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Association of antibiotic therapy within 60 days before the start of ICI therapy with survival in patients with NSCLC.

Cox proportional hazards regression models with inverse probability of treatment weighting using propensity score.

Gut dysbiosis caused by antibiotics impairs response to immune checkpoint blockade (ICB). Gut microbiota is becoming an attractive therapeutic target for cancer. The Clostridium butyricum MIYAIRI 588 strain is a probiotic therapy used to improve symptoms related to antibiotic-induced dysbiosis in Japan. We hypothesized that probiotic Clostridium butyricum therapy (CBT) may affect the therapeutic efficacy of ICBs. We retrospectively evaluated 118 patients with advanced non–small cell lung cancer treated with ICBs at Kumamoto University Hospital (Kumamoto-shi, Kumamoto, Japan). Survival analysis comparing patients given CBT before and/or after ICB was conducted using univariate analyses and Cox proportional hazards regression models using propensity score. Propensity score analyses confirmed that probiotic CBT significantly prolonged progression-free survival (PFS) and overall survival (OS). Probiotic CBT significantly associated with longer PFS and OS even in patients who received antibiotic therapy. This study suggests that probiotic CBT may have a positive impact on therapeutic efficacy of ICB in patients with cancer.See articles by Hakozaki et al., p. 1243, and Peng et al., p. 1251

The relationship between probiotic CBT and the incidence of immune-related enterocolitis/diarrhea during ICI therapy.

Indications and characteristics of probiotic CBT in NSCLC patients (N=39).

The aim of this study was to investigate whether a tumor microenvironment, abundant in microvessels, affects epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI) efficacy in patients with non-small cell lung cancer (NSCLC) and EGFR mutations. We retrospectively studied the data of 40 post-operative patients with recurrent NSCLC and EGFRmutations who received EGFR-TKIs as a first-line treatment at Kumamoto University Hospital between January 2010 and February 2021. Tumor sections were retrieved from the tissue registry and analyzed for CD34-positive microvessels using immunohistochemical techniques. The microvascular area ratio (MVR), which is the CD34-positive microvascular area compared to the total tumor area, was measured using StrataQuest. The predictive value of MVR on treatment outcome, assessed via progression-free survival (PFS), was evaluated using a multivariate Cox proportional hazard model. The median PFS in the high MVR group (≥0.058) was significantly shorter than that in the low MVR group (P=0.002). Multivariate analysis revealed that high MVR was an independent negative predictor of PFS (hazard ratio, 3.21 [95% CI: 1.18–8.76], P=0.022). High MVR may critically affect EGFR-TKI resistance in patients with NSCLC and EGFR mutations.

Purpose Microvessel density plays an essential role in tumor development. However, whether a tumor microenvironment, abundant in microvessels, affects epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI) efficacy in patients with non-small cell lung cancer (NSCLC) and EGFR mutations remains unclear. We aimed to investigate the impact of tumor microvessels on EGFR-TKI efficacy in patients with NSCLC and EGFR mutations. Methods We retrospectively studied the data of 40 post-operative patients with recurrent NSCLC and EGFR mutations who received EGFR-TKIs as a first-line treatment at Kumamoto University Hospital between January 2010 and February 2021. Tumor sections were retrieved from the tissue registry and analyzed for CD34-positive microvessels using immunohistochemical techniques. The microvascular area ratio (MVR), which is the CD34-positive microvascular area compared to the total tumor area, was measured using StrataQuest. The predictive value of MVR on treatment outcome, assessed via progression-free survival (PFS), was evaluated using a multivariate Cox proportional hazard model. Results The median MVR and PFS values of EGFR-TKI were 0.058 (range, 0.013–0.094) and 610 d (range, 102–2807 d), respectively. The median PFS in the high MVR group (≥ 0.058) was significantly shorter than that in the low MVR group (P = 0.002). Multivariate analysis revealed that high MVR was an independent negative predictor of PFS (hazard ratio, 3.21 [95% CI: 1.18–8.76], P = 0.022). Conclusions High MVR may critically affect EGFR-TKI resistance in patients with NSCLC and EGFR mutations.

T cells express an actin-binding protein, drebrin, which is recruited to the contact site between the T cells and antigen-presenting cells during the formation of immunological synapses. However, little is known about the clinical implications of drebrin-expressing, tumor-infiltrating lymphocytes (TILs). To address this issue, we evaluated 34 surgical specimens of pathological stage I–IIIA squamous cell lung cancer. The immune context of primary tumors was investigated using fluorescent multiplex immunohistochemistry. The high-speed scanning of whole-slide images was performed, and the tissue localization of TILs in the tumor cell nest and surrounding stroma was automatically profiled and quantified. Drebrin-expressing T cells were characterized using drebrin+ T cells induced in vitro and publicly available single-cell RNA sequence (scRNA-seq) database. Survival analysis using the propensity scores revealed that a high infiltration of drebrin+ TILs within the tumor cell nest was independently associated with short relapse-free survival and overall survival. Drebrin+ T cells induced in vitro co-expressed multiple exhaustion-associated molecules. The scRNA-seq analyses confirmed that the exhausted tumor-infiltrating CD8+ T cells specifically expressed drebrin. Our study suggests that drebrin-expressing T cells present an exhausted phenotype and that tumor-infiltrating drebrin+ T cells affect clinical outcomes in patients with resectable squamous cell lung cancer.

Gut dysbiosis caused by antibiotics impairs response to immune checkpoint blockade (ICB). Gut microbiota is becoming an attractive therapeutic target for cancer. The Clostridium butyricum MIYAIRI 588 strain is a probiotic therapy used to improve symptoms related to antibiotic-induced dysbiosis in Japan. We hypothesized that probiotic Clostridium butyricum therapy (CBT) may affect the therapeutic efficacy of ICBs. We retrospectively evaluated 118 patients with advanced non–small cell lung cancer treated with ICBs at Kumamoto University Hospital (Kumamoto-shi, Kumamoto, Japan). Survival analysis comparing patients given CBT before and/or after ICB was conducted using univariate analyses and Cox proportional hazards regression models using propensity score. Propensity score analyses confirmed that probiotic CBT significantly prolonged progression-free survival (PFS) and overall survival (OS). Probiotic CBT significantly associated with longer PFS and OS even in patients who received antibiotic therapy. This study suggests that probiotic CBT may have a positive impact on therapeutic efficacy of ICB in patients with cancer. See articles by Hakozaki et al., p. 1243, and Peng et al., p. 1251

We examined whether fluorine-18 2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) performed before chemotherapy could predict the onset of acute exacerbation of interstitial lung disease (AE-ILD) in patients with lung cancer and ILD treated with chemotherapy. Thirty-three patients with lung cancer and ILD who underwent 18F-FDG PET/CT and were treated with chemotherapy at Kumamoto University Hospital between April 2006 and March 2018 were retrospectively analyzed. The maximum standardized uptake value (SUVmax) of interstitial lesions was measured to quantify the background ILD activity. A prediction model of AE-ILD was developed using logistic regression analyses for the SUVmax, and receiver operating characteristic (ROC) curve analyses were conducted. Among the 33 patients, 7 experienced AE-ILD. The SUVmax of contralateral interstitial lesions was significantly higher in patients with vs. without AE-ILD (median SUVmax: 2.220 vs. 1.795, P = 0.025). Univariable logistic regression analyses showed that the SUVmax of contralateral interstitial lesions trended towards being significantly associated with the onset of AE-ILD [odds ratio: 8.683, 95% confidence interval (CI) 0.88–85.83, P = 0.064]. The area under the ROC curve of the SUVmax for predicting AE-ILD was 0.780 (95% CI 0.579–0.982, P = 0.025). The optimal cut-off value for SUVmax was 2.005, with sensitivity and specificity values of 0.857 and 0.769, respectively. The SUVmax of contralateral interstitial lesions in 18F-FDG PET/CT images might be useful for predicting the onset of AE-ILD in patients with lung cancer and ILD treated with chemotherapy.

Lung cancer patients have a high risk of cerebral infarction, but the clinical significance of cerebral infarction in advanced non-small cell lung cancer (NSCLC) remains unclear. This study aimed to comprehensively investigate the incidence, prognostic impact, and risk factors of cerebral infarction in patients with NSCLC.We retrospectively examined 710 consecutive patients with advanced or post-operative recurrent NSCLC treated between January 2010 and July 2020 at Kumamoto University Hospital. Cerebral infarction was diagnosed according to the detection of high-intensity lesions on diffusion-weighted magnetic resonance imaging regardless of the presence of neurological symptoms during the entire course from 3 months before NSCLC diagnosis. The prognostic impact and risk factors of cerebral infarction were evaluated based on propensity score matching (PSM) and multivariate logistic regression analysis.Cerebral infarction occurred in 36 patients (5%). Of them, 21 (58%) and 15 (42%) patients developed asymptomatic and symptomatic cerebral infarction, respectively. PSM analysis for survival showed that cerebral infarction was an independent prognostic factor (hazards ratio: 2.45, 95% confidence interval (CI): 1.24-4.85, P = 0.010). On multivariate logistic regression analysis, D-dimer (odds ratio [OR]: 1.09, 95% CI 1.05-1.14, P 0.001) and C-reactive protein (OR: 1.10, 95% CI 1.01-1.19, P = 0.023) levels were independent risk factors.Cerebral infarction occurred in 5% of NSCLC patients, and asymptomatic cerebral infarction was more frequent. Cerebral infarction was a negative prognostic factor and was associated with hyper-coagulation and inflammation. The high frequency of asymptomatic cerebral infarction and its risk in NSCLC patients with these conditions should be recognized.

Gut dysbiosis caused by antibiotics impairs response to immune checkpoint blockade (ICB). Gut microbiota is becoming an attractive therapeutic target for cancer. The

Introduction The impact of immune checkpoint blockade on immunity in cancer patients is not completely elucidated due to the complexity of the immune network. Recent studies have revealed a significant role of programed cell death‐ligand 2 (PD‐L2) in negatively controlling the production of CD4+ T helper type 2 (Th2) cytokines and airway hypersensitiveness, suggesting hypo‐responsive Th2 cells via the PD‐1/PD‐L2 inhibitory pathway in lung could be reawaken by PD‐1 blockade therapy. Methods We describe the first report of acute eosinophilic pneumonia (AEP), which is known as Th2‐associated pulmonary disease, triggered by nivolumab, an anti‐PD‐1 antibody, in an advanced non‐small cell lung cancer patient. Based on the current case report and literature, the present study proposes a potential mechanism of the onset of AEP as an immune‐related adverse event (irAE). Results A 62‐year‐old man was diagnosed with lung adenocarcinoma and nivolumab was selected as the third‐line regimen. After three cycles of nivolumab treatment, chest computed tomography revealed pulmonary infiltrates in both lungs. The patient was diagnosed with AEP based on the diagnostic criteria for AEP. Nivolumab was suspended and the patient was started on oral prednisolone. His symptoms and radiological findings had rapidly improved. Conclusions Given the increasing frequency of the use of anti‐PD‐1 antibodies, clinicians should be aware of the risk of AEP as a potential irAE. This study may improve our understanding of the pathophysiology underlying Th2‐associated irAEs and AEP.

BACKGROUND/AIM The impact of interstitial lung disease (ILD) on the clinical outcome of patients with small-cell lung cancer (SCLC) is not fully understood. The aim of this study was to investigate the impact of ILD on treatment and survival outcomes of SCLC patients. PATIENTS AND METHODS A retrospective analysis was performed on the clinical outcomes of SCLC patients, treated with chemotherapy, with or without ILD ([ILD group (n=16) and non-ILD group (n=51)]. RESULTS Median PFS and OS were significantly shorter in the ILD group than in the non-ILD group (median PFS, 184 vs. 290 days, p=0.008; median OS, 236 vs. 691 days, p

We examined whether fluorine-18 2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (Thirty-three patients with lung cancer and ILD who underwentAmong the 33 patients, 7 experienced AE-ILD. The SUVThe SUV

Objectives With the aim of searching for novel oncofetal tumor biomarkers of lung adenocarcinoma other than carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP), we developed a strategy involving monoclonal antibodies generated from embryonic tissue of miniature swine. Materials and methods Using immunohistochemistry, we selected suitable hybridoma clones that were reactive against swine fetal lung but not adult lung using tissue microarray loading of human normal lung, lung cancer, and fetal and adult swine tissues. Results The selected clones included several that were uniquely reactive against both swine fetal lung and human lung adenocarcinoma, and protein microarray revealed that the antigen they recognized was "drebrin" ( DBN1 ). We then examined the association between the pattern of drebrin expression and the clinicopathological characteristics of lung adenocarcinoma using surgically resected samples of human lung adenocarcinoma. Two hundred formalin-fixed and paraffin-embedded tumor samples were immunostained for drebrin using clone B246, one of the clones that were reactive against drebrin. The cases were divided into those with strong (n=85) and weak (n=115) drebrin expression. In terms of disease-free survival, cases showing strong drebrin expression had a significantly poorer prognosis than those with weak drebrin expression (p=0.033). Conclusion The present findings indicate that "drebrin" is a unique oncofetal protein that can be applied as a new biomarker of lung adenocarcinoma.

Backgrounds Adenocarcinoma in situ (AIS) of the lung has an extremely favorable prognosis. However, early but invasive adenocarcinoma (eIA) sometimes has a fatal outcome. We had previously compared the expression profiles of AIS with those of eIA showing lymph node metastasis or a fatal outcome, and found that stratifin (SFN, 14-3-3 sigma) was a differentially expressed gene related to cell proliferation. Here, we performed an in vivo study to clarify the role of SFN in initiation and progression of lung adenocarcinoma. Findings Suppression of SFN expression in A549 (a human lung adenocarcinoma cell line) by siSFN significantly reduced cell proliferation activity and the S-phase subpopulation. In vivo, tumor development or metastasis to the lung was reduced in shSFN-transfected A549 cells. Moreover, we generated SFN-transgenic mice (Tg-SPC-SFN+/−) showing lung-specific expression of human SFN under the control of a tissue-specific enhancer, the SPC promoter. We found that Tg-SPC-SFN+/− mice developed lung tumors at a significantly higher rate than control mice after administration of chemical carcinogen, NNK. Interestingly, several Tg-SPC-SFN+/− mice developed tumors without NNK. These tumor cells showed high hSFN expression. Conclusion These results suggest that SFN facilitates lung tumor development and progression. SFN appears to be a novel oncogene with potential as a therapeutic target. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0414-1) contains supplementary material, which is available to authorized users.

Many materials with differing surfaces have been developed for clinical implant therapy in dentistry and orthopedics. We analyzed the quantity of new bone formed in vivo around calcium-immobilized titanium implants with surfaces modified using pamidronate (PAM), a nitrogen-containing bisphosphonate (N-BP), implants of pure titanium, and titanium implants immobilized with calcium ions. New bone formation was visualized using fluorescent labeling (calcein blue and alizarin complexone) with intravenous injection at 1 and 3 weeks after implantation. After 4 weeks, undecalcified sections were prepared, and new bone formation around the implants was examined by morphometry using confocal laser scanning microscopy images. After 1 week, more new bone formed around the PAM-immobilized implant than around the calcium-immobilized and pure titanium implants. This was also seen with the new bone formation after 3 weeks. After 4 weeks, significantly more new bones were formed around the BP-immobilized implant than around the calcium ion-implanted and pure titanium implants. The new N-BP-modified titanium surface stimulates new bone formation around the implant, which might contribute to the success of implant therapy.

This study examined the influence of diabetes mellitus on bone formation around cylindrical titanium (Ti) implants (1.0 mm in diameter and 1.5 mm in length) inserted transcortically and extending into the medullary canal of rat tibiae using light and fluorescence microscopies and image processing. Forty-eight male Wistar King A rats (age 5 weeks) were used in this experiment. Streptozotocin was injected intraperitoneally to induce diabetes and the serum glucose concentration was checked to ensure the induction of diabetes prior to implant placement and at the time of sacrifice. The animals were sacrificed 7, 28, 56, or 84 days after placement. Toluidine blue-stained undecalcified sections were prepared for histological observation and image analysis. The Ti implants in the control group became increasingly encapsulated with a bone layer. The implants in the diabetes-induced (DI) group were also surrounded with a thin bone layer. Abundant adipocytes were observed in the DI group as compared with the control group. Quantitative evaluation indicated that the control group showed a significantly higher percent of bone contact, and thickness of surrounding bone and area than the DI group. Consequently, the present study suggests that uncontrolled diabetes would hinder bone formation around Ti implants in rats.

The present study was designed to compare the amount and regional distribution of bone formation around hydroxyapatite (HA) implants in normal (control) rats with that of animals with diabetes mellitus (DM), induced by streptozotocin 2 weeks prior to implant placement. Calcein (CAL), alizarin complexone (AL), and tetracycline (TC) were injected on the 7th, 14th, and 21st days after implantation, respectively, and the rats were sacrificed on the 28th day after implantation. Seventy-microns undecalcified sections of the HA-bone interface in both groups were then prepared for confocal laser scanning microscopy (CLSM) observation. In both groups, bone formation developed from the HA surface to the endosteum, periosteum, or bone marrow. In the control group, around the HA close to the endosteum and periosteum, the new bone showed an extensive lamination pattern of three color layers (CAL, AL, and TC), but in the DM group the labeling density of TC on the 21st day was low. In contrast, on the lateral part of the HA surface (away from the endosteum and periosteum), there was considerably less bone formation in the control group, and in the DM group it was almost completely suppressed. These findings indicate that bone formation around the HA was initiated from the HA surface in the control group, while in the DM group, bone formation along the lateral part of the HA away from the endosteum and periosteum was almost completely suppressed. Furthermore, it is also suggested that in the new bone along the HA close to the endosteum and periosteum, only calcification on the 21st day was depressed.

We conducted a 2-year histologic and histometric evaluation of the tibial bone-titanium (Ti) implant interface in male rats. Thirty male 6-week-old rats were used in this study. They were divided into two groups: 15 for day 28 and 15 for day 730. Microscopic observation at day 28 revealed that the newly formed bone around the implant almost surrounded the implant, but fibroblastlike cells were interposed in some histologic sections. At day 730, in contrast, such cells were rarely seen, and the bone around the implant presented a lamellar structure. Transmission electron microscopic observation at day 28 disclosed mature or poorly mineralized bone near the implant; however, an electron-dense amorphous zone about 50 nm in thickness was interposed between the bone and Ti. In places slender cells were interposed between the bone and Ti. The amorphous zone was also observed at the cell-Ti interface. At day 730, a poorly mineralized layer remained in some areas between the mature bone and the titanium, and the interposed amorphous zone was still observed. Occasionally, a 200-nm-thick layer, thought to be cell remnant, was seen. As calculated in an image-processing, system analysis, the percent bone contact and the thickness and area of the surrounding bone for the Ti implant at day 28 were 43.6%, 30.4 microns, and 0.10 mm2, respectively, and those at day 730 were 89.9%, 53.5 microns, and 0.19 mm2, respectively. In summary, although the passage of time may affect bone maturity, interfacial cells remain at the bone-Ti interface as a uniform layer together with unmineralized bone.

We examined the influence of diabetes on the implant-bone interface of hydroxyapatite (HA) implants inserted transcortically and extending into the medullary canal of rat tibiae, and quantitatively assessed the differences in bone reaction using an image processing system. Forty male Wistar King A rats (aged 5 weeks) were used in this experiment; they were sacrificed 84 days after implant placement. Toluidine blue-stained undecalcified sections were prepared for histological observation and image analysis, and the labeled sections were observed by confocal laser scanning microscopy. The HA implants in the bone marrow area in the control group were completely encapsulated with a bone layer, and there were some osteoblast-like cells in the bone lacunae apposing the implant surface. The HA implants in the diabetes-induced (DI) group were partially surrounded with a thin bone layer, and there were some fibroblasts running parallel to the implant surface at areas of no bone contact. Quantitative evaluation indicated that the control group showed significantly higher bone contact rate, bone contact thickness, and bone contact area than the DI group. The DI group showed approximately 30% reduction in the percentage of bone contact and 50% reduction in the thickness and the area of surrounding bone tissue.

The influence of diabetes on the implant-bone interface of titanium (Ti) implants, inserted transcortically and extending into the medullary canal of rat tibiae, was examined, and the differences in bone reaction were quantitatively assessed using an image processing system. Thirty male Wister King A rats (aged 5 weeks) were used in this experiment, and they were divided into 2 groups, 15 for the control and 15 for the diabetes-induced (DI) group. They were sacrificed 7, 28 and 84 days after implant placement. Toluidine blue-stained undecalcified sections were prepared for histological observation and image analysis. The Ti implants in the bone marrow area had been almost encapsulated in a thick bone layer. The Ti implants in the DI group had been partially surrounded by a thin bone layer, but the thickness of the surrounding bone had decreased. Quantitative evaluation indicated that the control group showed an increase of the percent of bone contact, the thickness of surrounding bone and the area of surrounding bone throughout the experimental period, while the DI group showed a decrease of the thickness of surrounding bone and the area of surrounding bone except for the percent of bone contact.

The purpose of this study was to investigate the tissue reaction to three kinds of membranes, Gore-Tex Augmentation Material (GTAM), Vicryl, and Dura Mater, placed on bone defects around the titanium implants. Nine adult dogs weighing 15kg were used in this study. The dogs were sacrificed either 2, 4, or 12 weeks after placement. Vicryl was exposed 2 weeks after placement. Histologically, it was found that Vicryl was completely resorbed, Dura Mater was replaced with connective tissue at 12 weeks, and bone defects using GTAM and Dura Mater but not Vicryl were partially filled with newly-formed bone tissue. Active bone formation was observed in the space between membranes and pre-existing bone tissue.

The bone reaction to hydroxyapatite (HA) implants inserted transcortically and extending into the medullary canal of rat tibiae was quantitatively assessed using light microscopy, confocal laser scanning microscopy and an image processing system. Sixty-five male rats (6 weeks old) were divided into two groups, 60 for histological observation and image analysis and five for time-labelling. In the histological observation, control sections of 168 days showed a few bone trabeculae in the fatty bone marrow, and Ti implants had become gradually encapsulated with a thick bone tissue layer; however, HA implants became almost completely encapsulated with a thin bone tissue layer during the 168 day experimental period. Histometrical analysis of the percent bone contact revealed that Ti implants showed a continuous increasing curve, and HA implants showed rapid increase in the initial healing period up to 14 days, with 96% bone contact reaching a plateau at 84 days after operation. There was a significant difference in the percent of bone contact between Ti and HA implants throughout the experimental period. Confocal laser scanning microscopic observations revealed the presence of calcein at the 14th day and only slight alizarin colour layer in the bone tissue at the 28th day, both indicating bone formation. These findings suggest that the activity of bone formation was higher at the 14th day than at the 28th day. Also, the percentage of bone contact of HA is superior to titanium throughout the experimental period, and the ascending patterns of both implants are quite different to each other.

We report a case of tuberculous pleurisy that required differentiation from pleurisy caused by Mycoplasma infection. A 28-year-old woman presented to a clinic with fever and pain on the left side of her chest. A chest radiograph revealed pleural effusion in the left thorax, and the condition was diagnosed as bacterial pleurisy. The patient was referred to our hospital because of an increase in the pleural effusion despite antibiotic treatment. Mycoplasma infection was suspected because the patient was young, the white blood cell count was not elevated, and the result of the ImmunoCard Mycoplasma test (IC) for Mycoplasma pneumoniae-specific IgM antibodies was positive. However, the fever persisted even after treatment with azithromycin and pazufloxacin. The left pleural effusion was exudative, with lymphocytosis and high adenosine deaminase (ADA) levels. The results of the QuantiFERON test were positive. Therefore, tuberculous pleurisy was diagnosed, and the effusion subsided after treatment with standard anti-tuberculosis chemotherapy. Although detection of Mycoplasma infection using the IC is rapid and simple, the accuracy of this test is poor. The patient was first diagnosed with pleurisy of Mycoplasma origin because of a single high-particle agglutination titer of 1: 320 and because of the presence of exudative pleural effusion with lymphocytosis and elevated ADA levels, which has been reported in patients with Mycoplasma infection. The results of the IC test and the ADA level of the pleural effusion might not be reliable when distinguishing between tuberculous pleurisy and pleurisy caused by Mycoplasma infection.

Vascular invasion (VI) has been accepted as a universally important prognostic factor for patients with lung carcinoma. However, the clinical significance of VI in each of the histological subtypes has been unclear. The aim of the present study was to investigate differences in the clinicopathological implications of VI between adenocarcinoma and squamous cell carcinoma.A total of 336 patients were evaluated, of whom 81 were diagnosed as having peripheral-type squamous cell carcinoma, and 255 as having adenocarcinoma.Among the 336 patients, the five-year survival rates for those who were VI-positive and VI-negative were 38.4% and 76.3%, respectively, the difference being significant (p0.0001). Multivariate analysis identified VI as an independent prognostic factor (hazard ratio: 1.86). Although the difference in cancer-free survival between VI-positive and -negative patients was statistically significant for adenocarcinoma (p0.0001), it was not significant for squamous cell carcinoma (p=0.086). For adenocarcinoma, the difference between the survival curves for VI-positive and -negative patients was significant for the subtypes with a predominant lepidic (p0.0001), papillary (p=0.0026), and acinar (p=0.0060) component, whereas that for the predominantly solid subtype was not significant (p=0.58). Squamous cell carcinomas were then divided into two groups on the basis of the diameter of vessels that had been invaded by the cancer cells: large-vessel invasion (LVI; 1000 μm or more) and small-vessel invasion (SVI; less than 1000 μm). Although there was no difference in the survival curves between the LVI and SVI groups, the LVI group showed a significantly higher incidence of cavity formation and distant metastasis.We conclude that VI is a useful prognostic indicator in lung carcinoma, although the clinical implications of VI differ between adenocarcinoma and squamous cell carcinoma.

High and low bone turnover situations, both of which are typically observed as postmenopausal and senile osteoporosis, were created by ovariectomy (OVX), and then an investigation of whether or not the difference of bone turnover affected peri-titanium (Ti) implant osteogenesis in rats was conducted. Female rats were divided into four groups. The experimental and control groups underwent OVX or sham operations at 15 or 27 weeks of age, as high or low bone turnover groups, respectively. Ti implants were inserted into the tibiae at 30 weeks, then fluorochromes were injected 10 or 20 days after the implantation for histometry. The implants were retained for 30 days and then ground sections were prepared. Afterward, the cortical bone growth rate, bone contact ratio (BCR) of the implant in both the cortical bone area and medullary canal area, and the average trabecular bone thickness around the implant were evaluated. Biochemical markers of bone turnover were also measured. Biochemical measurements indicated both increasing osteocalcin production in OVX rats and decreasing tartrate-resistant acid phosphatase activity in the low-turnover group. Histometrical measurements showed decreasing cortical growth and low BCR in the medullary canal of the low-turnover group. The high-turnover group demonstrated BCR as high as that of the control group. There was no significant difference in the average trabecular bone thickness around the implant among the groups. As a result, two types of osteoporotic situations were confirmed and it was shown that the difference of bone turnover was clearly due to the diverse osteogenesis around the Ti implant.

The purpose of this study was to examine early wound healing following grafting of dense hydroxyapatite granules (HA granules) and barrier placement in surgically-created bone defects surrounding implants. Eight healthy adult dogs with an average weight of 15 kg were used in this study. Thirty-two bone defects measuring 4 mm x 4 mm were removed with a surgical bur to form continuous bucco-lingual bone defects and 32 implants (16 titanium [Ti]) and 16 hydroxyapatite-coated [HA]) were then placed into the defects. Four implant groups were created: 1) grafting HA; 2) covering with an expanded polytetrafluoroethylene (ePTFE) membrane; 3) grafting HA and covering with ePTFE membrane; and 4) control (no treatment). Animals were sacrificed 28 days after surgery. Histological sections revealed large amounts of newly-formed bone in all bone defects surrounding the implants treated with ePTFE membranes alone. Fibrous encapsulation of HA granules was observed in the defects of the HA granules grafting group. In the group with grafting of HA granules and covering with ePTFE membranes, small amounts of bone tissue were observed among HA granules, but most HA granules were surrounded with fibrous tissue. Bone defects were completely filled with connective tissue in the control group. There were no differences in the histological findings between Ti and HA-coated implants in all cases. Histomorphometric data disclosed that the presence of HA granules in the bone defects significantly arrested bone formation. Our study suggests that the grafting of dense HA into bone defects surrounding implants will result in fibrous healing during the early healing stage.

The purpose of this study was to evaluate the radiologic, histologic, and histometric findings for a retrieved hydroxyapatite (HA)-coated implant which had been placed into a fresh extraction socket with autogenous bone graft 3 months previously. A periapical radiography disclosed a vertical bone loss around the implant cervix. Examination of histologic section disclosed that granulation tissue including bone chips around the cervix, and newly-formed bone tissue around the grafted bone tissue on the HA coated surface. In the confocal laser scanning microscopic findings toluidine blue-negative bone tissue showed autofluorescence. Histometric analysis indicated that the average percent bone contact was 29.2% (ranged 26.4% to 34.1%). Suspected reasons for failure were an early exposure of the barrier membrane, its early removal, the implant placement into an infected site, inadequate antibiotic premedication, and/or poor control of infections around teeth prior to implant surgery and around implants before and after placement of barrier membrane.

The purpose of this study was to evaluate the radiologic, histologic, and histometric findings of three failing hollow implants. On periapical radiographs, these implants showed vertical bone loss up to the hollow portion around the implant. Examination of the histologic sections disclosed that the hollow portions of all the implants were almost filled with bone tissue, although slight bone resorption and presence of granulation tissue infiltrated with inflammatory cells was observed coronal to the hollow portion. Histometric analysis disclosed that the average percent bone contact was 93.1% in case 1, 90.9% in case 2, and 84.3% in case 3 and the average percent bone filling was 42.1%, 50.5%, and 33.8%, respectively. Consequently, there seems to be some potential for successful treatment of these implants because the destructive changes were limited to the coronal aspects of the implant.

We histologically examined seven hydroxyapatite-coated (HA) blade implants removed from patients. Four of them radiologically showed severe bone loss and were easily removed with an elevator. Three radiologically showed vertical bone loss and were removed by surgical procedure. Our histological evaluation indicated that coating separation from the HA implants had occurred, and HA coating resorption by bone tissues was suspected in an implant left in situ for 8 years. Several multinucleated giant cells were seen with a few released particles of HA coating at the point lacking bone contact with the HA coating. The presence of microorganisms on and in the HA coating layer was also noted.