Pleuropulmonary Blastoma with Hotspot Mutations in RNase IIIb Domain of DICER 1: Clinicopathologic Study of 10 Cases in a Single-Institute Experience

Pathobiology ◽  
2021 ◽  
pp. 1-10
Author(s):  
Miseon Lee ◽  
Tae-im Kim ◽  
Se Jin Jang ◽  
Kyung-Ja Cho ◽  
Sang Min Lee ◽  
...  
Keyword(s):  
Early Stage ◽  
Medical Center ◽  
Pleuropulmonary Blastoma ◽  
Type I ◽  
Missense Mutations ◽  
Type Iii ◽  
Clinicopathologic Study ◽  
The Status ◽  
Hotspot Mutations ◽  
Hotspot Mutation

<b><i>Introduction:</i></b> Pleuropulmonary blastoma (PPB) is a rare sarcomatous malignancy involving the lung and pleura which occurs in early childhood. Cystic PPB in the early stage can be misdiagnosed as other cystic diseases. Early detection of this entity is important for appropriate treatment and prevention of disease progression. Hotspot mutations in the ribonuclease IIIb (RNase IIIb) domain of <i>DICER1</i> have been reported to have a crucial role as genetic factors of PPB and <i>DICER1</i> familial syndrome. We reviewed the clinicopathologic findings of PPB and the status of <i>DICER1</i> hotspot mutation and patients’ clinical course. <b><i>Methods:</i></b> We retrospectively reviewed all patients with histologically confirmed PPB at Asan Medical Center between 2000 and 2017. Ten cases were identified in the database, and their clinicopathologic parameters were evaluated. PPB was classified into the following 3 pathologic subtypes: type I (purely cystic), type II (mixed cystic and solid), and type III (entirely solid). The status of <i>DICER1</i> mutation in 2 hotspot regions of the RNase IIIb domain was evaluated by Sanger sequencing. <b><i>Results:</i></b> The most frequent PPB type was II (6 cases), followed by I and III (2 cases each). The age at diagnosis ranged from 16 months to 15 years. All patients underwent surgery, and all patients received adjuvant or neoadjuvant chemotherapy. Four of 7 patients had missense mutations in the RNase IIIb hotspot; the base and predicted corresponding amino acid changes were c.5113 G&#x3e;A (p.E1705K), c.5407 G&#x3e;A (p.E1803K), c.5425 G&#x3e;A (p.G1809R), and c.5428 G&#x3e;T (p.D1810Y). There was no particular association between the presence of the hotspot mutation and histologic type. Nine patients survived with no evidence of disease for a median interval of 93 (range, 13–199) months. Only 1 patient diagnosed with type III PPB at the age of 18 years had recurrence after 20.8 months and eventually died 66 months after the initial diagnosis. <b><i>Conclusions:</i></b> Late detection of solid PPB is associated with poor prognosis. Considering the rarity of PPB disease and the importance of <i>DICER1</i> hotspot mutation in pathogenesis, <i>DICER1</i> hotspot mutation testing and identification in the early cystic stage can improve patient outcomes.

DICER1 Hotspot Mutations in Pleuropulmonary Blastoma: A Case Series From a Tertiary Center

2019 ◽  
Vol 23 (3) ◽  
pp. 204-209 ◽  
Author(s):  
O Hurdogan ◽  
I Yilmaz ◽  
SB Bay ◽  
S Vural ◽  
D Tugcu ◽  
...  
Keyword(s):  
Survival Rate ◽  
Case Series ◽  
Pleuropulmonary Blastoma ◽  
Type I ◽  
Missense Mutations ◽  
Type Ii ◽  
Turkish Children ◽  
Type Iii ◽  
Tertiary Center ◽  
Hotspot Mutations

Pleuropulmonary blastoma (PPB) is a potentially aggressive, rare childhood neoplasia. We investigated histopathological features, survival, and DICER1 hotspot mutations among PPB patients. Archive records at our institution were reviewed, covering a 20-year period. Thirteen children (6 males and 7 females) with a mean age of 30.5 (range 6–83) months were included. The tumor subtypes were type I in 6 (46%), type II in 4 (31%), and type III in 3 (23%). Only tumors with type II and type III histology showed anaplasia (4/7, 57%). Median follow-up was 28 (range 9–216) months. Three-year overall survival rate was 83.3% and 3-year progression-free survival rate was 25%. Progression was seen in 60% (3/5) of type I and 66.7% (4/6) of type II and type III cases. Two patients died of disseminated disease at 9 and 44 months. Hotspot missense mutations on DICER1 gene were detected in all 11 patients with available tumor tissue. We found an additional novel germline loss-of-function mutation (c.5436dupT; p.E1813*) in 1 case. To the best of our knowledge, this is the first study to investigate hotspot missense mutations on DICER1 gene among the largest series of Turkish children with PPB.

Effects of Fractional CO2 Laser Treatment on Subglottic Scar in a Rabbit Model

2020 ◽  
pp. 019459982097825
Author(s):  
Kastley Marvin ◽  
Isaac Schwartz ◽  
Edward Utz ◽  
Justin Wilson ◽  
Christopher Johnson ◽  
...  
Keyword(s):  
Laser Treatment ◽  
Type I Collagen ◽  
Medical Center ◽  
Academic Medical Center ◽  
Rabbit Model ◽  
Study Endpoint ◽  
Type Iii Collagen ◽  
Type I ◽  
Respiratory Complications ◽  
Type Iii

Objective The objective of this study was to investigate the effects of fractional CO2 laser on subglottic scar. Study Design Randomized controlled animal study. Setting Academic medical center. Methods Subglottic scar was induced in 12 New Zealand white rabbits via an endoscopic brush technique. This was followed by an open airway surgery that included vertical division of the cricoid and proximal trachea. Eight rabbits underwent fractional CO2 laser treatment of the scar via a Lumenis Ultrapulse Deep FX handpiece. Four rabbits underwent the open surgical approach without laser treatment. Bronchoscopy was performed at weeks 1, 2, 4, and 8. The animals were euthanized and laryngotracheal complexes harvested 12 weeks postsurgery. Immunohistochemistry was performed to determine the collagen composition of treated and untreated scars. Results All 12 subjects survived to the study endpoint with no significant respiratory complications, despite 10 of 12 developing some degree of lateral tracheal narrowing. The median ratio of type I collagen to type III collagen in the laser group (1.57) was significantly more favorable than that of the untreated group (2.84; P = .03). Conclusion Treatment with fractional CO2 laser appears to have similar effects on subglottic scars as with cutaneous scars, improving the ratio of type I to type III collagen. Additionally, we developed an open airway approach in the rabbit model to deliver fractional CO2 laser treatment to the subglottis without introducing respiratory complications or compromising survival.

scholarly journals AN EXPERIMENTAL ANALYSIS OF THE CURATIVE ACTION OF PENICILLIN IN ACUTE BACTERIAL INFECTIONS

1956 ◽  
Vol 103 (4) ◽  
pp. 499-508 ◽  
Author(s):  
Mary Ruth Smith ◽  
W. Barry Wood
Keyword(s):  
Bacterial Infections ◽  
Total Population ◽  
Early Stage ◽  
Direct Action ◽  
Significant Degree ◽  
Bactericidal Effect ◽  
Suppressive Effect ◽  
Type I ◽  
Active Growth ◽  
Type Iii

Type I pneumococci injected into the leg muscles of otherwise normal mice reached a maximum total population of approximately 106 organisms. In mice rendered severely leucopenic by previous irradiation the maximum bacterial counts recorded were of the order of 109. Since the lesions in the latter animals were relatively acellular, the thousandfold difference in the two experiments represented a rough measure of the antibacterial action of the leucocytic exudate. The suppressive effect of the leucocytic exudate was shown by histologie studies to involve phagocytosis. The ingestion of pneumococci was clearly demonstrable within the first 12 to 18 hours. Accordingly, it was attributed to surface phagocytosis. In support of this conclusion was the finding that type III pneumococci reached a significantly higher total population in the myositis lesions than did type I. The type III strain used had been previously shown to be resistant to surface phagocytosis during active growth, whereas the type I strain was known to be susceptible throughout its growth phase. Evidence was also presented that the dense leucocytic exudate probably caused in addition a significant degree of bacteriostasis. When penicillin therapy was begun 9 hours after inoculation, the pneumococci were cleared from the lesions with equal rapidity regardless of the presence or absence of leucocytic exudate. At this early stage the pneumococci were multiplying rapidly in the lesions of both the irradiated and unirradiated mice and therefore were promptly killed by the direct action of the penicillin. When the start of treatment was delayed, however, until 24 hours after inoculation, the bacteria in both sets of lesions had already reached their maximum counts and therefore were presumably resistant to the bactericidal effect of the antibiotic. Under such circumstances the destruction of the bacteria was found to be significantly less prompt in the acellular lesions than in those with a normal cellular exudate. It is concluded from these findings that, in established pneumococcal myositis in mice, the curative effect of penicillin is due, not to the bactericidal action of the antibiotic alone, but rather to the combined effect of the drug and the cellular defenses of the host. The same conclusion also appears to be applicable to analogous acute infections in man, particularly when they are sufficiently advanced to be definitively diagnosed.

Effect of radiation on outcome of types II and III PPB: A report from the International Pleuropulmonary Blastoma Registry.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 9521-9521 ◽  
Author(s):  
Gretchen M Williams ◽  
John R. Priest ◽  
Marsha J Finkelstein ◽  
Anne Harris ◽  
Leslie Ann Doros ◽  
...  
Keyword(s):  
Overall Survival ◽  
Radiation Therapy ◽  
Prognostic Significance ◽  
Tumor Resection ◽  
Lung Neoplasm ◽  
Pleuropulmonary Blastoma ◽  
Type I ◽  
Tumor Type ◽  
Type Ii ◽  
Type Iii

9521 Background: Pleuropulmonary blastoma (PPB) is a rare dysembryonic lung neoplasm of early childhood with progression from a purely cystic (Type I) lesion to a solid high-grade sarcoma Type III (T-III), or a mixed solid/cystic stage Type II (T-II). Surgery and chemotherapy are required for T-II and T-III PPB, but the benefit of radiation therapy for T-II and T-III PPB is debated and is being evaluated in this study. Methods: This is a retrospective analysis of central pathology-reviewed Types II and III PPB from the IPPBR. Treatments were chosen by physician, were not randomized, and included surgery and chemotherapy. The outcome of patients treated with upfront radiation (before progression or relapse) was compared to patients who did not receive radiation. Event-free survival (EFS) and overall survival (OS) were determined to last follow-up, using the Kaplan-Meier analysis, with log-rank test. Results: Outcome for 212 patients (117 Type-II and 95 Type III) was significantly better for T-II than T-III: EFS for T-II was 68.1% vs. T-III 45.7% (P=0.002), and OS for T-II was 75.2% vs. T-III 57.9% (p=0.01). Excluding patients with incomplete therapy information, 174 were treated with surgery and chemotherapy. Of these 44 (25%) also received radiation therapy; 130 patients did not. The table below shows comparison of radiated vs. non-radiated. Radiation provided no additional survival benefit, overall or by tumor Type. Multivariate analysis showed that gender and extent of primary tumor resection (biopsy vs. gross total resection) had no effect on outcome, however T-II vs. T-III retained prognostic significance. Conclusions: For this collection of advanced-type PPB, outcome is significantly better for T-II than T-III. For patients treated initially with surgery and chemotherapy, adding radiation therapy offered no improvement in event-free or overall survival. Limitations of this study include its retrospective nature and non-uniform treatment regimens. [Table: see text]

Pleuropulmonary blastoma: The causative role of germ-line DICER1 mutations.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 10024-10024 ◽  
Author(s):  
Leslie Ann Doros ◽  
Jiandong Yang ◽  
Amanda Field ◽  
Christopher Rossi ◽  
Gretchen M Williams ◽  
...  
Keyword(s):  
Germ Line ◽  
Genetic Alterations ◽  
Pleuropulmonary Blastoma ◽  
Common Mutation ◽  
Type I ◽  
Causative Role ◽  
Mirna Regulation ◽  
Loss Of Function ◽  
Type Iii ◽  
Dismal Prognosis

10024 Background: Pleuropulmonary blastoma (PPB) is a rare, aggressive childhood lung cancer that is often the first manifestation of the PPB-DICER1 familial tumor predisposition which includes other benign and malignant conditions. The initial genetic mutation is inherited by a germ-line loss of function of DICER1 gene which was discovered by Hill et al. It is proposed that loss of DICER1 expression alters miRNA regulation of key regulatory cellular mechanisms which promote tumor growth. PPB can progress from the purely cystic, curable Type I to a high-grade Type III having a dismal prognosis. We sought to determine the frequency of DICER1mutation in the largest cohort of PPB patients to date. Methods: We obtained germ-line DNA from saliva or blood samples from 113 PPB patients collected from 2005-2012. DNA was extracted using the Maxwell 16 Research System (Promega Corporation, Madison WI). Sample quality and quantity was checked using the Nanodrop 2000 (Thermo Scientific, Wilmington, DE). Sequencing was performed using the Sanger sequencer. For a subset of cases we used targeted sequencing services or full gene sequence analysis (Ambry Genetics, Aliso Viejo, CA). Results: Seventy-four (65.5%) PPB patients were found to have deleterious DICER1germ-line mutations. The most common mutation type found was small insertion/deletions. These 74 samples were composed of 7 (9.5%)Type Ir PPBs, 22 (29.7%)Type I PPBs, 24 (32.4%) Type II PPBs, and 21 (28.4%)Type III PPBs. The following Table shows a summary of mutation types identified. Conclusions: Our results confirm that DICER1 germline mutations are the most common genetic alterations in PPB making it critical for genetic testing to be performed at diagnosis. Additionally, this underscores the need for important correlative studies to describe the genotype-phenotype relationship in order for appropriate screening guidelines to be developed and implemented to allow for early detection. While a majority of cases are explained by germline DICER1 mutations using current sequencing methods, further investigation is warranted to elucidate other possible mechanisms in the development of PPB. [Table: see text]

Differential immune-related microenvironment determines PD-1/PD-L1 blockade efficacy in advanced non-small cell lung cancer patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9044-9044
Author(s):  
Masayuki Shirasawa ◽  
Tatsuya Yoshida ◽  
Yukiko Shimoda ◽  
Daisuke Takayanagi ◽  
Kouya Shiraishi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Small Cell ◽  
Type I ◽  
Type Ii ◽  
Small Cell Lung ◽  
Lung Cancer Patients ◽  
Type Iii ◽  
Type Iv ◽  
The Status

9044 Background: Programmed death ligand-1 (PD-L1) expression is not a completely reliable predictive marker of the efficacy of anti-programmed cell death protein-1 (PD-1)/anti-PD-L1 therapy in advanced non-small cell lung cancer patients (NSCLC). Immune-related tumor microenvironment (TME) is classified into four different types based on the status of tumor-infiltrating lymphocytes (TILs) and PD-L1 expression. Methods: We retrospectively reviewed advanced NSCLC patients treated with anti-PD-1/anti-PD-L1 therapy between 2015 and 2019, and investigated the association between the efficacy of anti-PD-1/anti-PD-L1 therapy, the types of TME based on PD-L1 (clone: 22C3) expression, and the density of CD8-positive TILs by immunohistochemistry (/mm2), and mutational profiles assessed by next-generation sequencing. Results: Overall, 228 patients without driver mutation ( EGFR, ALK, ROS1, and RET) were included in the analysis. The patients were classified into four following groups: Type I: PD-L1High (tumor proportion score [TPS]≥50%)/TILHigh (≥85/mm2; n = 73), Type II: PD-L1Low (TPS < 50%)/TILLow ( < 85/mm2; n = 70), Type III: PD-L1High/TILLow (n = 37), and Type IV: PD-L1Low/TILHigh (n = 48). The progression-free survival (PFS) and objective response rate (ORR) of anti-PD-1/anti-PD-L1 therapy clearly differed according to the different tumor microenvironment (TME) types (ORR and median PFS; Type I: 64%, 14.5 months, Type II: 12%, 2.1 months, Type III: 24%, 3.6 months, Type IV: 41%, 10.8 months). In patients with PD-L1High tumors, Type I tumors had significantly better ORR and PFS than Type III(ORR: p < 0.001, and PFS: p < 0.001) tumors. Regarding the association between mutational profiles, histology and the TME types, the presence of TP53 mutation and KRAS mutation significantly related to TILHigh (Type I and IV) and PD-L1High tumors (Type I and III), respectively. Pleomorphic and NSCLC- not otherwise specified histology were associated with Type I tumors, while LCNEC was associated with PD-L1 low tumors (Type II and IV). Conclusions: Various factors (mutational profile and histology) are related to TME classification based on the status of TILs and PD-L1 expression. Differential types of TME, including PD-L1 expression and TILs status, can accurately predict the efficacy of anti-PD-1/anti-PD-L1 therapy.[Table: see text]

Methionine-Specific Staining of Collagen

1982 ◽  
Vol 40 ◽  
pp. 294-295
Author(s):  
E.M. Kuhn ◽  
K.D. Marenus ◽  
M. Beer
Keyword(s):  
Amino Acids ◽  
Collagen Fibers ◽  
Type Iii Collagen ◽  
Type I ◽  
Electron Microscopic ◽  
Good Correspondence ◽  
Specific Staining ◽  
Type Iii ◽  
Different Types ◽  
Sulfur Containing

Fibers composed of different types of collagen cannot be differentiated by conventional electron microscopic stains. We are developing staining procedures aimed at identifying collagen fibers of different types.Pt(Gly-L-Met)Cl binds specifically to sulfur-containing amino acids. Different collagens have methionine (met) residues at somewhat different positions. A good correspondence has been reported between known met positions and Pt(GLM) bands in rat Type I SLS (collagen aggregates in which molecules lie adjacent to each other in exact register). We have confirmed this relationship in Type III collagen SLS (Fig. 1).

Labelling of non-A, non-B hepatitis infected chimpanzee hepatocytes with nuclease-gold conjugates

1984 ◽  
Vol 42 ◽  
pp. 250-251
Author(s):  
G. D. Gagne ◽  
M. F. Miller ◽  
D. A. Peterson
Keyword(s):  
Endoplasmic Reticulum ◽  
Experimental Infection ◽  
Uranyl Acetate ◽  
Type I ◽  
Cellular Injury ◽  
Type Ii ◽  
Tubular Structures ◽  
Type Iii ◽  
Type Iv ◽  
Infected Chimpanzee

Experimental infection of chimpanzees with non-A, non-B hepatitis (NANB) or with delta agent hepatitis results in the appearance of characteristic cytoplasmic alterations in the hepatocytes. These alterations include spongelike inclusions (Type I), attached convoluted membranes (Type II), tubular structures (Type III), and microtubular aggregates (Type IV) (Fig. 1). Type I, II and III structures are, by association, believed to be derived from endoplasmic reticulum and may be morphogenetically related. Type IV structures are generally observed free in the cytoplasm but sometimes in the vicinity of type III structures. It is not known whether these structures are somehow involved in the replication and/or assembly of the putative NANB virus or whether they are simply nonspecific responses to cellular injury. When treated with uranyl acetate, type I, II and III structures stain intensely as if they might contain nucleic acids. If these structures do correspond to intermediates in the replication of a virus, one might expect them to contain DNA or RNA and the present study was undertaken to explore this possibility.

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