New evaluation of the tumor immune microenvironment of non-small cell lung cancer and its association with prognosis.

BACKGROUND: A better understanding of the tumor immune microenvironment (TIME) will facilitate the development of prognostic biomarkers and more effective therapeutic strategies in patients with lung cancer. However, little has been reported on the comprehensive evaluation of complex interactions among cancer cells, immune cells, and local immunosuppressive elements in the TIME. METHODS: Whole-exome sequencing and RNA sequencing were carried out on 113 lung cancers. We performed single sample gene set enrichment analysis on TIME-related gene sets to develop a new scoring system (TIME score), consisting of T-score (tumor proliferation), I-score (antitumor immunity) and S-score (immunosuppression). Lung cancers were classified according to a combination of high or low T-score, I-score, and S-scores (eight groups; G1-8). Clinical and genomic features, and immune landscape were investigated among eight groups. The external data sets of 990 lung cancers from The Cancer Genome Atlas and 76 melanomas treated with immune checkpoint inhibitors (ICI) were utilized to evaluate TIME scoring and explore prognostic and predictive accuracy. RESULTS: The representative histological type including adenocarcinoma and squamous cell carcinoma, and driver mutations such as epidermal growth factor receptor and TP53 mutations were different according to the T-score. The numbers of somatic mutations and predicted neoantigens were higher in Thi (G5-8) than Tlo (G1-4) tumors. Immune selection pressure against neoantigen expression occurred only in Thi and was dampened in Thi/Ilo (G5-6), possibly due to a reduced number of T cells with a high proportion of tumor specific but exhausted cells. Thi/Ilo/Shi (G5) displayed the lowest immune responses by additional immune suppressive mechanisms. The T-score, I-score and S-scores were independent prognostic factors, with survival curves well separated into eight groups with G5 displaying the worst overall survival, while the opposite group Tlo/Ihi/Slo (G4) had the best prognosis. Several oncogenic signaling pathways influenced on T-score and I-scores but not S-score, and PI3K pathway alteration correlated with poor prognosis in accordance with higher T-score and lower I-score. Moreover, the TIME score predicted the efficacy of ICI in patients with melanoma. CONCLUSION: The TIME score capturing complex interactions among tumor proliferation, antitumor immunity and immunosuppression could be useful for prognostic predictions or selection of treatment strategies in patients with lung cancer.

Group B streptococcal empyema necessitatis with pleural fistula after blunt trauma: A case report.

INTRODUCTION: We report the first case of empyema necessitatis (EN) with pleural fistula and septic arthritis caused by Streptococcus agalactiae following blunt trauma. PRESENTATION OF THE CASE: A 46-year-old man with diabetes mellitus and a history of recent right rib fracture and right knee bruising presented with dyspnea and right knee pain. He was diagnosed with EN and underwent chest drainage, followed by open-window thoracotomy. Septic arthritis occurred on day 8 after thoracotomy. The chest wall wound healed after 3 months. DISCUSSION: EN is a rare complication of empyema. In this patient, infection was invasive, causing necrotizing pneumonia with a pleural fistula. To our knowledge, there are no reports of group B streptococcal EN with a pleural fistula resulting from blunt chest trauma. CONCLUSION: Group B streptococcal infection might become invasive in immunocompromised patients, so careful follow-up for those patients is important.

Subxiphoid approach for extracting a giant solitary fibrous tumour of the pleura.

We describe a case of resection of a solitary fibrous tumour of the pleura using video-assisted thoracic surgery and removal of the giant tumour using a subxiphoid incision without the need for minithoracotomy. Use of the subxiphoid approach as a retrieval port is simple and feasible.

Risk assessment of perioperative mortality after pulmonary resection in patients with primary lung cancer: the 30- or 90-day mortality.

OBJECTIVES: Although 30-day mortality rate is adapted to evaluate perioperative mortality after surgery, whether 90-day mortality rate adequately evaluates perioperative mortality remains unknown. Therefore, we analyzed 30- and 90-day mortality rates after pulmonary resection in patients with primary lung cancer. METHODS: A total of 2207 pulmonary resections for primary lung cancer performed between 1996 and 2010 at the Aichi Cancer Center Hospital were analyzed and divided into two groups of almost equal number: the early period group (1070 patients, 1996-2004) and the late period group (1137 patients, 2005-2010). Sixty-six and 34 patients died within a year during the early and late periods, respectively. The causes of death (recurrence, bleeding, sudden death, respiratory failure, and adverse event of chemotherapy), and 30- and 90-day mortality rates were investigated. RESULTS: The 30-/90-day mortality rates in the early and late period groups were 0.56/0.75 and 0.35/0.79 %, respectively. The postoperative survival days of 75 patients who died from recurrence within 1 year after pulmonary resection and 7 patients from bleeding or sudden death were more than 91 days and <30 days, respectively. The median postoperative survival of patients who died from respiratory failure was 67 days (range 20-142 days) in the early period and 100 days (range 47-149 days) in the late period. In the late period, it was difficult to assess perioperative mortality of pulmonary complications with 30-day mortality. CONCLUSIONS: A risk assessment of perioperative mortality after pulmonary resection should be performed using the 30- and 90-day mortality.

Coffee and green tea consumption is associated with upper aerodigestive tract cancer in Japan.

The impact of coffee and green tea consumption on upper aerodigestive tract (UADT) cancer risk has not been established. Evaluation of the possible anticarcinogenic properties of their ingredients is confounded by the potential increase in risk owing to the high temperatures at which these beverages are generally consumed. We conducted a case-control study to evaluate the association between coffee and tea consumption and the risk of UADT cancer. The study enrolled 961 patients with UADT cancer and 2,883 noncancer outpatients who visited Aichi Cancer Center between 2001 and 2005. Information on coffee and green tea consumption and other lifestyle factors was collected via a self-administered questionnaire. Consumption of three or more cups of coffee per day had a significant inverse association with UADT cancer [odds ratio (OR) 0.73, 95% confidence interval (CI) 0.55-0.96]. In contrast, consumption of three or more cups of green tea per day had a significant positive association with UADT cancer (OR 1.39, 95% CI 1.13-1.70). These associations were evident for head and neck cancer but not for esophageal cancer. The association of coffee consumption with head and neck cancer was observed only among never smokers and alcohol drinkers. Similarly, the association of green tea consumption was observed among never smokers and never alcohol drinkers. No change in these associations was seen on stratification by each confounding factors. These findings suggest that consumption of coffee might be associated with a decreased risk of UADT cancer, whereas that of green tea might be associated with an increased risk.

Paravertebral block via the surgical field versus epidural block for patients undergoing thoracotomy: a randomized clinical trial.

PURPOSE: A paravertebral block (PVB) given via the surgical field can be safer and technically simpler than an epidural block (EP) for postoperative pain control. We conducted this clinical trial to confirm the effectiveness of PVB after thoracotomy. METHODS: In this non-inferiority trial, patients were randomly assigned to receive PVB (n = 35) or EP (n = 35). The primary endpoint was the pain assessed using the visual analog scale (VAS) at rest, 2, 24, and 48 h after thoracotomy, with the non-inferiority margin set at 15 mm. The secondary end points were the pain assessed using the VAS on exercising and on coughing, 2, 24, and 48 h after surgery, respectively, and the complications and need for additional analgesic agents. RESULTS: This trial revealed that PVB was not inferior to EP with respect to the primary end point: The mean VAS scores at rest, 2, 24, and 48 h after thoracotomy were 26.3, 10.8, and 8.3 mm in the PVB group and 23.6, 12.4, and 12.6 mm in the EP group, respectively (P < 0.01 for non-inferiority at all points). There were no significant differences between the groups in the incidence of complications or the need for additional analgesic agents. CONCLUSION: PVB may replace EP for postoperative pain control because of its technical simplicity and safety.

How long should small lung lesions of ground-glass opacity be followed?

INTRODUCTION: Pulmonary ground-glass nodules are frequently encountered. The purpose of this study was to evaluate the natural history of them and to gain some insights on how to follow them up. METHODS: We retrospectively studied patients with pulmonary nodules that met the following criteria: (1) tumor diameter of 3 cm or less, (2) ground-glass opacity proportion of 50% or more, and (3) observation without treatment for 6 months or more. Between 1999 and 2012, 108 pulmonary lesions in 61 patients fulfilled these criteria. We reevaluated their computed tomography images and analyzed changes in their size. RESULTS: The tumors were 1 cm or lesser in size in 69 lesions, 1.1 cm to 2 cm in 34, and 2.1 cm to 3 cm in five. The proportion of solid lesions was 0% for 82 lesions, 1% to 25% for 19, and 26% to 50 % for seven. At the median observation period of 4.2 years, 29 lesions had become larger, whereas the remaining 79 had persisted without changing in size (±1 mm). The median size change in the nodules that grew was 7 mm (range, 2-32 mm). All 29 tumors began to grow within 3 years of their first observation: 1 year or lesser in 13 lesions, after 1.1 years to 2 years in 12, and after 2.1 years to 3 years in four. CONCLUSIONS: Some small lung lesions exhibiting ground-glass opacity persisted without changes in size, whereas others grew gradually. The tendency to grow was clear within the first 3 years in all cases. Therefore, we conclude that these lesions should be followed for at least 3 years.

Solitary pulmonary metastasis from lung cancer harboring EML4-ALK after a 15-year disease-free interval.

It is often difficult to differentiate metachronous primary lung cancers from local pulmonary recurrences when the histopathological findings are similar. A 43-year-old man underwent right upper lobectomy with lymph node dissection for primary lung adenocarcinoma (p-T2aN0M0, stage IB). Fifteen years later, he developed a lung nodule in his right middle lobe. The tumor was preoperatively thought to be a metachronous second primary lung adenocarcinoma, and was surgically resected. Histopathological findings for both tumors were of poorly differentiated adenocarcinoma with mucus production. Both tumors also harbored the EML4 (echinoderm microtubule-associated protein-like 4)-ALK (anaplastic lymphoma kinase) fusion gene (variant 3a+b). Based on this molecular finding, the pulmonary nodule was considered to be a recurrence after very long latent period.

Pulmonary metastasectomy for gastric cancer: a 13-year single-institution experience.

PURPOSE: Pulmonary metastases from gastric cancer are rare, and the role of surgery is unclear. The purpose of this study was to determine which patients with metachronous metastatic gastric cancer (MGC) might benefit from pulmonary resection. METHODS: Between 1998 and 2011, 12 patients underwent 14 pulmonary resections for MGC. We reviewed their clinical courses and evaluated their radiological findings. RESULTS: Solitary pulmonary lesions were identified for 11 metastases, and the remaining three showed multiple pulmonary lesions. Six patients received treatment for the metastases before pulmonary resection. Lobectomy was performed for five lesions and wedge resection was performed for the remaining nine lesions. At the median follow-up time of 23.0 months, four patients were alive without disease, and the median DFS following pulmonary resection was 6.6 months. The overall 5-year survival rate following pulmonary resection was 58.4 %. In a univariate analysis, the number of lesions and the tumor doubling time (TDT) were significant predictors of the DFS, although prior treatment was not a significant predictor of the DFS. CONCLUSION: Pulmonary resection for MGC might be an effective therapeutic option when there is a solitary metastatic lesion that has a long TDT, even if the patient has been previously treated for metastases.

Time to first cigarette and upper aerodigestive tract cancer risk in Japan.

BACKGROUND: Cigarette smoking is the major cause for upper aerodigestive tract (UADT) cancers. The time to first cigarette (TTFC) of the day is a distinct indicator of nicotine dependence, but scanty information is available on its possible relation with UADT cancers (oral, oropharyngeal, hypopharyngeal, laryngeal, nasopharyngeal, and esophageal cancers). METHODS: This case-control study includes a total of 1,009 incident UADT cancer cases and 3,027 age- and sex-matched noncancer controls admitted to the Aichi Cancer Center (Nagoya, Japan) between 2001 and 2005. We estimated OR and 95% confidence intervals (CI) for TTFC using logistic regression models after adjustment for several potential confounders. RESULTS: TTFC was inversely related to the risk of UADT cancer, and this association was consistent across subtypes of head and neck cancer and esophageal cancer. For all UADT cancers considered among ever smokers and after accurate allowance for smoking quantity and duration, besides other relevant covariates, compared with TTFC more than 60 minutes, the adjusted ORs were 1.40 (95% CI: 0.93-2.11) for 31 to 60 minutes, 1.76 (95% CI: 1.20-2.58) for 6 to 30 minutes, and 2.43 (95% CI: 1.64-3.61) for within 5 minutes. No significant heterogeneity was found in strata of sex, age, alcohol consumption, fruit and vegetable intake, and occupation for overall and site-specific analysis. CONCLUSION: Nicotine dependence, as indicated by the TTFC, is associated with increased risk of UADT cancers and is therefore an independent marker of exposure to smoking. IMPACT: Our result indicates more detailed risk evaluation of UADT cancers that is enabled by the TTFC.

Clinicoradiologic characteristics of patients with lung adenocarcinoma harboring EML4-ALK fusion oncogene.

INTRODUCTION: The fusion oncogene of echinoderm microtubule-associated protein like 4 (EML4) and anaplastic lymphoma kinase (ALK) defines a new molecular subset of non-small-cell lung cancer. We explored the EML4-ALK gene in a relatively large cohort and reviewed the clinicoradiologic background of the patients. METHODS: We studied 720 patients with lung adenocarcinoma. The clinicopathological characteristics of each patient were compared among the subgroups stratified by the EML4-ALK gene status. For radiographic evaluation, we scored the proportion of the ground-glass opacity (GGO) component and calculated the tumor disappearance rate (TDR) in each tumor in the cohort of 168 patients that were extracted by using a case-matching procedure. RESULTS: Twenty-eight (3.9%) patients harbored the EML4-ALK gene. Younger age (p=0.001), no or light history of smoking (p=0.05) and normal serum carcinoembryonic antigen (CEA) level (p=0.04) were characteristics of the patients with EML4-ALK. No significant difference was observed for overall and disease free survival between the two groups. All but one tumor in the EML4-ALK-positive group exhibited no GGO, whereas half of the tumors (69/140 patients) in the EML4-ALK-negative group exhibited some GGO (p=0.0004). The mean TDRs were 0.33 and 0.54, respectively, which was significantly lower in the positive group (p=0.0006). CONCLUSIONS: We identified younger age, no or light history of smoking, and normal serum CEA as clinical features of patients with EML4-ALK-positive lung adenocarcinoma. In addition, EML4-ALK-positive tumors exhibited a solid pattern on CT. These features may be of value in predicting for patient selection for ALK inhibition therapy in the absence of genetic screening.

Inverse association between yoghurt intake and upper aerodigestive tract cancer risk in a Japanese population.

Although the combination of tobacco smoking and alcohol drinking account for approximately 80% of upper aerodigestive tract (UADT) cancer risk, the role of dietary factors, including dairy products, in the risk of these cancers remains controversial. We aimed to evaluate the association between dairy product intake and UADT cancer risk in a Japanese population. We conducted a case-control study in 959 patients with UADT cancer and 2877 sex- and age-matched noncancer control subjects who visited the Aichi Cancer Center in Nagoya, Japan. Data on lifestyle factors, including diet, were obtained by self-administered questionnaire. Associations were assessed by multivariate logistic regression models that considered potential confounders. We found a significant inverse association between yoghurt intake and UADT cancer risk with multivariate-adjusted odds ratios and 95% confidence intervals for <1 time/week, ≥ 1 time/week and <1 time/day, and ≥ 1 time/day consumption of yoghurt of 0.70 (95% confidence interval: 0.54-0.91), 0.67 (0.54-0.84), and 0.73 (0.55-0.95) relative to nonconsumers (P trend=0.005). When stratified by primary tumor site, this association was significant among patients with hypopharyngeal, laryngeal, and esophageal cancer. However, we saw no significant association between milk or butter intake and UADT cancer risk. In this study, we found that a high intake of yoghurt may lower the risk of developing UADT cancer in a Japanese population. Further investigation of this association is warranted.

Prognostic impact of the 6th and 7th American Joint Committee on Cancer TNM staging systems on esophageal cancer patients treated with chemoradiotherapy.

PURPOSE: The new 7th edition of the American Joint Committee on Cancer TNM staging system is based on pathologic data from esophageal cancers treated by surgery alone. There is no information available on evaluation of the new staging system with regard to prognosis of patients treated with chemoradiotherapy (CRT). The objective of this study was to evaluate the prognostic impact of the new staging system on esophageal cancer patients treated with CRT. METHODS AND MATERIALS: A retrospective review was performed on 301 consecutive esophageal squamous cell carcinoma patients treated with CRT. Comparisons were made of the prognostic impacts of the 6th and 7th staging systems and the prognostic impacts of stage and prognostic groups, which were newly defined in the 7th edition. RESULTS: There were significant differences between Stages I and III (p < 0.01) according to both editions. However, the 7th edition poorly distinguishes the prognoses of Stages III and IV (p = 0.36 by multivariate analysis) in comparison to the 6th edition (p = 0.08 by multivariate analysis), although these differences were not significant. For all patients, T, M, and gender were independent prognostic factors by multivariate analysis (p < 0.05). For the Stage I and II prognostic groups, survival curves showed a stepwise decrease with increase in stage, except for Stage IIA. However, there were no significant differences seen between each prognostic stage. CONCLUSIONS: Our study indicates there are several problems with the 7th TNM staging system regarding prognostic factors in patients undergoing CRT.

Docetaxel plus 5-fluorouracil and cisplatin (DCF) induction chemotherapy for locally advanced borderline-resectable T4 esophageal cancer.

BACKGROUND: This study aimed to evaluate the efficacy of docetaxel plus 5-fluorouracil and cisplatin (DCF) induction chemotherapy for locally advanced borderline-resectable T4 esophageal cancer. PATIENTS AND METHODS: We retrospectively analyzed data regarding thirty patients with borderline-resectable T4 tumor who received either DCF or cisplatin plus 5-fluorouracil (FP) as induction chemotherapy. RESULTS: The overall response rate was significantly better for the DCF group than the FP group. In the DCF group, 6/16 patients achieved a grade 2 histological post-chemotherapeutic effect after treatment, compared to 1/14 in FP group. Except for myelotoxicity, no other significant differences in toxicity were observed during induction chemotherapy between groups. The DCF regimen did not result in increased postoperative complications compared to the FP regimen. Postoperative recurrence or distant metastasis was observed in 7/10 of FP patients and 5/12 of DCF patients. CONCLUSION: DCF induction chemotherapy may be an option for conversion therapy of initially unresectable, locally advanced esophageal cancer.

Inverse association between toothbrushing and upper aerodigestive tract cancer risk in a Japanese population.

BACKGROUND: Oral hygiene is attracting increasing attention as a potential risk factor for cancers. To investigate the association between toothbrushing frequency and upper aerodigestive tract (UADT) cancer, the authors conducted a large-scale case-control study. METHODS: A total of 856 UADT cancer case participants and 2696 age- and sex-matched control subjects without cancer were included. Edentulous or participants with unknown frequency of toothbrushing or number of remaining teeth were excluded. Associations were assessed by odds ratios and 95% confidence intervals in logistic regression models with adjustment for potential confounders. RESULTS: Compared with toothbrushing once per day, the adjusted odds ratio for brushing twice or more was 0.82 (95% confidence interval: 0.68, 0.99) whereas that for not brushing was 1.79 (0.79, 4.05). This association was observed especially in subjects who had a history of heavy smoking or drinking. CONCLUSIONS: The authors suggest that toothbrushing could have a protective effect for UADT cancer.

Serum carcinoembryonic antigen level as a surrogate marker for the evaluation of tumor response to chemotherapy in nonsmall cell lung cancer.

PURPOSE: Carcinoembryonic antigen (CEA) is a tumor marker widely used for nonsmall cell lung cancer (NSCLC). The aim of this study was to evaluate changes in serum CEA levels as a surrogate marker for tumor response to chemotherapy in NSCLC. METHODS: From 1995 through 2005, we retrospectively analyzed 24 NSCLC patients who had high serum CEA levels (>5 ng/ml) and who received chemotherapy followed by surgery. We compared serum CEA levels with tumor response, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) or World Health Organization (WHO) criteria, as well as with histological response. RESULTS: Serum CEA levels after chemotherapy significantly decreased in patients who achieved partial response, defined by RECIST or WHO criteria (p = 0.004 and p = 0.008, respectively), when compared with the CEA levels before chemotherapy. In contrast, there was no significant difference in CEA levels in patients with either stable disease or no response to chemotherapy. They decreased significantly, however, in patients in whom less than one-third of tumor cells was viable by pathological examination, but not in patients in whom more than a third was viable (p = 0.008). Using the receiver-operating characteristic (ROC) curve analysis, we found that a 60% reduction of CEA levels was an appropriate cutoff value in predicting a good response to chemotherapy. When the value was set at that level, the sensitivity of CEA for RECIST was 82%, and the specificity was 69%. CONCLUSION: Serum CEA concentration was a useful surrogate marker for the evaluation of tumor response to chemotherapy and seemed to be comparable with RECIST in NSCLC patients who had elevated CEA levels prior to treatment.

Comparison between self-reported facial flushing after alcohol consumption and ALDH2 Glu504Lys polymorphism for risk of upper aerodigestive tract cancer in a Japanese population.

Some Japanese exhibit facial flushing after drinking alcohol. Facial flushing was considered to be caused by acetaldehydemia. The concentration of blood acetaldehyde was concerned with the catalytic activity of acetaldehyde dehydrogenase (ALDH). Acetaldehyde dehydrogenase (ALDH)-2 polymorphism (rs671, Glu504Lys) was known to be associated with upper aerodigestive tract (UAT) cancer due to modulation of ALDH2 enzyme activity. It remains controversial whether facial flushing is useful in predicting UAT cancer risk as a surrogate marker of ALDH2 polymorphism. We conducted a case-control study to assess the risk of UAT cancer and facial flushing and ALDH2 polymorphism. Cases and controls were 585 UAT cancer patients and matched 1170 noncancer outpatients of Aichi Cancer Center Hospital. Information on facial flushing and other lifestyle factors was collected via a self-administered questionnaire. Association between facial flushing, polymorphism, and UAT cancer was assessed by odds ratios and 95% confidence intervals by using conditional logistic regression models. The facial flushing had no significant association with UAT cancer, although ALDH2 Lys allele was significantly associated with UAT cancer. No significant interaction between facial flushing and alcohol consumption was observed in this study, whereas ALDH2 Lys allele had significant association with UAT cancer. The misclassification between facial flushing and ALDH2 genotype was observed in 18% of controls with ALDH2 Glu/Glu genotype and in 16% of controls with ALDH2 Glu/Lys genotype. Facial flushing was less useful to predict UAT cancer risk than genotyping ALDH2 polymorphism.

Heavy smoking history interacts with chemoradiotherapy for esophageal cancer prognosis: a retrospective study.

Smoking is a well-known risk factor for esophageal cancer. However, there are few reports that directly evaluate smoking as a prognostic factor for esophageal cancer. Moreover, scarce evidence is available on whether smoking interacts with major treatment modalities of esophageal cancer. In this study we retrospectively analyzed 364 patients with esophageal squamous cell cancer who were treated between 2001 and 2005 at our institution. Background characteristics, including smoking history, were analyzed as potential prognostic factors. Of the 363 patients, 76 patients (20.9%) were non-smokers or light smokers (non-heavy), whereas 287 patients (79.1%) were heavy smokers. The 5-year survival rate for non-heavy smokers and heavy smokers was 61.8% (95% confidence interval [CI]: 49.1-72.2) vs 44.6% (95% CI: 38.2-50.9), respectively. In a multivariate Cox model (adjusted for age, gender, performance status, alcohol consumption, histology, tumor length, International Union Against Cancer [UICC] stage, and treatment), the hazard ratio for heavy smokers in comparison with non-heavy smokers was 1.73 (95% CI: 1.12-2.68; P = 0.013). When we stratified by treatment method, heavy smoking was significantly associated with poor survival only in patients treated by chemoradiotherapy (hazard ratio, 2.43; 95% CI: 1.38-4.27; P = 0.002). More importantly, a statistically significant interaction between heavy smoking history and treatment modality was observed (P = 0.041). Our results indicated that smoking history is strongly associated with poor prognosis in patients with esophageal cancer, especially those treated by chemoradiotherapy. Further investigation is warranted to explain this different prognosis.