Clinical correlations with EGFR circulating tumor DNA testing in all-stage lung adenocarcinoma.

BACKGROUND: Information on genetic alterations, notably EGFR mutations, is important for guiding non-small-cell lung cancer (NSCLC) treatment. Circulating tumor DNA (ctDNA) analysis represents a less invasive alternative to tissue biopsy for analyzing mutation status, but its clinical value may vary across disease stages. OBJECTIVE: To explore clinical correlates of ctDNA and tissue/plasma-based EGFR mutation (EGFRm) status across all NSCLC stages. METHODS: Ninety patients were analyzed, representing three cohorts: newly-diagnosed early-stage, advanced-stage, and recurrent NSCLC. Relationships among clinical/surgical parameters, ctDNA, EGFRm status, and survival outcomes were analyzed. RESULTS: Plasma/tissue EGFRm concordance was lower in early-stage (58.6%) than in advanced-stage patients (87.5%). In early-stage patients, ctDNA levels were variable and not significantly associated with clinical/surgical parameters. In advanced-stage patients, time to EGFR-TKI treatment failure (TTF), but not overall survival (OS), was significantly longer in EGFRm-positive vs. EGFRm-negative patients. In patients with recurrent disease, 40% of plasma samples were EGFRT790M-positive at recurrence. In T790M-positive patients, we noted slight trends toward longer OS with vs. without osimertinib treatment and longer OS and TTF with second-line vs. later-line osimertinib. CONCLUSIONS: Our results affirm the use of ctDNA testing in advanced-stage and recurrent NSCLC. Further studies on osimertinib as early-line therapy, clinical correlates and the utility of plasma-based testing in early-stage NSCLC are warranted.

Rapidly progressive interstitial pneumonia associated with anti-NXP2 antibody secondary to malignancy.

The diagnosis of a diffuse lung disease is challenging for physicians and it requires a multidisciplinary team approach to solve this problem. Herein, we present a case of common bile duct obstruction from pancreatic ductal adenocarcinoma after biliary stent placement, which developed a rapidly progressive bilateral lung infiltration after oesophagogastroduodenoscopy. After a diagnostic evaluation based on clinical, radiographic, and pathological findings, a diagnosis of rapidly progressive interstitial pneumonia associated with anti-nuclear matrix protein (NXP) 2 antibody secondary to malignancy was made. In patients with interstitial lung disease with unclear aetiologies, autoantibodies, including antinuclear antibody and myositis-specific antibodies should be evaluated, even if there are no clinical signs of autoimmune disease. Although this is the first case report of an acute interstitial pneumonitis-associated anti-NXP2 antibody, physicians should recognise this condition as it can rapidly cause acute fulminant respiratory failure.

Myeloperoxidase-antineutrophil cytoplasmic antibody-associated diffuse alveolar hemorrhage caused by denosumab.

Denosumab is a bone anti-resorptive drug, commonly used for treating osteoporosis. Pulmonary involvement has rarely been reported as a possible serious adverse effect of this medication. Herein, we report the case of a 67-year-old woman who presented with non-massive hemoptysis, anemia, and extensive pulmonary opacities on a chest radiograph for 3 days after receiving denosumab. The patient was diagnosed with myeloperoxidase-antineutrophil cytoplasmic antibody-associated pulmonary hemorrhage secondary from denosumab. She was treated with high doses of intravenous methylprednisolone and cyclophosphamide combined with plasmapheresis. Subsequently, her clinical and radiological findings improved without residual abnormalities after treatment.

Combined Pulmonary Tuberculosis with Pulmonary and Pleural Cryptococcosis in a Patient Receiving Ruxolitinib Therapy.

With an advance in therapy, there are increasing emerging and re-emerging opportunistic infections among patients with hematologic conditions and malignancy. Herein, we present a 56-year-old woman with primary myelofibrosis who developed combined tuberculosis (TB) and cryptococcosis with extensive pulmonary, pleural, and nodal involvement during ruxolitinib therapy. Marked clinical and radiologic improvements were undoubtedly evident after receiving anti-TB and antifungal therapies and pleural drainage. Hence, the presence of atypical clinical and radiologic manifestations and incomplete responses, despite receiving adequate antimicrobial treatment, should raise concerns regarding the combined emerging and re-emerging opportunistic infections and the possibility of unusual radiologic manifestations of cryptococcosis in a ruxolitinib-treated patient.

Non-Small Cell Lung Carcinoma with Concomitant Localized Pulmonary Melioidosis: A Rare Co-Existing Disease.

Melioidosis is caused by Burkholderia pseudomallei, water-and-soil gram-negative bacteria predominantly found in Southeast Asia and Australia. Herein, we reported a 63-year-old Thai man presenting with prolonged fever, non-productive cough, and weight loss for 3 months. He underwent deceased donor kidney transplantation 4 years ago and was on many immunosuppressive agents after transplantation. At presentation, his chest radiograph showed a mass-like lesion in the left upper lobe. Histopathological examination of a transthoracic needle lung biopsy yielded adenocarcinoma, while tissue culture grew for B. pseudomallei. He was diagnosed with stage IIIA non-small cell lung cancer (T4N0M0) co-existing with localized pulmonary melioidosis. After intensive and eradication therapy for melioidosis, his well-being improved with the resolution of fever. He sequentially underwent left upper lobectomy, but the procedure was not accomplished due to severe adhesions surrounding the left lung and great vessels. After surgery, he received concurrent chemoradiation therapy for his lung cancer. Nevertheless, the disease progressed, and he finally passed away. Since fever is not a common manifestation of lung cancer, co-existing infection, such as tuberculosis, fungal infection, and melioidosis, should always be excluded in patients suspected of having lung cancer presenting with unexplained fever.

Association of histologic subtypes with genetic alteration and PD-L1 expression in pulmonary adenocarcinoma.

Genetic alteration and programmed death-ligand 1 (PD-L1) expression have been revealed to be associated with various subtypes of pulmonary adenocarcinoma (ADC). The present study aimed to explore the association between histological subtypes and genetic alterations and PD-L1 expression. A total of 375 cases of pulmonary ADC were included. Genetic alterations were determined using next generation sequencing (NGS) in 136 cases. PD-L1 expression was detected by immunohistochemistry (based on clone 22C3) in the remaining 239 cases. Mutations in the epidermal growth factor receptor gene (EGFR) were detected in 76 (55.8%) cases associated with the papillary subtype (P=0.038). Mutations in the Kirsten rat sarcoma viral oncogene homolog gene (KRAS) were present in 46 (33.8%) cases associated with the lepidic subtype (P<0.001) and mucinous ADC (P=0.037). PD-L1 expression was identified in 63 (26.4%) cases associated with the solid subtype (P<0.001). In conclusion, the present study demonstrated that EGFR and KRAS mutations, alongside PD-L1 protein expression are significantly associated with specific subtypes of pulmonary ADC. These results should aid our ability to accurately select appropriate areas of the heterogeneous tumor for molecular testing methods and to predict patient outcomes and prognosis.

Role of BIM Deletion Polymorphism and BIM Expression as Predictive Biomarkers to Maximize the Benefit of EGFR-TKI Treatment in EGFR-Positive NSCLC.

OBJECTIVE: BIM is a modulator of apoptosis that is triggered by EGFR-TKIs. This study evaluated the role of BIM deletion and its expression as predictor of EGFR-TKI treatment outcome. METHODS: The medical record of 185 EGFR-positive advanced non-small cell lung cancer (NSCLC) patients with/ without EGFR-TKI treatment between 9/2012 and 12/2014 were retrospectively reviewed. BIM deletion polymorphism and expression were tested by RT-PCR and immunohistochemistry, respectively. Survival outcomes in EGFR-TKI-treated patients were analyzed according to treatment sequence and EGFR mutation. The correlation between BIM deletion polymorphism, expression, response rate (as a function of EGFR-TKI treatment) and schedule was also explored. RESULT: EGFR-TKIs were administered to 139 (75.1%) of the 185 patients: as the first-line in 52 (37.4%) patients and as later-line treatment in 87 (62.6%) patients. Median overall survival (mOS) was significantly longer in EGFR-TKIs treated patients (28.9 vs. 7.4 months, P<0.001). Among L858R-mutated patients, median progression-free survival (mPFS) was significantly longer in first-line EGFR TKI treatment than a later-line (12.6 vs. 6.3 months, P=0.03). BIM deletion polymorphism and expression was detected in 20.2% and 52.7%, respectively. Patients without BIM deletion polymorphism had a significantly longer mOS when treated with a first-line than with a later-line EGFR-TKI (28.9 vs. 20.7 months, P= 0.04). Patients without BIM expression had a significantly longer mPFS (9.6 vs. 7.3 months, P=0.01) better mOS and response rate (RR). CONCLUSION: BIM deletion polymorphism and expression may predict an EGFR-TKI response in patients with EGFR-positive during therapy.

Asbestos Bodies Burden in the Autopsy Lung Tissue from General Thai Population.

BACKGROUND: Chrysotile asbestos has been used in Thailand for over 30 years mainly in asbestos-cement wall and roof tiles. In non-exposed subject, asbestos fiber can contaminate in ambient indoor and outdoor environments. OBJECTIVE: The aim of the present study is to evaluate the current prevalence and volume of AB load in general Thai population. METHODS: Lung tissues were obtained from 200 autopsy cases. Asbestos Bodies (AB) were identified with light microscopy using the tissue digestion and membrane filtration method. Results are reported as AB/g wet lung tissue. RESULTS: AB was identified in 97(48.5%) out of 200 cases. The AB level ranged from 0.19-14.4 AB/g wet lung. Most of the positive cases (99%) have less than 10 AB/g wet lung. Only one case exhibited a high value at 14.4 AB/g wet lung. Age, gender, occupation and hometown were found to have no effect on AB burden in autopsy lung tissue from this study. CONCLUSION: The prevalence of AB in autopsy lung tissue from general Thai population is 48.5% and the AB level ranges from 0-14.4 AB/g wet lung in consistent with non-occupational asbestos exposure level regarding several reference reports.

Clinical and Pathological Correlation in Pediatric Invasive Pulmonary Aspergillosis.

INTRODUCTION: Invasive' pulmonary aspergillosis (IPA) has been one of the major causes of mortality in immunocompromised patients. The gold standard method for a diagnosis of IPA is histopathological examination of the lung tissue; however, post-procedural bleeding limits the feasibility of lung biopsy. The European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and The National Institute of Allergy and Infectious Disease Mycoses Study Group (EORTC/MSG) defined IPA. The objective of this study was to validate the EORTC/MSG 2008 definition of IPA, compared with histopathology in the pediatric population. METHODS: Histopathological examinations of lung tissues of children aged 1 month-18 years with respiratory tract infection at the time of obtaining biopsy were retrieved. Retrospective chart reviews for clinical characteristics were performed. IPA diagnosis was classified according to the EORTC/MSG 2008 definition. RESULTS: During the 10-year period, there were 256 lung tissues, of which 58 specimens were suspected to have pulmonary infection. Fourteen patients (24%) were noted to have IPA. Seven patients (50%) with proven IPA were classified as probable, while the remaining 50% were classified as possible, and none were classified as no IPA, by using EORTC/MSG 2008 definition. Other 44 specimens demonstrated 14 (32%), 14 (32%), and 16 (36%) were classified as probable, possible, and no IPA, respectively. When comparing probable or possible IPA with no IPA, we found that the EORTC/MSG 2008 definition had 100% sensitivity, 36% specificity, 33% positive predictive value, and 100% negative predictive value in diagnosis of IPA. CONCLUSION: Our study illustrated that the EORTC/MSG 2008 definition provided an excellent sensitivity but low specificity for diagnosing IPA.

KRAS mutation is predictive of outcome in patients with pulmonary sarcomatoid carcinoma.

AIMS: Pulmonary sarcomatoid carcinoma (PSC) is a poorly differentiated non-small-cell lung carcinoma (NSCLC) with aggressive behaviour. This study aimed to evaluate the prognostic clinicopathological and genetic characteristics of PSCs. METHODS AND RESULTS: Fifty-three cases of surgically treated PSCs were selected, 23 of which were subjected to mutation and copy number variation analysis using the 50-gene Ion AmpliSeq Cancer Panel. The majority of the patients were male (32 of 53, 60.3%) and smokers (51 of 53, 96.2%). Overall, 25 (47.1%) patients died within 2-105 months (mean = 22.7 months, median = 15 months) after diagnosis, and 28 were alive 3-141 months (mean = 38.7 months, median = 21.5 months) after diagnosis. Five-year overall survival was 12.5%. KRAS codon 12/13 mutation in adenocarcinomas (P = 0.01), age more than 70 years (P = 0.008) and tumour size ≥4.0 cm (P = 0.02) were associated strongly with worse outcome. TP53 (17 of 23, 74.0%) and KRAS codon 12 of 13 mutations (10 of 23, 43.4%) were the most common genetic alterations. Potentially actionable variants were identified including ATM (four of 23, 17.3%), MET, FBXW7 and EGFR (two of 23, 8.7%), AKT1, KIT, PDGFRA, HRAS, JAK3 and SMAD4 (one of 23, 4.3%). MET exon 14 skipping and missense mutations were identified in two (11.1%) cases with adenocarcinoma histology. Copy number analysis showed loss of RB1 (three of 23, 13%) and ATM (two of 23, 8.7%). Copy number gains were seen in EGFR (two of 23, 13.0%) and in one (4.3%) of each PIK3CA, KRAS, MET and STK11. CONCLUSIONS: Potentially targetable mutations can be identified in a subset of PSC, although most tumours harbour currently untargetable prognostically adverse TP53 and KRAS mutations.

A comparative study of conventional cytology and cell block method in the diagnosis of pleural effusion.

BACKGROUND: In a patient with pleural effusion, cytological study (CS) is one of the most useful investigations, especially when malignancy is suspected. Instead of applying only CS, the pleural fluid can be further processed using the cell block (CB) technique, which may augment the diagnostic utility. The aim of this study was to compare the diagnostic yields of CS, CB, and the combination of both, regardless of the etiology of pleural effusion. METHODS: A cross-sectional study was conducted on patients with pleural effusions who underwent thoracentesis from June 2015 to May 2016. All samples were submitted for routine biochemical analysis, CS, and CB histology. The results of cytopathological studies were compared to the final diagnoses. RESULTS: Out of a total of 353 samples, the final diagnoses included 278 (78.8%) malignancies, 41 (11.6%) infectious diseases, 16 (4.5%) other inflammatory diseases, and 18 (5.1%) transudative pleural effusions. CS and CB provided a similar diagnostic yield (48.7% vs. 49.9%, P=0.69), while the combination of both gave a higher yield (57.2%) (P<0.001, compared with CS). Among 278 malignant pleural effusions (MPE), the diagnostic yields of CS and CB were 61.2% and 61.9%, respectively. Combined CS and CB improved the diagnostic yield to 71.2% (P<0.001). However, both CS and CB had low diagnostic yields in infectious pleuritis, other inflammatory diseases, and transudative pleural effusions. CONCLUSIONS: In MPE, CB provides a similar diagnostic performance to CS, while application of both techniques can significantly increase the diagnostic yield. However, in other pleural diseases, CB and CS had limited values in diagnosis.

ALK FISH patterns and the detection of ALK fusions by next generation sequencing in lung adenocarcinoma.

Break-apart ALK FISH probe is the FDA approved approach for detection of ALK rearrangements in lung carcinoma patients who may benefit from ALK kinase inhibitors. The FISH assay can be technically challenging and difficult to interpret. ALK immunohistochemistry and next generation sequencing have been proposed as alternative approaches. In this study, we compared various ALK -FISH patterns to next -generation sequencing (NGS) for gene fusion detection, ALK immunohistochemistry (IHC) and tumor responses to crizotinib. 72 (4%) of 2116 lung adenocarcinoma were positive by ALK- FISH. Of 28 ALK-FISH positive cases selected for the study, FISH patterns included 15 (54%) cases with split signal, 10 (36%) with single orange signal and 3 (10%) with "mixed pattern". 12 (80%) cases with split signal and 4 (40%) cases with single orange signal were positive by NGS and IHC, while mixed cases were all negative. Mutation analysis of discordant cases revealed multiple mutations including oncogenic mutations in EGFR, KRAS, BRAF and ATM genes. All discordant cases in groups with split and mixed signal showed a lower number of cells with rearrangement (mean 28.5%; range 20.5-36.9%). No statistically significant association between response to crizotinib and FISH patterns was observed (p=0.73). In contrast, NGS fusion positive cases were associated with more responses to crizotinib than NGS negative cases (p= 0.016). Our study suggests that ALK FISH alone may not be the most reliable assay for detection of ALK gene rearrangements, and probably should be used in parallel with ALK IHC and NGS for detection of gene fusions and mutations.

ALK-rearranged pulmonary adenocarcinoma in Thai Patients: From diagnosis to treatment efficacy.

BACKGROUND: Anaplastic lymphoma kinase (ALK) gene rearrangement is detected in 3% to 13% of non-small cell lung carcinoma patients, and these patients benefit from ALK inhibitors. The aim of this study was to determine the prevalence, the clinical and histological characteristics and the treatment outcomes of ALK-rearranged lung adenocarcinoma using immunohistochemistry (IHC) IHC, reverse transcription polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) methodologies. METHODS: A total of 268 pulmonary adenocarcinoma patients were screened for ALK expression by ALK IHC, which was confirmed by FISH and/or RT-PCR for ALK gene rearrangement. The treatment outcomes of ALK-rearranged patients were retrospectively reviewed. RESULTS: ALK gene rearrangement was identified in 26 cases (9.7%) with no EGFR co-mutation, and it showed significant associations with younger age, female sex and non-smoker status (p < 0.05). A cribriform growth pattern was identified as the dominant histologic feature, and a solid signet ring cell component was focally present in a minority of the cases. Among 12 ALK-rearranged patients with conventional treatment, seven cases in the early stage of disease were cured and alive, and five patients in the late stage of the disease progressed and died, with a median overall survival (OS) at 14 months. Of the 14 patients receiving crizotinib, all of them had clinical benefit from crizotinib treatment, with one patient having a complete response (CR), 12 patients having a partial response (PR) and one patient having stable disease (SD). On the cutoff date, six of 14 patients were continuing crizotinib treatment with a median time of response of 7.5 (3-13) months, while eight patients had disease progression, and five of them died with a median OS at 8 months. CONCLUSION: ALK gene rearrangement tended to occur in younger, non-smoking, female patients. ALK IHC is a reliable screening method to detect ALK gene rearrangement. Crizotinib therapy provided treatment benefit in ALK-rearranged adenocarcinoma patients especially in advanced stages of the disease.

Morphological and molecular approach to synchronous non-small cell lung carcinomas: impact on staging.

Distinction between multiple primary cancers and intrapulmonary metastases in patients with synchronous multifocal lung cancer can be challenging. Histological and genotypic assessment of multifocal lung tumors have been suggested to influence the staging. The aim of this study was to determine the role of morphology and genotype in staging of surgically treated multifocal non-small cell lung carcinoma. Synchronous lung cancers from 60 patients (42 with adenocarcinoma and 18 with squamous cell carcinoma), clinically considered to represent intrapulmonary metastases, were histologically subtyped according to the 2015 World Health Organization classification of lung tumors and subjected to genotypic analysis (KRAS, EGFR, BRAF, PIK3CA, ALK, MET and ROS1 in adenocarcinoma and PIK3CA and p16 in squamous cell carcinoma). Concordance between clinical criteria and histological subtyping was identified in about 50% of cases (P<0.0001). Genotypically, 44% of adenocarcinomas and 60% of squamous cell carcinomas with identified molecular alterations were considered to be intrapulmonary metastases. Concordance between histological and molecular staging was observed in 89% of adenocarcinomas and 56% of squamous cell carcinomas. Univariate survival analyses failed to demonstrate significant differences in overall or cancer-specific survival in patients with adenocarcinoma and squamous cell carcinomas restaged according to histology and/or molecular profile. Lymph node metastases (N1/N2 vs N0) (P=0.03) and age >65 years (P=0.05) were associated with shorter overall survival. In addition, squamous cell carcinomas with p16 deletion showed shorter overall survival when compared with squamous cell carcinomas without p16 deletion (P=0.05). No correlation between other molecular alterations, clinico-pathological characteristics and prognosis was found. Our study demonstrates that a comprehensive genotypic and morphological assessment of surgically treated multifocal lung cancers is feasible but not sufficient to establish their clonal relationship and prognosis.

Accuracy of the IASLC/ATS/ERS histological subtyping of stage I lung adenocarcinoma on intraoperative frozen sections.

Histological subtyping of surgically resected lung adenocarcinoma has been shown to be of prognostic significance, and limited surgical resection has been proposed as a treatment of choice for early-stage lung adenocarcinoma. The accuracy of histological subtyping has been recently assessed in the surgical resection and small biopsy specimens; however, the accuracy of intraoperative subtyping on frozen sections remains relatively unknown. The aim of this study was to determine diagnostic accuracy and interobserver variability in histological subtyping of lung adenocarcinoma on intraoperative frozen sections. Overall, 112 consecutive cases of surgically resected stage I lung adenocarcinoma were reviewed independently by three pathologists. Histological patterns (acinar, lepidic, papillary, micropapillary, and solid) and mucinous variant were recorded in 5% increments for each intraoperative frozen and permanent sections. Primary and secondary histological patterns were assigned in each case. Kappa scores were calculated to evaluate agreement between pathologists in the assessment of histological subtype on intraoperative frozen sections versus permanent sections. Overall agreement between intraoperative frozen and permanent sections was moderate for primary pattern (69.7% of cases), with kappa scores ranging from 0.43 to 0.58, with more consistent agreement for stage IA tumors. Kappa scores for the secondary pattern ranged from 0.16 to 0.32. Acinar and solid patterns were most likely to be correctly identified as primary growth patterns. Micropapillary pattern was recognized in only 11-55% of cases. The main reasons for discrepancies between intraoperative frozen and permanent sections were inadequate sampling and poor quality of frozen sections. Our study suggests that it is difficult to predict the primary adenocarcinoma pattern on a single representative frozen section. This observation suggests a potential impact on the extent of frozen section sampling by pathologists at the time of intraoperative consultation, if surgical management of stage I lung adenocarcinoma will be guided by its histological subtype.

Determination of asbestos bodies in bronchoalveolar lavage fluids in Thailand.

OBJECTIVE: Asbestos bodies (AB), ferroprotein-coated asbestos fiber may be present in bronchoalveolar lavage fluid (BALF) of asbestos exposed persons. The present study was conducted to evaluate the prevalence and number of asbestos bodies in the BALF of tenable asbestos exposed workers compare to general population in Thailand. MATERIAL AND METHOD: Thirty workers of cement pipe and roof tile factories using chrysotile asbestos and 30 unexposed patients that underwent diagnostic bronchoscopy were included in this study. Determination of asbestos bodies was made by membrane filtration method as described in earlier reports. RESULTS: The findings were positive in six workers and in one control subject (0.1-3.6 vs. 0.2 AB/ml of BALF, p = 0.449). CONCLUSION: AB was identified in workers more often than in pulmonary disease patient. Two of workers had more than 1 AB/ml of BALF.

Clinical and radiologic manifestations of pulmonary cryptococcosis in immunocompetent patients and their outcomes after treatment.

PURPOSE: We aimed to investigate clinical and radiologic manifestations of pulmonary cryptococcosis in immunocompetent patients and their outcomes after treatment. MATERIALS AND METHODS: We retrospectively reviewed the medical records, initial and follow-up chest computed tomography scans and/or radiographs for initial clinical and radiologic manifestations and outcomes following antifungal treatment of 12 immunocompetent patients diagnosed with pulmonary cryptococcosis between 1990 and 2012. RESULTS: Twelve patients (age range, 21-62 years; males, eight patients [66.7%]) were included. Nine (75%) patients were symptomatic, eight of whom had disseminated infection with central nervous system involvement. Initial pulmonary abnormalities consisted of single nodules/masses (n=5), single segmental or lobar mass-like consolidation (n=3), multiple cavitary and noncavitary nodules (n=1), and multifocal consolidation plus nodules (n=3). These lesions ranged from less than 1 cm to 15 cm in greatest diameter. Distinct subpleural and lower lung predominance was observed. Seven patients (58.3%) had one or more atypical/aggressive findings, namely endobronchial obstruction (n=4), calcified (n=1) or enlarged (n=4) mediastinal/hilar lymph nodes, vascular compression (n=1), pericardial involvement (n=1), and pleural involvement (n=2). Following antifungal therapy, radiologic resolution was variable within the first six months of eight nonsurgical cases. Substantial (>75%) improvement with some residual abnormalities, bronchiectasis, cavitation, and/or fibrotic changes were frequently observed after 12-24 months of treatment (n=6). CONCLUSION: Pulmonary cryptococcosis in immunocompetent patients frequently causes disseminated infection with atypical/aggressive radiologic findings that are gradually and/or incompletely resolved after treatment. The presence of nonenhanced low-attenuation areas within subpleural consolidation or mass and the absence of tree-in-bud appearance should raise concern for pulmonary cryptococcosis, particularly in patients presenting with meningitis.

Glomerular macrophage is an indicator of early treatment response in diffuse proliferative lupus nephritis.

BACKGROUND: Patients with diffuse proliferative lupus nephritis (class IV) who responded to treatment within 6 months had better renal outcome than those who did not. Glomerular macrophage is known to be associated with poor renal outcome in glomerular diseases. OBJECTIVE: To evaluate association between glomerular macrophage number and early treatment response in lupus nephritis class IV patients. MATERIAL AND METHOD: Renal biopsies (n = 90, 86 females) diagnosed with lupus nephritis class IV were included in the study. The patients were divided into 2 groups (n = 45 each) according to response to treatment within 6 months. The treatment response group was defined as having decreased serum creatinine at least 25% from baseline and 24 hr urine protein or UPCR (urine protein creatinine ratio) < 1. The non-response group was defined as stable or increased serum creatinine and 24 hr urine protein or UPCR > or = 1. Immunohistochemistry for macrophage marker (CD68) was performed and the glomerular macrophages were counted on each biopsy. The relevant clinicopathologic data were collected. RESULTS: The glomerular macrophage number in response and non-response group was 4.5 +/- 2.5 and 6.2 +/- 4.5 respectively (p = 0.029). The glomerular macrophage number was conversely and inversely correlated with activity (r = 0.281, p = 0.007) and chronicity (r = -0.358, p < 0.001) index, respectively CONCLUSION: Lupus nephritis class IV patients who responded to treatment within 6 months had lower glomerular macrophages than those who did not. The glomerular macrophage number may be used to determine treatment response in lupus nephritis class IV patients.

Androgenic pathway in triple negative invasive ductal tumors: its correlation with tumor cell proliferation.

Triple negative breast cancer (TNBC) is defined by estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 negativity. Patients with TNBC frequently undergo an aggressive clinical course due to the unavailability of specific targeted therapies. Androgen receptor (AR) was reported to be expressed in up to 60% of TNBC cases but there have been controversies as to the roles of androgen signaling through AR in TNBC. Therefore, in this study, we analyzed the status of AR in combination with androgen synthesizing enzymes (5α-reductase type 1 (5αR1) and 17ß-hydroxysteroid dehydrogenase type 5 (17ßHSD5)] in order to further understand androgenic actions in TNBC. Androgen receptor, 5αR1, and 17ßHSD5 were immunolocalized in a cohort of 203 TNBC patients from Thailand and Japan. We then correlated the findings with clinicopathological characteristics (age, stage, tumor diameter, lymph node invasion, metastatic spread, Ki-67 labeling index, disease-free survival, and overall survival) of the patients. Univariate analysis revealed that AR+/enzyme+ cases were associated with a significantly lower Ki-67 labeling index than AR-/enzyme- samples. Multivariate analysis indicated the presence of significant positive correlations between AR and enzyme status in tumor cells, and between tumor diameter, lymph node invasion, and distant metastasis. Significant negative correlations were also detected between Ki-67 labeling index and AR status (P = 0.04) or 5αR1 (P < 0.001). Cox proportional hazards analysis showed that Ki-67 labeling index and stage were the only factors predicting disease-free and overall survival of the patients, although univariate Kaplan-Meier analysis revealed AR/5αR1 negativity suggested a more adverse clinical course up to 80 months after surgery. These results suggest that the presence of androgen synthesizing pathways in addition to AR expression in tumor cells could confer a better clinical outcome through suppression of cell proliferation.