Relationship of maternal inflammatory response and fetal inflammatory response to duration and intensity of intra-amniotic infection and inflammation.

INTRODUCTION: We aimed to use two indices, amniotic fluid interleukin-6 (IL-6) concentration at diagnosis and diagnosis-to-delivery interval, to clarify the frequencies of maternal inflammatory response (MIR) and fetal inflammatory response (FIR) in the placenta of patients with intra-amniotic infection and intra-amniotic inflammation (IAI). METHODS: This is a single-center retrospective cohort study. From August 2014 to April 2020, participants were diagnosed with IAI with or without microbial invasion of the amniotic cavity (MIAC) using amniocentesis. IAI was defined as concentrations of amniotic IL-6 ≥ 2.6 ng/mL. MIAC was defined as a positive amniotic fluid culture. IAI with MIAC was defined as an intra-amniotic infection. We calculated the cut-off values for IL-6 concentration in the amniotic fluid at diagnosis and the diagnosis-to-delivery interval for MIR-positive cases among those with intra-amniotic infection. RESULTS: The amniotic fluid IL-6 concentration at diagnosis and diagnosis-to-delivery interval were 15.8 ng/mL and 12 h, respectively. Among cases with intra-amniotic infection, MIR was 98% (52/53) positive, i.e., when either of the two cut-off values was exceeded. There were no significant differences between the frequencies of MIR and FIR. In cases with IAI but no MIAC, the frequencies of MIR and FIR were significantly lower than those with intra-amniotic infection, except when neither of the two cut-off values was exceeded. DISCUSSION: We clarified the MIR- and FIR-positive cases in intra-amniotic infection and cases with IAI but no MIAC according to condition, including the diagnosis-to-delivery interval.

Diagnostic accuracy of amniotic fluid interleukin-6 for fetal inflammatory response syndrome.

AIM: This study aimed to clarify the diagnostic accuracy of amniotic fluid interleukin-6 for fetal inflammatory response syndrome (FIRS). METHODS: This retrospective cohort study was conducted in a single institution and targeted cases of preterm birth within 24 h after amniocentesis among singleton cases that underwent amniocentesis at our hospital for suspected intraamniotic inflammation (IAI) from gestational ages of 22-36 weeks between August 2014 and March 2020. FIRS was defined as >11.0 pg/mL of umbilical cord blood interleukin-6. RESULTS: The analysis included 158 pregnant women. There was a strong correlation between amniotic fluid interleukin-6 and umbilical cord blood interleukin-6 (r = 0.70, p < 0.001). The area under the receiver operating characteristic curve of amniotic fluid interleukin-6 for FIRS was 0.93, with a cutoff value of 15.5 ng/mL, and showed high sensitivity and specificity (0.91 and 0.88, respectively). An amniotic fluid interleukin-6 cutoff value of ≥15.5 ng/mL was associated with a significant risk of FIRS (adjusted odds ratio: 27.9; 95% confidence interval: 6.3-123.0; p < 0.001). CONCLUSIONS: The results of this study show that amniotic interleukin 6 alone can be used to diagnose FIRS prenatally. While there is a need for validation, it may be possible to treat IAI while preventing damage to the central nervous and respiratory systems in the uterus by keeping the amniotic fluid interleukin-6 below the cutoff value.

Contribution of Fetal Inflammatory Response Syndrome (FIRS) with or without Maternal-Fetal Inflammation in The Placenta to Increased Risk of Respiratory and Other Complications in Preterm Neonates.

This study classifies fetal inflammatory response syndrome (FIRS) based on the presence or absence of maternal-fetal inflammation in the placenta and clarifies the association of FIRS with neonatal morbidities. Women (330) who delivered at gestational ages of 22w0d-33w6d were enrolled and grouped into four based on FIRS and maternal/fetal inflammatory response (MIR/FIR) statuses: Group A: without FIRS and MIR/FIR (reference group); Group B: MIR/FIR alone; Group C: FIRS and MIR/FIR; and Group D: FIRS without MIR/FIR. The associations between bronchopulmonary dysplasia (BPD), adverse neonatal outcomes, extremely low gestational age and Groups B, C, and D were investigated after adjustment for potential confounders. Among patients with FIRS, 29% were in Group D. The risk of BPD was increased in Groups C (adjusted odds ratio (aOR): 3.36; 95% confidence interval (CI): 1.14-9.89) and D (aOR: 4.17; 95% CI: 1.03-16.9), as was the risk of adverse neonatal outcomes (Group C: aOR: 7.17; 95% CI: 2.56-20.1; Group D: aOR: 6.84; 95% CI: 1.85-25.2). The risk of extremely low gestational age was increased in Group D (aOR: 3.85; 95% CI: 1.56-9.52). Therefore, FIRS without MIR/FIR is not rare and may be associated with neonatal morbidities more than FIRS and MIR/FIR.

Estimated time to emergence of secondary intra-amniotic infection or inflammation since the onset of the preterm premature rupture of membranes.

OBJECTIVE: Prematurity is the most important prognostic factor for infants born following preterm premature rupture of membranes (PPROM). Therefore, when PPROM occurs between 22 and 33 weeks of gestation, prolonging pregnancy is recommended. Determination of management strategies requires screening for the presence of intra-amniotic infection or inflammation at the time of PPROM diagnosis. If intra-amniotic infection/inflammation is not detected, it is important to monitor the patient to diagnose any new infection/inflammation. We examined the period from PPROM to secondary intra-amniotic infection/inflammation and associated factors. MATERIALS AND METHODS: This retrospective study was conducted at a single facility. We examined 26 patients who experienced PPROM between 26 and 33 weeks of gestation and were negative for intra-amniotic infection/inflammation at the time of diagnosis and underwent serial amniocentesis. Antibiotic therapy comprising ampicillin, amoxicillin, and clarithromycin for 7 days was started after the first amniocentesis. The period from PPROM to secondary intra-amniotic infection/inflammation was analyzed using a Kaplan-Meier survival curve. The onset of intra-amniotic infection/inflammation was considered as the time at which amniotic fluid bacterial culture results became positive, the time when amniotic fluid Interleukin (IL)-6 increased beyond 2.6 ng/mL, or the day of delivery if histological chorioamnionitis was observed in the delivered placenta. Patients were treated as censored if no intra-amniotic infection/inflammation could be confirmed in the amniotic fluid and delivered placenta. RESULTS: The median time from PPROM to secondary intra-amniotic infection/inflammation was 18 days. Six patients developed intra-amniotic infection/inflammation, while 13 patients without intra-amniotic infections/inflammation delivered fewer than 7 days after PPROM. No confounding factors at the time of PPROM diagnosis were associated with the time from PPROM until secondary intra-amniotic infection/inflammation. CONCLUSIONS: The time between PPROM and onset of secondary intra-amniotic infection/inflammation appears prolonged. Treatments other than antimicrobial agents may need to be added to prolong pregnancy.

A case of squamous cell lung cancer treated with anamorelin in combination with a multidisciplinary collaborative approach for treating cancer cachexia.

Anamorelin (ANA) is approved for treating cancer cachexia (CCX) in Japan. We report the case of a 69-year-old man with stage IVB squamous cell lung cancer complicated by CCX, having a 13.6% weight loss in 6 months. After chemotherapy was initiated, his weight was further reduced. Therefore, we started ANA combined with a treatment approach by a multidisciplinary collaboration, including nutritionists and physical therapists. After initiation of ANA, the body weight, appetite, psoas muscle index, and physical functions rapidly improved during chemotherapy. ANA administration combined with a multidisciplinary collaboration approach can be an effective supportive therapy against CCX during chemotherapy.

Endometrial polyps with increased plasma cells are associated with chronic endometritis in infertility patients: Hysteroscopic findings and post-polypectomy pregnancy rates.

PURPOSE: The relationship between endometrial polyps (EPs), chronic endometritis (CE), hysteroscopic findings, and antimicrobial in infertility patients was determined. METHODS: We retrospectively enrolled 115 infertility patients with suspected EPs who underwent office hysteroscopy. Patients were divided into 3 groups: 38 with increased plasma cells in EPs (group 1); 31 without increased plasma cells in EPs (group 2); and 46 without EPs (group 3). The 3 groups underwent hysteroscopy with or without polypectomies, and immediately thereafter, an endometrial aspiration biopsy (EAB) was performed. CE was diagnosed based on plasma cell infiltration in the non-polypoid endometrium obtained by EAB. RESULTS: The percentage of CE was 68.4%, 32.2%, and 28.3% in groups 1, 2, and 3, respectively. CE was more frequent in group 1 than group 2 or 3 (P = .01 and P = .002, respectively). The number of polyps was higher in group 1 than group 2. After adjustment for age and assisted reproductive technology, antibiotic therapy was not associated with pregnancy (adjusted odds ratio, 0.44; 95% confidence interval, 0.05-3.57) in patients with EPs and CE. CONCLUSIONS: Group 1 was associated with CE, and hysteroscopic findings were different from group 2. Antibiotic therapy after polypectomy for EPs with CE may not always be necessary.

Analysis of vaginal and endometrial microbiota communities in infertile women with a history of repeated implantation failure.

PURPOSE: To identify specific bacterial communities in vaginal and endometrial microbiotas as biomarkers of implantation failure by comprehensively analyzing their microbiotas using next-generation sequencing. METHODS: We investigated α- and ß-diversities of vaginal and endometrial microbiotas using 16S rRNA gene sequencing and compared their profiles between 145 women with repeated implantation failure (RIF) and 21 controls who lacked the factors responsible for implantation failure with a high probability of being healthy and fertile to identify specific bacteria that induce implantation failure. RESULTS: The endometrial microbiotas had higher α-diversities than did the vaginal microbiotas (P < .001). The microbiota profiles showed that vaginal and endometrial samples in RIF patients had significantly higher levels of 5 and 14 bacterial genera, respectively, than those in controls. Vaginal Lactobacillus rates in RIF patients were significantly lower at 76.4 ± 38.9% compared with those of the controls at 91.8 ± 22.7% (P = .018), but endometrial Lactobacillus rates did not significantly differ between the RIF patients and controls (56.2 ± 36.4% and 58.8 ± 37.0%, respectively, P = .79). CONCLUSIONS: Impaired microbiota communities containing specific bacteria in both the endometrium and vagina were associated with implantation failure. The vaginal Lactobacillus rates, but not the endometrial, may be a biomarker for RIF.

Relationship between MRI findings and invasive breast cancer with podoplanin-positive cancer-associated fibroblasts.

OBJECTIVE: Purpose of our study is to assess the relationship between MRI findings and invasive breast cancer (IBC) with cancer-associated fibroblasts (CAFs) that are positive for podoplanin. METHODS: We retrospectively analyzed the consecutive 109 IBCs. The IBCs were dichotomized as with (+) or without (-) podoplanin-positive CAFs. In MRI analyses, the dichotomized IBCs were compared the lesion to muscle ratio (L/M ratio) in STIR images, the ADC value, the distribution of kinetic parameters, and morphological findings. RESULTS: Of the 109 IBCs, 28 (26%) IBCs had podoplanin(+) CAFs. Compared to the podoplanin(-) group, the podoplanin(+) group tended to have a more malignant pathological status. In the STIR images, the podoplanin(+) group had significantly higher L/M ratio (7.59 vs. 6.55, p = 0.040). In a dynamic study, the podoplanin(+) group had a significantly higher percentage of the washout pattern (42.21% vs. 29.43%, p = 0.045). There were 23 mass lesions and 5 non-mass enhancement (NME) lesions in the podoplanin(+) group, and 69 mass lesions and 12 NME lesions in the podoplanin(-) group. The mass lesions of the podoplanin(-) group had a significantly higher likelihood of showing an irregular shape (n = 47 vs. 8, p = 0.035). The podoplanin(+) group's lesions had a significantly higher likelihood of showing a circumscribed margin (n = 14 vs. 6, p < 0.001) and a rim enhancement (n = 10 vs. 13, p = 0.047). In multivariate analyses, only high nuclear grade was significant predictive value of podoplanin(+) CAFs. CONCLUSION: Although not significant in multivariate analyses, MRI findings may be used to determine the podoplanin-positive CAF status of invasive breast cancer.

Amniotic fluid Gram stain and interleukin-6 can predict early-onset neonatal sepsis.

AIM: To clarify whether amniotic fluid findings (Gram stain and interleukin [IL]-6 level) can predict early-onset neonatal sepsis (EONS) before delivery. METHODS: We compared the sensitivity and specificity and the values of the area under the receiver-operating characteristic (AUROC) curve of maternal inflammatory responses and amniotic fluid findings using IL-6 and Gram stain to predict EONS. Patients who underwent amniocentesis for suspected intra-amniotic infection (IAI) after 22 weeks and 0 days of gestation and delivered on the same day at our hospital between January 2013 and December 2018 were included. RESULTS: Out of 200 patients, EONS developed in 9 patients. The AUROC curves of maternal white blood cells count, C-reactive protein and body temperature were low (range, 0.6-0.7), whereas that of amniotic fluid IL-6 was high (0.90). Sensitivity and specificity for amniotic fluid findings were, respectively, 100% and 67% for IL-6 (cut-off value: 17.4 ng/mL) and 100% and 88% for the Gram stain; these values were superior to those of maternal inflammatory responses. When examining the accuracy of the amniotic fluid Gram stain separately before and after 34 gestation weeks, similar results were obtained. Amniotic fluid IL-6 before 34 gestation weeks showed specificity similar to that of the Gram stain; however, there were large differences in cut-off values based on gestational age. CONCLUSION: Gram stain results of amniotic fluid can predict EONS with high sensitivity and specificity when IAI is suspected. False-negative amniotic fluid Gram stain results can be prevented by measuring amniotic fluid IL-6 simultaneously.

Successful treatment of severe intra-amniotic inflammation and cervical insufficiency with continuous transabdominal amnioinfusion and cerclage: A case report.

Severe intra-amniotic inflammation, even with a negative bacterial culture, can lead to premature labor. We report a 43-year-old multiparous woman with severe intra-amniotic inflammation and cervical insufficiency at 23 weeks and 5 days of gestation. Continuous transabdominal amnioinfusion was started 2 days after the diagnosis. The amniotic fluid interleukin-6 level normalized after 2 days of treatment. She underwent Shirodkar cervical cerclage on day 7. Despite termination of amnioinfusion and catheter removal on day 16, the pregnancy was maintained without any subsequent treatment. At 33 weeks and 5 days of gestation, an intrauterine Ureaplasma parvum infection and the onset of contractions led to repeat cesarean delivery. The birth weight was 2292 g, and the Apgar scores were 8/8. Both mother and infant had good outcomes. Continuous transabdominal amnioinfusion may have eliminated factors causing intra-amniotic inflammation, thereby prolonging the pregnancy and improving the infant's prognosis.

Tumor-stromal ratio (TSR) of invasive breast cancer: correlation with multi-parametric breast MRI findings.

OBJECTIVE: To correlate the tumor-stromal ratio (TSR) of invasive breast cancer and MRI findings. METHODS: This study was approved by our institutional review board. 126 consecutive patients with surgically proven invasive breast cancer were included. All patients underwent MRI exams including short-tau inversion-recovery (STIR) T 2 weighted imaging, diffusion-weighted imaging (DWI) and post-contrast dynamic imaging. The mean signal intensity (SI) and apparent diffusion coefficient (ADC) value of each lesion were measured. To objectively evaluate the STIR images, the ratio of the SI of the lesion to the muscle (L/M ratio) was also measured. Percentages of MRI kinetic parameters obtained from dynamic images were also measured. The TSR was defined as the percentage of the stromal component, and categorized into high-stroma (> 50%) and low-stroma (< 50%) groups. Intergroup differences in the SI, L/M ratio, ADC value and percentages of kinetic parameters were examined. RESULTS: The SI and L/M ratio of the high-stroma group were significantly lower than those of the low-stromal group (208.64 vs 331.86 for SI, 5.69 vs 9.31 for L/M ratio) (p < 0.001). The high-stroma group had significantly lower percentages of a washout pattern (25% vs 34.7 %) (p = 0.012) and significantly higher percentages of a persistent pattern (36.92% vs 28.26 %) (p = 0.044). There were no significant correlations between the TSR and ADC value. CONCLUSION: STIR and dynamic sequence of breast MRI reflects the stromal component of invasive breast cancer. ADVANCES IN KNOWLEDGE: This is the first study to correlate TSR and MRI findings. STIR and post-contrast dynamic study correlated with the stromal component of breast cancer.

Necrotizing Sarcoid Granulomatosis with Natural Resolution after a Surgical Lung Biopsy.

Necrotizing sarcoid granulomatosis (NSG) is a rare disease that is diagnosed based on pathological findings. We herein report the case of a 27-year-old man who had multiple nodular shadows in bilateral lung fields on chest radiography and elevated levels of C-reactive protein (CRP). The pathological evaluation of a lung biopsy specimen showed the infiltration of lymphocytes, granulomas with necrosis and granulomatous angiitis. He was therefore diagnosed with NSG. He has been followed without treatment, as his fever and CRP levels decreased immediately after the surgical lung biopsy. Thereafter, the pulmonary nodular shadows gradually recovered without any treatment within a few months. Our experience suggests the possibility that surgical invasion might trigger an improvement in disease activity.

[Myocardial Ischemia in Acute Type A Aortic Dissection; Coronary Artery Dissection and Functional Ischemia].

Myocardial ischemia due to acute type A dissection is a fatal complication. This study was undertaken to evaluate the surgical results of acute type A aortic dissection with myocardial ischemia. Between 1986 and 2014, 364 patients were treated for acute type A dissection in our hospital. Twenty-four patients were underwent myocardial revascularization. Preoperative coronary artery stent placement was involved in 2, coronary-artery bypass grafting (CABG) 18 (right 12, left 4, both 2), reCABG 2, and Carrel patch with coronary orifice restoration 2. Seven of CABG group had no symptom of myocardial ischemia, but right coronary artery was circumferentially detached from the intimal ostia. Hospital mortality was 20.1% in patients who underwent CABG. Sixteen patients with significant electrocardiogram ischemic change were not undertaken with CABG, because coronary artery was not involved by dissection. In these cases, acute aortic valve regurgitation, loss of backward pressure from distal aorta, or valve formation by intimal tear in ascending aorta might decrease diastolic pressure at aortic root and make myocardial ischemia.

CT findings of thoracic manifestations of primary Sjögren syndrome: radiologic-pathologic correlation.

Primary Sjögren syndrome is an immune-mediated exocrinopathy characterized by lymphoplasmacytic infiltration of the salivary and lacrimal glands. Various systemic extraglandular disorders are associated with primary Sjögren syndrome, and the thorax is commonly affected. The pulmonary manifestations of primary Sjögren syndrome may be categorized as airway abnormalities, interstitial pneumonias, and lymphoproliferative disorders; in each category, bronchiectasis or centrilobular nodules, nonspecific interstitial pneumonia, and lymphoid interstitial pneumonia are common. These manifestations do not usually occur in isolation; they are concomitantly seen with other types of lesions. Mucosa-associated lymphoid tissue (MALT) lymphoma and amyloidosis are key components of lymphoproliferative disorders, and MALT lymphoma should always be considered because its morphologic characteristics are similar to those of benign lymphoproliferative disorders. Amyloidosis is rare but important because it carries a risk for underlying MALT lymphoma or plasmacytoma, and it may lead to hemoptysis during biopsy. In addition, thin-walled air cysts are characteristic of primary Sjögren syndrome, irrespective of the main pulmonary manifestations. Lymphadenopathy and multilocular thymic cysts may be seen in the mediastinum. During the follow-up period, there is a risk for acute exacerbation of interstitial pneumonia and development of malignant lymphoma. Often, primary Sjögren syndrome is subclinical, but there are various underlying risks. Thus, imaging findings are important. In addition to the various types of interstitial pneumonia and airway abnormalities, air cysts and mediastinal manifestations may help diagnose primary Sjögren syndrome.

Phosphaturic mesenchymal tumor, nonphosphaturic variant, causing fatal pulmonary metastasis.

Phosphaturic mesenchymal tumors of the mixed connective tissue type (PMT-MCTs) are rare neoplasms, most of which are benign and cause tumor-induced osteomalacia because of overproduction of a phosphaturic hormone, fibroblast growth factor 23 (FGF23). This entity may have been unrecognized or misdiagnosed as other mesenchymal tumors, such as giant cell tumor, hemangiopericytoma, and osteosarcoma. Ten percent of these tumors, without phosphaturia, were diagnosed only by their histologic features. We report here the first case of malignant PMT-MCT, nonphosphaturic variant, resulting in fatal multiple lung metastases. Chondromyxoid matrix with "grungy" calcification, multinucleated giant cell proliferation, and expression of FGF23 mRNA (reverse transcription-polymerase chain reaction) and fibroblast growth factor 23 protein (immunohistochemistry) were seen in the primary and recurrent tumors of the right foot. The lung metastases showed flocculent calcification and FGF23 protein expression as well as giant cell proliferation. This unique case highlights the need for careful histologic assessment of PMT-MCTs, especially the nonphosphaturic variant, and the need for recognition of its rare malignant behavior.

[Primary cardiac leiomyosarcoma originating from the left atrium].

Primary malignant cardiac tumors occur extremely rarely. Among these, leiomyosarcomas are exceptionally rare. We described a case of left atrial leiomyosarcoma in which surgical intervention was followed by adjuvant radiation therapy. A 74-year-old male was admitted for dyspnea. Chest X-ray showed severe pulmonary congestion. Echocardiography revealed large tumor in the left atrium. Emergency operation was performed. The tumor invaded the left atrial wall and the mitral valve, and the lesion was resected as extensively as possible. Postoperative pathologic examination confirmed leiomyosarcoma. He underwent adjuvant radiotherapy postoperatively. However, early local recurrence was recognized. He died due to sudden circulatory collapse in 8th postoperative month. As cardiac leiomyosarcomas have extremely poor prognosis, complete resection and effective postoperative adjuvant therapy are necessary.

A case of typical carcinoid of the larynx.

We report herein a rare case of typical carcinoid occurring primarily in the epiglottis. The patient was a 70-year-old man. On initial examination, a polypoid lesion with irregular surface near the center right-hand side of the laryngeal surface of the epiglottis was observed, and a biopsy was performed. Pathological examination of the specimen suggested the possibility of adenocarcinoma. Surgical excision was performed by means of laryngomicrosurgery. A Weerda-type laryngoscope was used to open the larynx, supplemented by rigid nasal sinus surgery endoscopes, and the right-hand half of the epiglottis were excised was ensured using a CO(2) laser. Postoperative pathological diagnosis was negative for adenocarcinoma and squamous cell cancer; typical carcinoid was diagnosed according to the World Health Organization criteria. Aspiration occurred postoperatively, swallowing training was therefore provided, and the patient was discharged from hospital 2 months after surgery when he was able to eat normally. As of 4 years after surgery, the patient remains under follow-up observation by means of PET-CT and neck, thoracic, and abdominal CT administered at appropriate intervals, but no findings indicating obvious recurrence or metastasis have been observed, and the patient displays good swallowing function.

The utility of a novel antibody in the pathological diagnosis of pancreatic acinar cell carcinoma.

AIMS: Acinar cell carcinomas (ACCs) are rare tumours of the exocrine pancreas accounting for about 1-2% of all pancreatic neoplasms in adults. It is therefore difficult to come across a large number of ACC cases in a single medical institution, and only a few serial studies have been published. Since ACCs present a wide variety of morphological patterns, immunohistochemical analysis is useful. In this study, the authors established a novel monoclonal antibody 2P-1-2-1 by means of a subtractive immunisation method. METHODS: Immunohistochemical staining was performed using 50 primary pancreatic tumors, including 7 ACCs, 7 neuroendocrine tumours (NETs), 5 solid-pseudopapillary neoplasms (SPNs), and 31 ductal carcinomas and organs other than the pancreas. RESULTS: Non-neoplastic acinar cells were stained diffusely, but epithelial cells of the pancreatic duct and the islets of Langerhans were not stained. In pancreatic tumours, all the seven ACCs were diffusely positive for the 2P-1-2-1 antibody. However, no positive staining was found in other pancreatic tumours including NETs, SPNs and ductal adenocarcinomas. The sensitivity and specificity of the 2P-1-2-1 antibody for ACCs were both 100%. In other organs studied, positive staining was observed only in the ectopic pancreas. CONCLUSIONS: It was shown that the 2P-1-2-1 antibody specifically stained the pancreatic acinar cells and tumours of acinar cell origin, such as ACCs. Although it remains unclear at this time to which proteins the monoclonal antibody 2P-1-2-1 is directed, it is suggested to be useful for the pathological diagnosis of ACCs and for the exclusion of other pancreatic tumours.

Co-existence of positive MET FISH status with EGFR mutations signifies poor prognosis in lung adenocarcinoma patients.

MET, a receptor tyrosine kinase for hepatocyte growth factor, is associated with tumor progression and acquired resistance to epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI). Therefore, MET gene alterations could be both prognostic and predictive. Fluorescence in situ hybridization (FISH) is one method for assessing gene alteration, but the frequency of positive cases varies due to a lack of standardized criteria. We evaluated MET gene copy number in lung adenocarcinoma and its association with clinicopathological characteristics. FISH was applied to evaluate high MET gene copy number and true amplification in 138 lung adenocarcinoma patients using two criteria: the Cappuzzo scoring system and PathVysion. MET positive cases according to the Cappuzzo scoring system evidenced both aneuploidy and true amplification, whereas PathVysion revealed only amplification. Proportion of MET FISH positive cases was 15% and 4% determined by the Cappuzzo system and PathVysion, respectively. PathVysion demonstrated higher frequencies of MET FISH positives among men and smokers and evidenced no MET FISH positives in patients with bronchioloalveolar carcinoma. Prognosis was significantly associated with MET FISH positive only as defined by the PathVysion system (gene amplification), not by the Cappuzzo system. However, progression-free survival time of patients with both EGFR mutations and MET FISH positive defined by the Cappuzzo scoring system was significantly shorter than with EGFR mutations alone. These results suggest that MET FISH is a potential prognostic factor and coexistence of MET FISH with EGFR mutations signifies worse prognosis.