77 (4%) were found to have SSPT (i.e, two malignancies identified within one month of each other). The 18-month and 5-year OS rates in patients without SSPT and with SSPT were 82% and 69%, and 72% and 53%, respectively (p = 0.0063). Patients with SSPT were further divided into patients with either esophageal cancer or hepatocellular carcinoma (eso-HCC subgroup, n = 8) and other tumors (NO eso-HCC subgroup, n = 69). After multivariate analysis, neck nodal extracapsular spread (ECS, n = 18) and the presence of eso-HCC were identified as independent adverse prognostic factors. The 18-month OS rates of SSPT patients with both eso-HCC and ECS (n = 5) vs. the remaining patients (n = 72) were 0% and 78%, respectively (p < 0.0001).

Conclusion

OSCC patients with neck nodal ECS and esophageal cancer or hepatocellular carcinoma as SSPT have a dismal short-term prognosis.     

Unique Characteristics and Outcomes of Patients Diagnosed With Both Primary Thyroid and Primary Renal Cell Carcinoma

Objective: Patients with multiple primary malignancies may exhibit unique clinical characteristics that suggest a common predisposition or lead to different disease management. Given the association of primary thyroid (TC) and renal cell carcinoma (RCC), we characterized the clinicopathologic features of patients treated for both malignancies (TC/RCC).Methods: TC/RCC patients were identified through the institutional tumor registry and using data compiled by retrospective chart review. To compare with broader institutional and national cohorts, we examined patients admitted with TC or RCC institution-wide and reviewed the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program for these cancers.Results: Overall, 51% of patients developed TC before RCC, 27% developed RCC before TC, and 22% were diagnosed within 1 year of each other. The mean age at TC diagnosis was 52 ± 15 (18–77), which was significantly older than institutional TC patients (45 ± 16.5 years, P≤.0001), and the mean age at RCC diagnosis was 59 ± 12 (32–79). The TC/RCC cohort had a balanced sex distribution (51% female) compared with the institutional TC group (67% female, P = .0003) and the institutional RCC group (31% female, P<.0001). Similar age and sex ratio differences were seen when compared with SEER cohorts. In the TC/RCC cohort, 43% of patients developed other cancers (52% of females, 33% of males; P = .04); among the females, 45% developed breast cancer.Conclusion: Individuals who develop both TC and RCC may represent a unique subset of cancer patients. Further prospective research is warranted to explore the unanticipated association with breast cancer in female patients and to investigate a possible common pathogenesis underlying these malignancies.Abbreviations: RCC = renal cell carcinoma SEER = Surveillance, Epidemiology, and End Results SPC = second primary cancer SPTC = subsequent primary thyroid cancer TC = thyroid cancer VHL = von Hippel-Lindau     

Radiologic Predictors for Clinical Stage IA Lung Adenocarcinoma with Ground Glass Components: A Multi-Center Study of Long-Term Outcomes

Objective

This study was to define preoperative predictors from radiologic findings for the pathologic risk groups based on long-term surgical outcomes, in the aim to help guide individualized patient management.

Methods

We retrospectively reviewed 321 consecutive patients with clinical stage IA lung adenocarcinoma with ground glass component on computed tomography (CT) scanning. Pathologic diagnosis for resection specimens was based on the 2011 IASLC/ATS/ERS classification of lung adenocarcinoma. Patients were classified into different pathologic risk grading groups based on their lymph node status, local regional recurrence and overall survival. Radiologic characteristics of the pulmonary nodules were re-evaluated by reconstructed three-dimension CT (3D-CT). Univariate and multivariate analysis identifies independent radiologic predictors from tumor diameter, total volume (TV), average CT value (AVG), and solid-to-tumor (S/T) ratio. Receiver operating characteristic curves (ROC) studies were carried out to determine the cutoff value(s) for the predictor(s). Univariate cox regression model was used to determine the clinical significance of the above findings.

Results

A total of 321 patients with clinical stage IA lung adenocarcinoma with ground glass components were included in our study. Patients were classified into two pathologic low- and high- risk groups based on their distinguished surgical outcomes. A total of 134 patients fell into the low-risk group. Univariate and multivariate analyses identified AVG (HR: 32.210, 95% CI: 3.020–79.689, P<0.001) and S/T ratio (HR: 12.212, 95% CI: 5.441–27.408, P<0.001) as independent predictors for pathologic risk grading. ROC curves studies suggested the optimal cut-off values for AVG and S/T ratio were-198 (area under the curve [AUC] 0.921), 2.9 (AUC 0.996) and 54% (AUC 0.907), respectively. The tumor diameter and TV were excluded for the low AUCs (0.778 and 0.767). Both the cutoff values of AVG and S/T ratio were correlated with pathologic risk classification (p<0.001). Univariate Cox regression model identified clinical risk classification (RR: 3.011, 95%CI: 0.796–7.882, P = 0.095) as a good predictor for recurrence-free survival (RFS) in patients with clinical stage IA lung adenocarcinoma. Statistical significance of 5-year OS and RFS was noted among clinical low-, moderate- and high-risk groups (log-rank, p = 0.024 and 0.010).

Conclusions

The AVG and the S/T ratio by reconstructed 3D-CT are important preoperative radiologic predictors for pathologic risk grading. The two cutoff values of AVG and S/T ratio are recommended in decision-making for patients with clinical stage IA lung adenocarcinoma with ground glass components.     

Pulmonary Sarcomatoid Carcinoma with ALK Rearrangement: Frequency,Clinical-Pathologic Characteristics,and Response to ALK Inhibitor

PURPOSE: The incidence of anaplastic lymphoma kinase (ALK) rearrangement in pulmonary sarcomatoid carcinoma (PSC) is controversial. In this study, we aimed to reveal the reliable frequency and the clinical-pathologic characteristics of pulmonary sarcomatoid carcinoma (PSC) with ALK rearrangement in Chinese population, and to provide insight into the translatability of anti-ALK treatment in this treatment-refractory disease. METHODS: Immunohistochemistry (IHC) using a Ventana anti-ALK (D5F3) rabbit monoclonal antibody was performed in 141 PSC specimens collected from multiple medical centers. IHC-positive cases were then confirmed using ALK fluorescent in situ hybridization (FISH). The incidence rates and clinical-pathologic characteristics of ALK-rearranged PSC were then analyzed. Response to ALK inhibitor crizotinib in a patient with ALK-rearranged PSC was evaluated according to the response evaluation criteria for solid tumors (RECIST) version 1.1. RESULTS: Five of 141 (3.5%) of PSCs showed ALK rearrangement-positive by IHC and then were confirmed by FISH. Two were carcinosarcomas and the other three were pulmonary pleomorphic carcinoma (PPC). Strong positive ALK rearrangement was observed in both the epithelioid and sarcomatoid components. The median age of ALK-positive patients was younger than that of ALK-negative patients. PSCs in never-smokers were more likely to harbor ALK rearrangement than those in former or current smokers (P < .05). A 40-year-old woman diagnosed with ALK-rearranged PPC experienced a partial response (?32%) to the ALK inhibitor crizotinib. CONCLUSIONS: The incidence rates of ALK rearrangement in PSC in the Chinese population are similar to those of other subtypes of NSCLC. PSCs in younger never-smokers are more often to harbor ALK rearrangement. ALK inhibitors may serve as an effective treatment for ALK-rearranged PSC.     

Clinical Characteristics and Outcomes of Candidemia Caused by Meyerozyma guilliermondii Complex in Cancer Patients Undergoing Surgery

Although Meyerozyma guilliermondii complex is an uncommon cause of invasive candidiasis worldwide, reported cases, mainly regarding bloodstream infections, increased over years, and patients with cancer who have undergone recent surgery are most commonly affected. However, the clinical characteristics and outcomes of candidemia caused by M. guilliermondii complex remain poorly understood. A retrospective case–control study was conducted to evaluate the clinical characteristics and mortality of candidemia caused by M. guilliermondii complex in cancer patients undergoing surgery. Demographic and clinical data were collected from the hospital medical records system with a standardized data collection form and were analyzed with SPSS 20.0. Sixty-six cancer patients who have undergone recent surgery and were diagnosed with candidemia caused by M. guilliermondii complex were included in the study. Regarding the clinical manifestations, most patients’ body temperatures ranged from 38 to 40 °C, with a median fever duration of 4 (IQR: 3–6) days. Multivariate analysis indicated that the presence of central venous catheter (OR: 6.68; 95% CI 2.80–15.94) and gastric tube (OR: 3.55; 95% CI 1.22–10.34) were independent risk factors for M. guilliermondii complex fungemia. The 30-day crude mortality of candidemia caused by M. guilliermondii complex was 12.1%, twice that of the control group. Moreover, increased WBC count, age ≥?60 years, septic shock, and ICU admission were identified as predictors of mortality through univariate analysis. These findings will provide a foundation for the clinical management of candidemia caused by M. guilliermondii complex in post-surgical cancer patients.

     

The Frequency and Clinical Implication of ROS1 and RET Rearrangements in Resected Stage IIIA-N2 Non-Small Cell Lung Cancer Patients

To evaluate the frequency and clinicopathological features of ROS1 and RET rearrangements in N2 node positive stage IIIA (IIIA-N2) non-small cell lung cancer (NSCLC) patients, we retrospectively screened 204 cases with a tissue microarray (TMA) panel by fluorescent in situ hybridization (FISH), and confirmed by direct sequencing and immunohistochemistry (IHC). The relationship between ROS1 or RET rearrangements, clinicopathological features, and prognostic factors were analyzed in resected stage IIIA-N2 NSCLC. Of the 204 cases, 4 cases were confirmed with ROS1 rearrangement, but no RET rearrangement was detected. All 4 ROS1-rearranged cases were adenocarcinomas. The predominant pathological type was acinar pattern in ROS1-rearranged tumors, except for 1 case harboring a mixture acinar and mucous tumor cells. Variants of ROS1 rearrangement were SDC4-ROS1 (E2:E32), SDC4-ROS1 (E4:E32) and SDC4-ROS1 (E4:E34). There was no significant association between ROS1 rearrangement and clinicopathological characteristics. In this cohort, multivariate analysis for overall survival (OS) indicated that squamous cell carcinoma and lobectomy were independent predictors of poor prognosis; R0 surgical resection and non-pleural invasion were independent predictors of good prognosis. In resected stage IIIA-N2 NSCLC patients, ROS1-rearranged cases tended to occur in younger patients with adenocarcinomas. The prognosis of resected stage IIIA-N2 is generally considered poor, but patients with ROS1 rearrangement will benefit from the targeted therapy.     

顺铂联合多西他赛、培美曲塞及吉西他滨治疗晚期肺腺癌的临床效果比较

目的:比较吉西他滨、培美曲塞、多西他赛联合顺铂三种化疗方案治疗晚期肺腺癌患者的近期疗效与安全性。方法:选择2014年7月至2015年8月在本院肿瘤科住院的经病理或细胞学证实为ⅢB~Ⅳ期肺腺癌的患者共140例,随机分为三组,分别采用多西他赛+顺铂(多西他赛组,n=38)、培美曲塞+顺铂(培美曲塞组,n=56)、吉西他滨+顺铂(吉西他滨组,n=46)三种化疗方案。对三组患者的近期疗效和Ⅲ、Ⅳ度毒性反应的发生情况进行比较。结果:吉西他滨组无完全缓解(CR)患者,部分缓解(PR)患者20例,稳定(SD)患者16例,进展(PD)患者10例,总有效率(RR)43.5%,疾病控制率(DCR)为78.3%;多西他赛组无CR患者,PR患者16例,SD患者12例,PD患者10例,RR42.1%,DCR73.7%;培美曲塞组无CR患者,PR患者28例,SD患者20例,PD患者8例,RR50.0%,DCR为85.7%。三组患者RR及DCR相比较差异无统计学意义(P0.05)。三组化疗方案的主要毒副反应为骨髓抑制,无Ⅲ~Ⅳ度皮疹和末梢神经炎等毒性反应发生。其中,培美曲塞组的严重骨髓抑制即Ⅲ度+Ⅳ度白细胞减少、中性粒细胞减少及血小板减少的发生率明显低于吉西他滨组和多西他赛组(P0.05)。三组化疗方案Ⅲ度+Ⅳ度血红蛋白下降、胃肠道反应、脱发、肝肾功能异常等毒性反应的发生率相比较差异均无显著性(P0.05)。结论:培美曲赛、多西他赛、吉西他滨联合顺铂方案治疗晚期肺腺癌的疗效相当,但培美曲塞组安全性更高。     

The Molecular Detection and Clinical Significance of ALK Rearrangement in Selected Advanced Non-Small Cell Lung Cancer: ALK Expression Provides Insights into ALK Targeted Therapy

Background

This study aimed to elucidate clinical significance of anaplastic lymphoma kinase (ALK) rearrangement in selected advanced non-small cell lung cancer (NSCLC), to compare the application of different ALK detection methods, and especially evaluate a possible association between ALK expression and clinical outcomes in crizotinib-treated patients.

Methods

ALK status was assessed by fluorescent in situ hybridization (FISH), immunohistochemistry (IHC) and quantitative RT-PCR (qRT-PCR) in 173 selected advanced NSCLC patients. Clinicopathologic data, genotype status and survival outcomes were analyzed. Moreover, the association of ALK expression with clinical outcomes was evaluated in ALK FISH-positive crizotinib-treated patients including two patients with concurrent epidermal growth factor receptor (EGFR) mutation.

Results

The positivity detection rate of ALK rearrangement by FISH, IHC and qRT-PCR was 35.5% (59/166), 35.7% (61/171), and 27.9% (34/122), respectively. ALK rearrangement was observed predominantly in young patients, never or light smokers, and adenocarcinomas, especially with signet ring cell features and poor differentiation. Median progression-free survival (PFS) of crizotinib-treated patients was 7.6 months. The overall survival (OS) of these patients was longer compared with that of crizotinib-naive or wild-type cohorts, but there was no significant difference in OS compared with patients with EGFR mutation. ALK expression did not associate with PFS; but, when ALK expression was analyzed as a dichotomous variable, moderate and strong ALK expression had a decreased risk of death (P = 0.026). The two patients with concomitant EGFR and ALK alterations showed difference in ALK expression, response to EGFR and ALK inhibitors, and overall survival.

Conclusions

Selective enrichment according to clinicopathologic features in NSCLC patients could highly improve the positivity detection rate of ALK rearrangement for ALK-targeted therapy. IHC could provide more clues for clinical trial design and therapeutic strategies for ALK-positive NSCLC patients including patients with double genetic aberration of ALK and EGFR.