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2.
Am J Surg Pathol ; 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34469333

RESUMO

While most resection specimens from patients with neoadjuvantly treated esophageal squamous cell carcinoma show therapy-related changes in the form of inflammation and fibrosis, others harbor a florid foreign body-type giant cell response to keratin debris. The purpose of our study was to perform a detailed clinicopathologic analysis of these histologic types of treatment responses and correlate these findings with patient outcome. Clinical and pathologic parameters from 110 esophagogastrectomies were recorded and analyzed. Two main types of histologic responses were observed: inflammatory-predominant response (59%) and florid foreign body-type giant cell response to keratin (41%). Irrespective of cG, cTNM, and amount of residual cancer, florid foreign body-type giant cell reaction was predominantly noted deep within the esophageal wall, while the inflammatory response was restricted to the mucosa, submucosa, and inner half of muscularis propria. Patients with foreign body-type giant cell response showed significantly better overall survival compared with the inflammatory response group (log-rank test P=0.015). Florid foreign body-type giant cell response was the only factor associated with improved survival in a multivariable analysis for overall survival (hazard ratio=0.5; 95% confidence interval=0.3-1.0; P=0.038), but not in the model for disease-specific survival, whereas ypTNM stage II was the only significant risk factor for disease-specific survival in multivariable analysis (hazard ratio=3.4; 95% confidence interval=1.0-11.2; P=0.047). Our results suggest that in addition to the College of American Pathologists Tumor Regression Score and ypTNM stage, subtype of histologic response to therapy may represent another prognostic marker for neoadjuvantly treated esophageal squamous cell carcinoma.

3.
Histopathology ; 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34506637

RESUMO

INTRODUCTION: IgG4 related disease (IgG4-RD) is a multisystem disease, characterized by tumefactive lesions and a swift response to immunosuppressive therapy. Although elevated serum and tissue IgG4 are characteristic, T-cells appear to be the primary driver of this immunologically mediated disease. The overarching goal was to examine the role of immunomodulatory cells in IgG4-RD. METHODS: Biopsies from patients with IgG4-RD (n=39) and mimics of this disease (n=78) were evaluated for IgG4, IgG, CD8, PD-L1 and a subset (n=18) evaluated for CD4, PU.1, Foxp3, PD-L1, PD-1, IDO1 and LAG3. Data pertaining to demographics and laboratory findings at baseline evaluation was extracted from electronic medical records. RESULTS: When compared to mimics, IgG4-RD showed increased numbers of PD-L1 (p=0.0001), PD-1 (p=0.001), IDO1 (p=0.03), LAG3 (p=0.04) and Foxp3 (p=0.04) positive immune cells. The PD-L1 positive cells were enriched within aggregates of CD4 and CD8 positive T-cells. 31 of 39 (80%) IgG4-RD cases showed greater than 5 PD-L1 positive cells per HPF, while 4 of 78 (5%) mimics of this disease exceeded this cut point. In IgG4-RD PD-L1 positive macrophages correlated with PD-1 (p=0.002), LAG3 (p=0.001) and IDO1 positive cells (p=0.001); a positive correlation was also noted between IgG4/IgG ratio and PD-L1, PD-1, and IDO1 positive cells. CONCLUSIONS: IgG4-RD shows expansion of mechanisms that maintain peripheral tolerance. The spatial and temporal relationship between T-cells and the PD-L1-PD1 axis, and the upregulation of multiple immunomodulatory proteins suggests that these immunoregulatory mechanisms play a significant role in IgG4-RD.

4.
Cancer Cell ; 39(10): 1342-1360.e14, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34358448

RESUMO

The CD155/TIGIT axis can be co-opted during immune evasion in chronic viral infections and cancer. Pancreatic adenocarcinoma (PDAC) is a highly lethal malignancy, and immune-based strategies to combat this disease have been largely unsuccessful to date. We corroborate prior reports that a substantial portion of PDAC harbors predicted high-affinity MHC class I-restricted neoepitopes and extend these findings to advanced/metastatic disease. Using multiple preclinical models of neoantigen-expressing PDAC, we demonstrate that intratumoral neoantigen-specific CD8+ T cells adopt multiple states of dysfunction, resembling those in tumor-infiltrating lymphocytes of PDAC patients. Mechanistically, genetic and/or pharmacologic modulation of the CD155/TIGIT axis was sufficient to promote immune evasion in autochthonous neoantigen-expressing PDAC. Finally, we demonstrate that the CD155/TIGIT axis is critical in maintaining immune evasion in PDAC and uncover a combination immunotherapy (TIGIT/PD-1 co-blockade plus CD40 agonism) that elicits profound anti-tumor responses in preclinical models, now poised for clinical evaluation.

6.
Am J Surg Pathol ; 45(10): 1314-1323, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34334689

RESUMO

Inflammatory pseudotumor is a term used to designate inflammation-rich tumefactive lesions. Following the exclusion of specific entities such as IgG4-related disease and other neoplastic entities previously included in this entity, the majority of hepatic pseudotumors show a prominent fibrohistiocytic inflammatory reaction and have been previously categorized as fibrohistiocytic variant of hepatic pseudotumor (FHVHPT). The goal of this study was to examine the clinical, radiologic, histologic, and etiologic aspects of this entity. After excluding neoplastic diseases, we identified 30 patients with FHVHPT from 3 institutions between 2009 and 2019. We extracted demographic and clinical data, liver function tests as well as culture results and radiologic information. Hematoxylin and eosin-stained slides were reviewed for pattern of inflammation as well as its cellular composition. Immunohistochemistry for IgG4 and IgG was performed in all cases. The mean age of the 30 lesions characterized as FHVHPT was 56 years (range: 23 to 79 y). Nineteen patients showed solitary lesions; 11 were multiple. The mean size of the lesion was 3.8 cm (range: 1 to 7.5 cm). On imaging, a neoplastic process or metastasis was the leading diagnostic consideration (n=15, 50%). The most common symptom was abdominal pain (n=14/30); 8 patients presented with symptoms compatible with an infectious process, including fever. The inflammatory infiltrate was dominated by lymphocytes and plasma cells, and in most cases, a prominent histiocytic infiltrate (22/30). Neutrophils were identified in 12 cases, with microabscess noted in 8. Storiform pattern of fibrosis was seen in 14/30 cases; obliterative phlebitis was not identified. Culture identified a microorganism in 4 of 9 cases evaluated. The mean IgG4 count was 9.3 per HPF (range: 0 to 51) with 9 of the 26 (35%) biopsies showing >10 IgG4 positive plasma cells per HPF. The mean IgG4 to IgG ratio was 8% (range: 8% to 46%). A hepatectomy was performed in 4 cases. On broad spectrum antibiotics (n=14) the lesions either resolved or decreased in size. Eight patients did not receive specific therapy, nevertheless, the lesion(s) resolved spontaneously in 6 cases, remained stable or decreased in size in 2 cases. Notably, none of these patients showed evidence of a hepatic recurrence. FHVHPT, a tumefactive lesion that mimics hepatic neoplasia, is histologically characterized by a fibrohistiocytic infiltrate. In the majority of patients FHVHPT represents the organizing phase of hepatic abscess and can be successfully managed with antibiotic therapy.


Assuntos
Antibacterianos/uso terapêutico , Granuloma de Células Plasmáticas/tratamento farmacológico , Abscesso Hepático/tratamento farmacológico , Fígado/efeitos dos fármacos , Adulto , Idoso , Diagnóstico Diferencial , Feminino , Granuloma de Células Plasmáticas/diagnóstico por imagem , Granuloma de Células Plasmáticas/microbiologia , Granuloma de Células Plasmáticas/patologia , Humanos , Fígado/patologia , Abscesso Hepático/diagnóstico por imagem , Abscesso Hepático/microbiologia , Abscesso Hepático/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de Risco , Resultado do Tratamento , Adulto Jovem
7.
Histopathology ; 2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34292620

RESUMO

AIMS: Coronavirus disease 2019 (COVID-19) has been recognised as a predominantly respiratory tract infection, but some patients manifest severe systemic symptoms/coagulation abnormalities. The aim of this study was to evaluate the impact of severe COVID-19 infection on the gastrointestinal tract. METHODS AND RESULTS: We examined clinicopathological findings in 28 resected ischaemic bowels from 22 patients with severe COVID-19. Most patients required intubation preoperatively and presented with acute decompensation shortly before surgery. D-dimer levels were markedly elevated in all measured cases (mean, 5394 ng/ml). Histologically, 25 cases (19 patients) showed evidence of acute ischaemia with necrosis. In this group, the most characteristic finding was the presence of small vessel fibrin thrombi (24 of 25 cases, 96%), which were numerous in 64% of cases. Patients with COVID-19 were significantly more likely than a control cohort of 35 non-COVID-19-associated acute ischaemic bowels to show isolated small intestine involvement (32% versus 6%, P < 0.001), small vessel fibrin thrombi (100% versus 43%, P < 0.001), submucosal vessels with fibrinous degeneration and perivascular neutrophils (90% versus 54%, P < 0.001), fibrin strands within submucosal vessels (58% versus 20%, P = 0.007), and histological evidence of pneumatosis (74% versus 34%, P = 0.010). Three cases in this cohort had histopathological findings normally seen in the setting of chronic ischaemia, notably prominent fibroblastic proliferation affecting the outer layer of the muscularis propria. CONCLUSIONS: Herein, we describe the histopathological findings in COVID-19-associated ischaemic bowels and postulate a relationship with the hypercoagulable state seen in patients with severe COVID-19 infection. Additional experience with these cases may further elucidate specific features or mechanisms of COVID-19-associated ischaemic enterocolitis.

8.
Am J Surg Pathol ; 45(8): 1127-1137, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34115673

RESUMO

Sarcoma diagnosis has become increasingly complex, requiring a combination of morphology, immunohistochemistry, and molecular studies to derive specific diagnoses. We evaluated the role of anchored multiplex polymerase chain reaction-based gene fusion assay in sarcoma diagnostics. Between 2015 and 2018, bone and soft tissue sarcomas with fusion assay results were compared with the histologic diagnosis. Of 143 sarcomas tested for fusions, 43 (30%) had a detectable fusion. In review, they could be classified into 2 main categories: (1) 31 tumors with concordant morphologic and fusion data; and (2) 12 tumors where the fusion panel identified an unexpected rearrangement that played a significant role in classification. The overall concordance of the fusion assay results with morphology/immunohistochemistry or alternate confirmatory molecular studies was 83%. Collectively, anchored multiplex polymerase chain reaction-based solid fusion assay represents a robust means of detecting targeted fusions with known and novel partners. The predictive value of the panel is highest in tumors that show a monomorphic cell population, round cell tumors, as well as tumors rich in inflammatory cells. However, with an increased ability to discover fusions of uncertain significance, it remains essential to emphasize that the diagnosis of bone and soft tissue neoplasms requires the integration of morphology and immunohistochemical profile with these molecular methods, for accurate diagnosis and optimal clinical management of sarcomas.


Assuntos
Neoplasias Ósseas/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Reação em Cadeia da Polimerase Multiplex/métodos , Sarcoma/diagnóstico , Neoplasias de Tecidos Moles/diagnóstico , Adolescente , Adulto , Idoso , Neoplasias Ósseas/genética , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sarcoma/genética , Neoplasias de Tecidos Moles/genética , Adulto Jovem
9.
Phys Rev Lett ; 126(21): 216802, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34114831

RESUMO

Electronic analogs of optical interferences are powerful tools to investigate quantum phenomena in condensed matter. In carbon nanotubes (CNTs), it is well established that an electronic Fabry-Perot interferometer can be realized. Other types of quantum interferences should also arise in CNTs, but have proven challenging to realize. In particular, CNTs have been identified as a system to realize the electronic analog of a Sagnac interferometer-the most sensitive optical interferometer. To realize this Sagnac effect, interference between nonidentical transmission channels in a single CNT must be observed. Here, we use suspended, ultraclean CNTs of known chiral index to study both Fabry-Perot and Sagnac electron interferences. We verify theoretical predictions for the behavior of Sagnac oscillations and the persistence of the Sagnac oscillations at high temperatures. As suggested by existing theoretical studies, our results show that these quantum interferences may be used for electronic structure characterization of carbon nanotubes and the study of many-body effects in these model one-dimensional systems.

10.
Histopathology ; 79(4): 642-649, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33960520

RESUMO

AIMS: Oesophageal verrucous carcinoma (VSCC) is a rare and morphologically distinct type of oesophageal squamous cell carcinoma (SCC). Diagnosing VSCC on biopsy material is challenging, given the lack of significant atypia and the presence of keratinising epithelium and exophytic growth. The molecular pathogenesis of VSCC remains unclear. The aim of this study was to characterise the genomic landscape of VSCC in comparison to conventional oesophageal SCC. METHODS AND RESULTS: Three cases of VSCC from the Brigham and Women's Hospital pathology archive were identified. Formalin-fixed, paraffin-embedded (FFPE) tumour tissue was used for p16 immunohistochemistry (IHC), high-risk human papillomavirus (HPV) in-situ mRNA hybridisation (ISH) and DNA isolation. Tumour DNA was sequenced using a targeted massively parallel sequencing assay enriched for cancer-associated genes. Three additional cases of VSCC were identified by image review of The Cancer Genome Atlas (TCGA) oesophageal SCC cohort. VSCC cases were negative for p16 IHC and high-risk HPV ISH. TP53 mutations (P < 0.001) and copy number variants (CNVs) for CDKN2A (P < 0.001), CDKN2B (P < 0.01) and CCND1 (P < 0.01) were absent in VSCC and significantly less frequent in comparison to conventional SCC. Five VSCC cases featured SMARCA4 missense mutations or in-frame deletions compared to only four of 88 conventional SCC cases (P < 0.001). VSCC featured driver mutations in PIK3CA, HRAS and GNAS. Recurrent CNVs were rare in VSCC. CONCLUSIONS: VSCC is not only morphologically but also genetically distinct from conventional oesophageal SCC, featuring frequent SMARCA4 mutations and infrequent TP53 mutations or CDKN2A/B CNVs. Molecular findings may aid in establishing the challenging diagnosis of VSCC.

11.
Am J Surg Pathol ; 2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-33999556

RESUMO

Immune checkpoint inhibitors target checkpoint proteins with the goal of reinvigorating the host immune system and thus restoring antitumor response. With the dramatic increase in the use of checkpoint inhibitors for cancer treatment, surgical pathologists have assumed a major role in predicting the therapeutic efficacy (score based on programmed cell death ligand 1 immunohistochemistry and mismatch repair protein loss) as well as diagnosing the complications associated with these medications. Immune-related adverse events (irAEs) manifest as histologic changes seen in both the upper and lower gastrointestinal tract, and when viewed in isolation, may be morphologically indistinguishable from a wide range of diseases including infections, celiac disease, and inflammatory bowel disease, among others. Evaluation of biopsies from both the upper and lower gastrointestinal tract can aid in the distinction of gastrointestinal irAEs from their mimics. In the liver, the histologic changes of hepatic irAEs overlap with de novo diseases associated with hepatitic and cholangitic patterns of injury. The diagnosis of irAEs requires communication and collaboration from the pathologist, oncologist, and gastroenterologist. This review provides a background framework and illustrates the histologic features and differential diagnosis of gastrointestinal and hepatic irAEs.

12.
Am J Surg Pathol ; 2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34001695

RESUMO

Inflammatory myofibroblastic tumor (IMT) is a distinctive fibroblastic and myofibroblastic spindle cell neoplasm with an accompanying inflammatory cell infiltrate and frequent receptor tyrosine kinase activation at the molecular level. The tumor may recur and rarely metastasizes. IMT is rare in the head and neck region, and limited information is available about its clinicopathologic and molecular characteristics in these subsites. Therefore, we analyzed a cohort of head and neck IMTs through a multi-institutional approach. Fourteen cases were included in the provisional cohort, but 1 was excluded after molecular analysis prompted reclassification. Patients in the final cohort included 7 males and 6 females, with a mean age of 26.5 years. Tumors were located in the larynx (n=7), oral cavity (n=3), pharynx (n=2), and mastoid (n=1). Histologically, all tumors showed neoplastic spindle cells in storiform to fascicular patterns with associated chronic inflammation, but the morphologic spectrum was wide, as is characteristic of IMT in other sites. An underlying fusion gene event was identified in 92% (n=11/12) of cases and an additional case was ALK-positive by IHC but could not be evaluated molecularly. ALK represented the driver in all but 1 case. Rearrangement of ALK, fused with the TIMP3 gene (n=6) was most commonly detected, followed by 1 case each of the following fusion gene partnerships: TPM3-ALK, KIF5B-ALK, CARS-ALK, THBS1-ALK, and a novel alteration, SLC12A2-ROS1. The excluded case was reclassified as spindle cell rhabdomyosarcoma after detection of a FUS-TFCP2 rearrangement and retrospective immunohistochemical confirmation of rhabdomyoblastic differentiation, illustrating an important diagnostic pitfall. Two IMT patients received targeted therapy with crizotinib, with a demonstrated radiographic response. One tumor recurred but none metastasized. These results add to the growing body of evidence that kinase fusions can be identified in the majority of IMTs and that molecular analysis can lead to increased diagnostic accuracy and broadened therapeutic options for patients.

13.
Front Oncol ; 11: 598001, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33912442

RESUMO

Purpose: The aim of this study was to characterize chondrosarcoma tumor infiltration by immune cells and the expression of immunologically relevant molecules. This information may contribute to our understanding of the role of immunological events in the pathogenesis of chondrosarcoma and to the rational design of immunotherapeutic strategies. Patients and Methods: A tissue microarray (TMA) containing 52 conventional and 24 dedifferentiated chondrosarcoma specimens was analyzed by immunohistochemical staining for the expression of parameters associated with tumor antigen-specific immune responses, namely, CD4+ and CD8+ tumor infiltrating lymphocytes (TILs) and the expression of HLA class I heavy chain, beta-2 microglobulin (ß2m), HLA class II and immune checkpoint molecules, B7-H3 and PD-1/PD-L1. The results were correlated with histopathological characteristics and the clinical course of the disease. Results: CD8+ TILs were present in 21% of the conventional and 90% of the dedifferentiated chondrosarcoma tumors tested. B7-H3 was expressed in 69% of the conventional and 96% of the dedifferentiated chondrosarcoma tumors tested. PD-1 and PD-L1 were expressed 53% and 33% respectively of the dedifferentiated tumors tested. PD-L1 expression was associated with shorter time to metastasis. Conclusion: The tumor infiltration by lymphocytes suggests that chondrosarcoma is immunogenic. Defects in HLA class I antigen and expression of the checkpoint molecules B7-H3 and PD-1/PD-L1 suggest that tumor cells utilize escape mechanisms to avoid immune recognition and destruction. This data implies that chondrosarcoma will benefit from strategies that enhance the immunogenicity of tumor antigens and/or counteract the escape mechanisms.

14.
Future Oncol ; 17(16): 2057-2074, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33709779

RESUMO

Background: IDH1 mutations occur in approximately 13% of intrahepatic cholangiocarcinomas (IHCCs). The oral, targeted, mutant IDH1 (mIDH1) inhibitor ivosidenib (AG-120) suppresses production of the oncometabolite D-2-hydroxyglutarate, promoting disease stabilization and improved progression-free survival (PFS) in mIDH1 IHCC. Materials & methods: Harnessing matched baseline and on-treatment biopsies, we investigate the potential mechanisms underlying ivosidenib's efficacy. Results: mIDH1 inhibition leads to decreased cytoplasm and expression of hepatocyte lineage markers in patients with prolonged PFS. These findings are accompanied by downregulation of biliary fate, cell cycle progression and AKT pathway activity. Conclusion: Ivosidenib stimulates a hepatocyte differentiation program in mIDH1 IHCC, a phenotype associated with clinical benefit. mIDH1 inhibition could be a paradigm for differentiation-based therapy in solid tumors. Clinical trial registration: NCT02073994 (ClinicalTrials.gov).

16.
Clin Cancer Res ; 27(8): 2314-2325, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33547202

RESUMO

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) lethality is multifactorial; although studies have identified transcriptional and genetic subsets of tumors with different prognostic significance, there is limited understanding of features associated with the minority of patients who have durable remission after surgical resection. In this study, we performed laser capture microdissection (LCM) of PDAC samples to define their cancer- and stroma-specific molecular subtypes and identify a prognostic gene expression signature for short-term and long-term survival. EXPERIMENTAL DESIGN: LCM and RNA sequencing (RNA-seq) analysis of cancer and adjacent stroma of 19 treatment-naïve PDAC tumors was performed. Gene expression signatures were tested for their robustness in a large independent validation set. An RNA-ISH assay with pooled probes for genes associated with disease-free survival (DFS) was developed to probe 111 PDAC tumor samples. RESULTS: Gene expression profiling identified four subtypes of cancer cells (C1-C4) and three subtypes of cancer-adjacent stroma (S1-S3). These stroma-specific subtypes were associated with DFS (P = 5.55E-07), with S1 associated with better prognoses when paired with C1 and C2. Thirteen genes were found to be predominantly expressed in cancer cells and corresponded with DFS in a validation using existing RNA-seq datasets. A second validation on an independent cohort of patients using RNA-ISH probes to six of these prognostic genes demonstrated significant association with overall survival (median 17 vs. 25 months; P < 0.02). CONCLUSIONS: Our results identified specific signatures from the epithelial and the stroma components of PDAC, which add clarity to the nature of PDAC molecular subtypes and may help predict survival.

17.
Clin Imaging ; 76: 46-52, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33549919

RESUMO

PURPOSE: The purpose of this study was to determine if CT and MRI features can accurately differentiate mucinous cystic neoplasms (MCNs) from simple liver cysts and to compare accuracy of CT and MRI in detecting these features. METHODS: Eighty-four surgically treated lesions with pre-operative CT or MRI were evaluated by two abdominal radiologists for upstream biliary dilatation, perfusional change, internal hemorrhage, thin septations, thick septations/nodularity, lobar location, and number of coexistent liver cysts. Odds ratios, sensitivities, specificities, and positive and negative predictive values were calculated for association of each feature with MCNs. RESULTS: Of 84 liver lesions, 13 (15%) were MCNs, all in women, and 71 (85%) were simple cysts, in 59 women and 12 men. Thick septations/nodularity, upstream biliary dilation, thin septations, internal hemorrhage, perfusional change, and fewer than 3 coexistent liver cysts were more frequent in MCNs than in simple cysts. The combination of thick septations/nodularity and at least one additional associated feature showed high specificity for MCNs (94-98%). MRI detected significant associations of biliary dilation, thin septations, and hemorrhage/debris with MCNs which CT did not. CONCLUSION: Surgically treated MCNs of the liver with preoperative imaging occurred at our institution only in women. Thick septations or nodularity, biliary dilation, thin septations, internal hemorrhage or debris, perfusional change, and fewer than 3 coexistent liver cysts are features that help differentiate MCNs from simple cysts. MRI has advantages over CT in detecting these features.


Assuntos
Cistos , Hepatopatias , Neoplasias Hepáticas , Neoplasias Pancreáticas , Cistos/diagnóstico por imagem , Feminino , Humanos , Hepatopatias/diagnóstico por imagem , Neoplasias Hepáticas/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Tomografia Computadorizada por Raios X
18.
Ann Surg Oncol ; 28(8): 4592-4601, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33393047

RESUMO

BACKGROUND: Microscopically positive margins (R1) negatively impact survival in pancreatic ductal adenocarcinoma (PDAC). For patients with close/positive margins, intraoperative radiotherapy (IORT) can improve local control. The prognostic impact of an R1 resection in patients who receive total neoadjuvant therapy (TNT; FOLFIRINOX with chemoradiation) and IORT is unknown. METHODS: Clinicopathologic data were retrospectively collected for borderline/locally advanced (BR/LA) PDAC patients who received TNT and underwent resection between 2011 and 2019. Disease-free (DFS) and overall survival (OS) measured from time of diagnosis were compared between groups. RESULTS: Two hundred one patients received TNT and were resected, with a median DFS and OS of 24 months and 47 months, respectively. Eighty-eight patients (44%) received IORT; of these, 69 (78%) underwent an R0 and 19 (22%) an R1 resection. There was no significant difference in clinicopathologic factors between the IORT and no-IORT groups, except for resectability status (LA: IORT 69%, no-IORT 53%, p = 0.021) and surgeons' concern for a positive/close margin. R1 resection was associated with worse DFS and OS in the no-IORT population. However, among patients who received IORT, there was no difference in DFS (R0: 29 months, IQR 14-47 vs R1: 20 months, IQR 15-28; p = 0.114) or OS (R0: 48 months, IQR 25-not reached vs R1: 37 months, IQR 30-47; p = 0.307) between patients who underwent R0 vs R1 resection. In multivariate analysis, within the IORT group, R1 resection was not associated with DFS or OS. CONCLUSION: IORT may mitigate the adverse effect of an R1 resection on DFS and OS in BR/LA PDAC patients receiving TNT.


Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fluoruracila , Humanos , Irinotecano , Leucovorina , Terapia Neoadjuvante , Oxaliplatina , Neoplasias Pancreáticas/tratamento farmacológico , Estudos Retrospectivos , Taxa de Sobrevida
19.
J Gastrointest Surg ; 2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33501584

RESUMO

BACKGROUND: Dynamic survival data based on time already survived are lacking for resected borderline resectable/locally advanced (BR/LA) pancreatic ductal adenocarcinoma (PDAC) patients who received total neoadjuvant therapy (TNT) with FOLFIRINOX followed by chemoradiation. Conditional survival, i.e., the probability of surviving an additional length of time after having already survived an amount of time, offers such information. We aimed to determine actuarial and conditional overall (OS, COS) and disease-free survival (DFS, CDFS) among this cohort. METHODS: Clinicopathologic data were retrospectively collected for resected BR/LA PDAC patients who received TNT (2011-2019). COS and CDFS rates were calculated for patients being event (death/recurrence)-free at multiple intervals and by recurrence status. RESULTS: After a median follow-up of 32.1 months, the 183 patients had a median OS and DFS of 39.1 months and 16.8 months, respectively. COS and CDFS increased as a function of time already survived. The probability of surviving an additional 24 months if a patient survived 2 years post-operatively was 70%, whereas the 4-year actuarial OS was 47%. Similarly, the probability of surviving disease-free an additional 24 months after 2 years was 66%, while actuarial 48-month DFS was 27%. COS for disease-free patients increased further over time. For patients remaining disease-free 12 months post-operatively, BR vs. LA status at diagnosis, tumor ≤ 4 cm at diagnosis, and R0 resection were independent predictors of favorable additional OS and DFS. CONCLUSIONS: For resected TNT-treated BR/LA PDAC patients, the probability of surviving an additional length of time increases as a function of survival already accrued. Dynamic survival estimates may allow personalized follow-up and counseling.

20.
Bioinspir Biomim ; 2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33470971

RESUMO

Natural hard composites like human bone possess a combination of strength and toughness that exceeds that of their constituents and of many engineered composites. This augmentation is attributed to their complex hierarchical structure, spanning multiple length scales; in bone, characteristic dimensions range from nanoscale fibrils to microscale lamellae to mesoscale osteons and macroscale organs. The mechanical properties of bone have been studied, with the understanding that the isolated microstructure at micro- and nano-scales gives rise to superior strength compared to that of whole tissue, and the tissue possesses an amplified toughness relative to that of its nanoscale constituents. Nanoscale toughening mechanisms of bone are not adequately understood at sample dimensions that allow for isolating salient microstructural features, because of the challenge of performing fracture experiments on small-sized samples. We developed an in-situ three-point bend experimental methodology that probes site-specific fracture behavior of micron-sized specimens of hard material. Using this, we quantify crack initiation and growth toughness of human trabecular bone with sharp fatigue pre-cracks and blunt notches. Our findings indicate that bone with fatigue cracks is two times tougher than that with blunt cracks. In-situ data-correlated electron microscopy videos reveal this behavior arises from crack-bridging by nanoscale fibril structure. The results reveal a transition between fibril-bridging (~1µm) and crack deflection/twist (~500µm) as a function of length-scale, and quantitatively demonstrate hierarchy-induced toughening in a complex material. This versatile approach enables quantifying the relationship between toughness and microstructure in various complex material systems and provides direct insight for designing biomimetic composites.

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