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Intrabdominal dissemination of malignant mesothelioma (MM) and pseudomyxoma peritonei (PMP) is poorly characterized with respect to the stemness window which malignant cells activate during their reshaping on the epithelial-mesenchymal (E/M) axis. To gain insights into stemness properties and their prognostic significance in these rarer forms of peritoneal metastases (PM), primary tumor cultures from 55 patients selected for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy were analyzed for cancer stem cells (CSC) by aldehyde dehydrogenase 1 (ALDH1) and spheroid formation assays, and for expression of a set of plasticity-related genes to measure E/M transition (EMT) score. Intratumor heterogeneity was also analyzed. Samples from PM of colorectal cancer were included for comparison. Molecular data were confirmed using principal component and cluster analyses. Associations with survival were evaluated using Kaplan-Meier and Cox regression models. The activity of acetylsalicylic acid (ASA), a stemness modifier, was tested in five cultures. Significantly increased amounts of ALDH1bright-cells identified high-grade PMP, and discriminated solid masses from ascitic/mucin-embedded tumor cells in both forms of PM. Epithelial/early hybrid EMT scores and an early hybrid expression pattern correlated with pluripotency factors were significantly associated with early peritoneal progression (p = .0343 and p = .0339, respectively, log-rank test) in multivariable models. ASA impaired spheroid formation and increased cisplatin sensitivity in all five cultures. These data suggest that CSC subpopulations and hybrid E/M states may guide peritoneal spread of MM and PMP. Stemness could be exploited as targetable vulnerability to increase chemosensitivity and improve patient outcomes. Additional research is needed to confirm these preliminary data.
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BACKGROUND: Long-term daily use of aspirin reduces incidence and mortality due to colorectal cancer (CRC). This study aimed to analyze the effect of aspirin on the tumor microenvironment, systemic immunity, and on the healthy mucosa surrounding cancer. METHODS: Patients with a diagnosis of CRC operated on from 2015 to 2019 were retrospectively analyzed (METACCRE cohort). Expression of mRNA of immune surveillance-related genes (PD-L1, CD80, CD86, HLA I, and HLA II) in CRC primary cells treated with aspirin were extracted from Gene Expression Omnibus-deposited public database (GSE76583). The experiment was replicated in cell lines. The mucosal immune microenvironment of a subgroup of patients participating in the IMMUNOREACT1 (ClinicalTrials.gov NCT04915326) project was analyzed with immunohistochemistry and flow cytometry. RESULTS: In the METACCRE Cohort, 12% of 238 patients analyzed were aspirin users. Nodal metastasis was significantly less frequent (p = .008) and tumor-infiltrating lymphocyte infiltration was higher (p = .02) among aspirin users. In the CRC primary cells and selected cell lines, CD80 mRNA expression was increased following aspirin treatment (p = .001). In the healthy mucosa surrounding rectal cancer, the ratio of CD8/CD3 and epithelial cells expressing CD80 was higher in aspirin users (p = .027 and p = .034, respectively). CONCLUSIONS: These data suggested that regular aspirin use may have an active role in enhancing immunosurveillance against CRC.
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Aspirina , Neoplasias Colorretais , Vigilância Imunológica , Linfócitos do Interstício Tumoral , Microambiente Tumoral , Humanos , Aspirina/uso terapêutico , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Feminino , Masculino , Microambiente Tumoral/imunologia , Idoso , Pessoa de Meia-Idade , Vigilância Imunológica/efeitos dos fármacos , Estudos Retrospectivos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Antígeno B7-1/metabolismo , Antígeno B7-1/genética , Antígeno B7-H1/metabolismo , Linhagem Celular TumoralRESUMO
BACKGROUND: Colon cancer in young patients is often associated with hereditary syndromes; however, in early-onset rectal cancer, mutations of these genes are rarely observed. The aim of this study was to analyse the features of the local immune microenvironment and the mutational pattern in early-onset rectal cancer. METHODS: Commonly mutated genes were analysed within a rectal cancer series from the University Hospital of Padova. Mutation frequency and immune gene expression in a cohort from The Cancer Genome Atlas ('TCGA') were compared and immune-cell infiltration levels in the healthy rectal mucosa adjacent to rectal cancers were evaluated in the IMMUNOlogical microenvironment in REctal AdenoCarcinoma Treatment 1 and 2 ('IMMUNOREACT') series. RESULTS: In the authors' series, the mutation frequency of BRAF, KRAS, and NRAS, as well as microsatellite instability frequency, were not different between early- and late-onset rectal cancer. In The Cancer Genome Atlas series, among the genes with the most considerable difference in mutation frequency between young and older patients, seven genes are involved in the immune response and CD69, CD3, and CD8ß expression was lower in early-onset rectal cancer. In the IMMUNOlogical microenvironment in REctal AdenoCarcinoma Treatment 1 and 2 series, young patients had a lower rate of CD4+ T cells, but higher T regulator infiltration in the rectal mucosa. CONCLUSION: Early-onset rectal cancer is rarely associated with common hereditary syndromes. The tumour microenvironment is characterized by a high frequency of mutations impairing the local immune surveillance mechanisms and low expression of immune editing-related genes. A constitutively low number of CD4 T cells associated with a high number of T regulators indicates an imbalance in the immune surveillance mechanisms.
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BACKGROUND: The DNA mismatch repair (MMR) system is a highly preserved protein complex recognizing short insertions, short deletions, and single base mismatches during DNA replication and recombination. MMR protein status is identified using immunohistochemistry. Deficit in one or more MMR proteins, configuring deficient MMR status (dMMR), leads to frameshift mutations particularly clustered in microsatellite repeats. Thus, microsatellite instability (MSI) is the epiphenomenon of dMMR. In colorectal cancer (CRC), MMR/MSI status is a biomarker with prognostic and predictive value of resistance to 5-fluorouracil and response to immune checkpoint inhibitor therapy. SUMMARY: In this Review, we describe the challenges the practicing pathologist may face in relation to the assessment of MMR/MSI status and any open issues which still need to be addressed, focusing on pre-analytic issues, pitfalls in the interpretation, and technical aspects of the different assays. KEY MESSAGES: The current methods of detecting dMMR/MSI status have been optimized for CRCs, and whether these techniques can be applied to all tumor and specimen types is still not fully understood. Following the Food and Drug Administration (FDA), tissue/site agnostic drug approval of pembrolizumab for advanced/metastatic MSI tumors, MMR/MSI status in gastrointestinal tract is a common request from the oncologist. In this setting, several issues still need to be addressed, including criteria for sample adequacy.
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Adenocarcinoma , Neoplasias Colorretais , Humanos , Instabilidade de Microssatélites , Reparo de Erro de Pareamento de DNA/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologiaRESUMO
BACKGROUND: Papillary thyroid carcinoma (PTC) is a common neoplasia with multiple variants. One of these extremely rare and poorly described variants is PTC with fibromatosis-like stroma (PTC-FMS), a peculiar entity distinguished by its predominant mesenchymal component. This paper reviews the literature, discusses the diagnostic challenges, and the clinical and surgical implications of this type of tumor which has fewer than 30 cases reported in the literature. CASE PRESENTATION: We reported a case of PTC-FMS found in a 41-year-old Italian woman, who came to our Institute with a recent growth in the form of a mass on the neck. Further immunohistochemical examination showed ß-catenin aberrant staining both in the nuclei and cytoplasm of the mesenchymal cells. The patient underwent total thyroidectomy and received radioactive iodine (RAI) 2 months after surgery. CONCLUSION: Given the possibility of recurrence of PTC-FMS and the ineffectiveness of RAI therapy, complete surgical resection represents the main treatment for this type of tumor. Despite the fact that the specific nature of these lesions has yet to be determined, guidelines for classical PTC should be followed.
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Carcinoma Papilar , Fibroma , Neoplasias da Glândula Tireoide , Feminino , Humanos , Adulto , Câncer Papilífero da Tireoide/diagnóstico , Câncer Papilífero da Tireoide/cirurgia , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/cirurgia , Neoplasias da Glândula Tireoide/patologia , Radioisótopos do Iodo/uso terapêutico , Carcinoma Papilar/diagnóstico , Carcinoma Papilar/cirurgia , Carcinoma Papilar/patologia , Tireoidectomia , Fibroma/tratamento farmacológico , Fibroma/cirurgiaRESUMO
The Food and Drug Administration (FDA) has approved MAPK inhibitors as a treatment for melanoma patients carrying a mutation in codon V600 of the BRAF gene exclusively. However, BRAF mutations outside the V600 codon may occur in a small percentage of melanomas. Although these rare variants may cause B-RAF activation, their predictive response to B-RAF inhibitor treatments is still poorly understood. We exploited an integrated approach for mutation detection, tumor evolution tracking, and assessment of response to treatment in a metastatic melanoma patient carrying the rare p.T599dup B-RAF mutation. He was addressed to Dabrafenib/Trametinib targeted therapy, showing an initial dramatic response. In parallel, in-silico ligand-based homology modeling was set up and performed on this and an additional B-RAF rare variant (p.A598_T599insV) to unveil and justify the success of the B-RAF inhibitory activity of Dabrafenib, showing that it could adeptly bind both these variants in a similar manner to how it binds and inhibits the V600E mutant. These findings open up the possibility of broadening the spectrum of BRAF inhibitor-sensitive mutations beyond mutations at codon V600, suggesting that B-RAF V600 WT melanomas should undergo more specific investigations before ruling out the possibility of targeted therapy.
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Melanoma , Neoplasias Cutâneas , Masculino , Humanos , Proteínas Proto-Oncogênicas B-raf/genética , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Oximas/farmacologia , Oximas/uso terapêutico , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico , Neoplasias Cutâneas/patologiaRESUMO
PEComa has become a widely accepted entity, and increased recognition has led to descriptions of this tumor in a wide variety of anatomic sites, including the adrenal gland. PEComa (perivascular epithelioid cell tumor) is a mesenchymal tumor composed of perivascular cells, and the most frequent sites of PEComas are the uterus and retroperitoneum. The incidence is <1 per 1,000,000 people. We report a case of adrenal metastatic PEComa in a 63-year-old man discovered by a spontaneous hematoma of the rectus abdominis. In our case, PEComa of the adrenal gland was a significant diagnostic dilemma as the morphologic and immunophenotypic features of this neoplasm may easily be confused with those of other more commonly encountered lesions.
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Neoplasias de Células Epitelioides Perivasculares , Masculino , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias de Células Epitelioides Perivasculares/diagnósticoRESUMO
BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) leads to prolonged survival for selected patients with colorectal (CRC) peritoneal metastases (PM). This study aimed to analyze the prognostic role of micro-satellite (MS) status and RAS/RAF mutations for patients treated with CRS. METHODS: Data were collected from 13 Italian centers with PM expertise within a collaborative group of the Italian Society of Surgical Oncology. Clinical and pathologic variables and KRAS/NRAS/BRAF mutational and MS status were correlated with overall survival (OS) and disease-free survival (DFS). RESULTS: The study enrolled 437 patients treated with CRS-HIPEC. The median OS was 42.3 months [95% confidence interval (CI), 33.4-51.2 months], and the median DFS was 13.6 months (95% CI, 12.3-14.9 months). The local (peritoneal) DFS was 20.5 months (95% CI, 16.4-24.6 months). In addition to the known clinical factors, KRAS mutations (p = 0.005), BRAF mutations (p = 0.01), and MS status (p = 0.04) were related to survival. The KRAS- and BRAF-mutated patients had a shorter survival than the wild-type (WT) patients (5-year OS, 29.4% and 26.8% vs 51.5%, respectively). The patients with micro-satellite instability (MSI) had a longer survival than the patients with micro-satellite stability (MSS) (5-year OS, 58.3% vs 36.7%). The MSI/WT patients had the best prognosis. The MSS/WT and MSI/mutated patients had similar survivals, whereas the MSS/mutated patients showed the worst prognosis (5-year OS, 70.6%, 48.1%, 23.4%; p = 0.0001). In the multivariable analysis, OS was related to the Peritoneal Cancer Index [hazard ratio (HR), 1.05 per point], completeness of cytoreduction (CC) score (HR, 2.8), N status (HR, 1.6), signet-ring (HR, 2.4), MSI/WT (HR, 0.5), and MSS/WT-MSI/mutation (HR, 0.4). Similar results were obtained for DFS. CONCLUSION: For patients affected by CRC-PM who are eligible for CRS, clinical and pathologic criteria need to be integrated with molecular features (KRAS/BRAF mutation). Micro-satellite status should be strongly considered because MSI confers a survival advantage over MSS, even for mutated patients.
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Neoplasias Colorretais , Hipertermia Induzida , Neoplasias Peritoneais , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/terapia , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução/métodos , Humanos , Quimioterapia Intraperitoneal Hipertérmica , Instabilidade de Microssatélites , Repetições de Microssatélites , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/terapia , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: We report the first case of a patient affected by peritoneal metastases from colon cancer, arising in the context of Lynch syndrome with pathological complete response. The patient was treated with immunotherapy and cytoreductive surgery. This paper discusses the implications of these novel therapies for the management of PM. CASE PRESENTATION: A 50-year-old man affected by Lynch syndrome was referred to our institution for metachronous peritoneal recurrence of ascending colon adenocarcinoma. As a second-line treatment, he received Nivolumab therapy with stable disease. Patient underwent cytoreductive surgery with residual disease and a pathological complete response. Flow cytometry described a particular immune sub-population response. There was no evidence of disease progression after nine months. CONCLUSION: This is the first report of a Lynch patient affected by peritoneal metastases of colorectal cancer, treated with cytoreductive surgery (CRS) and resulting in a pathological complete response after immune checkpoint inhibitors treatment (ICIs). This case report may suggest that patients with peculiar immunological features could benefit from a tailored approach, since "classical" CRS paradigms may not effectively predict the clinical outcome. Further large-scale studies are needed to determine the correct operative management of such patients (tailored or "standard" CRS), defining the correct surgical timing and eventual discontinuation of ICI therapy after surgery.
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Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Hipertermia Induzida , Neoplasias Peritoneais , Neoplasias Colorretais/terapia , Terapia Combinada , Procedimentos Cirúrgicos de Citorredução , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Neoplasias Peritoneais/terapia , Taxa de SobrevidaRESUMO
Gastroesophageal adenocarcinoma (GEA) patients with the microsatellite instability (MSI) subtype emerged as optimal candidates for immunotherapy. To date, immunohistochemistry (IHC) is the gold standard for MSI assessment in formalin-fixed paraffin-embedded (FFPE) specimens. However, IHC, although useful for diagnostic typing, cannot be used to analyze cell-free DNA (cfDNA) in liquid biopsy, a tool that could overcome tumor heterogeneity and enable longitudinal monitoring. In order to find an alternative diagnostic method to IHC, we analyzed 86 retrospective GEAs FFPE samples with multiplex PCR. Moreover, to verify the feasibility of MSI detection in liquid biopsy, cfDNA samples of five patients that resulted in having MSI in a prospective cohort of 35 patients were evaluated by multiplex PCR, real-time PCR and droplet digital PCR (ddPCR). Analysis of FFPE showed 100% concordance between multiplex PCR and IHC (Cohen's Kappa agreement = 1). On the contrary, only ddPCR was able to detect MSI in cfDNAs of T3/T4 GEA patients. In conclusion, data highlight the molecular analysis as an optimal alternative to IHC for the diagnostic typing and suggest that the ddPCR assay can be considered as the most reliable and promising molecular approach to detect MSI in the cfDNA of GEA patients.
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Adenocarcinoma/genética , Adenocarcinoma/patologia , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Ácidos Nucleicos Livres/genética , Feminino , Humanos , Biópsia Líquida/métodos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos RetrospectivosRESUMO
Hepatocellular carcinoma (HCC) typically presents in patients with a chronic liver disease and rarely develops in healthy liver, especially within an accessory liver lobe. We present a case of a healthy 64-years-old woman who showed a serum alpha-fetoprotein (AFP) value of 226.3 µg/mL during a screening blood test. Past medical history was negative for chronic liver disease or cirrhosis. Intraoperative finding was an ovaloid mass connected with the second hepatic segment by a thin pedicle of hepatic tissue. Lesion was safely resected by laparoscopic approach. Histopathology analysis showed a trabecular hepatocellular carcinoma. After a 6-month follow up, there was no evidence of recurrent disease. This case report showed how serum AFP remains a highly sensitive marker, although the presentation of HCC was unusual. To our knowledge, this is the second case reported in the literature.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Biomarcadores Tumorais , Carcinoma Hepatocelular/diagnóstico por imagem , Feminino , Humanos , Cirrose Hepática/complicações , Neoplasias Hepáticas/diagnóstico , Pessoa de Meia-Idade , alfa-FetoproteínasRESUMO
The aim of the present study was to investigate serum HER2 extracellular domain (ECD) as a putative surrogate marker of the shedding phenomenon of HER2 receptor from the tumor tissue of primary breast cancer (BC) patients. A pilot retrospective study was conducted on 100 matched serum and tissue samples from patients with node-positive primary BC, stage II/III. Analysis of association and concordance between serum HER2 ECD levels (measured by chemiluminescence immunoassay) and the expression in matched tumor tissue of HER2 ECD and intracellular receptor domain (ICD) (determined by immunohistochemistry) were performed. The median serum HER2 ECD level was 9.4 ng/ml and cutoff values were set at 15.2 ng/ml or 13.0 ng/ml. HER2 ICD and ECD were overexpressed in tumor tissue of 19.8% and 6.9% of patients, respectively. Statistically significant associations were found between serum HER2 ECD levels and tissue expression of both HER2 ICD and ECD (p < .001; Fisher analysis). Moreover, strong concordances were found between serum HER2 ECD levels and tissue expression of HER2 ICD or ECD (cutoff 15.2 ng/ml: 80 and 92.5%, respectively). Our findings support a role for serum HER2 ECD as a surrogate marker of tissue HER2 status in primary BC, both for HER2 ICD or ECD expression.
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Neoplasias da Mama/metabolismo , Espaço Extracelular/metabolismo , Receptor ErbB-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/sangue , Neoplasias da Mama/cirurgia , Feminino , Humanos , Espaço Intracelular , Pessoa de Meia-Idade , Domínios Proteicos , Receptor ErbB-2/sangue , Receptor ErbB-2/químicaAssuntos
Neoplasias da Mama , Tumores Neuroendócrinos , Mama , Feminino , Humanos , Músculo EsqueléticoRESUMO
Hodgkin lymphoma (HL) is traditionally diagnosed by the presence of neoplastic Hodgkin and Reed-Sternberg (HRS) cells found in minority within a typical inflammatory microenvironment. It is now recognized that the majority of these T CD4 cells are T regulatory (Treg) and play an important immunosuppressive role and contribute to tumour persistence. Flow cytometric immunophenotyping of lymphocytes was performed on lymph node samples over a 12-year period (2000-2012) to identify the Hodgkin-specific subset and potential biomarkers related to Treg cells. CD3, CD19 and T CD4(+)CD26(-)CD38(+) subsets were measured in the lymphocytic infiltrate of 108 consecutive lymph node samples concurrently diagnosed histologically as HL and in 43 cases of benign reactive lymphoid hyperplasia (BRLH). HL, compared to BRLH, shows statistically significant differences within the reactive microenvironmental population: decreased CD19(+) cells (23 % vs 39 %; p < 0.001), increased CD3(+) (74 % vs 58 %; p < 0.001) and CD4(+)CD26(-)CD38(+) cells (38 % vs 11.5 %; p < 0.001). By using the co-expressed markers CD38 and CD26 for logistic analysis, the obtained receiver operating characteristic (ROC) curves confirm that the CD4(+)CD26(-)CD38(+) subset is strongly expressed in HL (ROC AUC = 0,8639). Flow cytometric detection of CD4(+)CD26(-)CD38(+) cells seems able to identify the cellular microenvironmental pattern in HL and to distinguish it from BRLH. Although there is extensive experience in flow cytometric analysis of non-HL, it is not routinely applied in cases of HL and our findings suggest that it may be useful in quickly and easily characterizing its cellular para-neoplastic inflammatory background.
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Linfócitos T CD4-Positivos/patologia , Citometria de Fluxo , Doença de Hodgkin/imunologia , Imunofenotipagem/métodos , Linfonodos/imunologia , Linfócitos do Interstício Tumoral/patologia , Subpopulações de Linfócitos T/patologia , Linfócitos T Reguladores/patologia , Microambiente Tumoral/imunologia , ADP-Ribosil Ciclase 1/análise , Área Sob a Curva , Doadores de Sangue , Linfócitos T CD4-Positivos/imunologia , Diagnóstico Diferencial , Dipeptidil Peptidase 4/análise , Doença de Hodgkin/sangue , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/patologia , Humanos , Linfonodos/patologia , Glicoproteínas de Membrana/análise , Pseudolinfoma/diagnóstico , Pseudolinfoma/imunologia , Pseudolinfoma/patologia , Curva ROC , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologiaRESUMO
PURPOSE: Small-cell lung cancer (SCLC) is an aggressive disease with a dismal prognosis. The addition of immune checkpoints inhibitors to standard platinum-based chemotherapy in first-line setting achieves a durable benefit only in a patient subgroup. Thus, the identification of predictive biomarkers is an urgent unmet medical need. EXPERIMENTAL DESIGN: Tumor samples from naive extensive-stage (ES) SCLC patients receiving atezolizumab plus carboplatin-etoposide were analyzed by gene expression profiling and two 9-color multiplex immunofluorescence panels, to characterize the immune infiltrate and SCLC subtypes. Associations of tissue biomarkers with time-to-treatment failure (TTF), progression-free survival (PFS) and overall survival (OS), were assessed. RESULTS: 42 patients were included. Higher expression of exhausted CD8-related genes was independently associated with a longer TTF and PFS while increased density of B lymphocytes correlated with longer TTF and OS. Higher percentage of M2-like macrophages close to tumor cells and of CD8+T cells close to CD4+T lymphocytes correlated with increased risk of TF and longer survival, respectively. A lower risk of TF, disease progression and death was associated with a higher density of ASCL1+tumor cells while the expression of POU2F3 correlated with a shorter survival. A composite score combining the expression of exhausted CD8-related genes, B lymphocyte density, ASCL1 tumor expression and quantification of CD163+macrophages close to tumor cells, was able to stratify patients into high-risk and low-risk groups. CONCLUSIONS: In conclusion, we identified tissue biomarkers and a combined score that can predict a higher benefit from chemoimmunotherapy in ES-SCLC patients.
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Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carboplatina , Etoposídeo , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Microambiente Tumoral , Humanos , Carboplatina/uso terapêutico , Carboplatina/administração & dosagem , Carboplatina/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Feminino , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Etoposídeo/uso terapêutico , Etoposídeo/farmacologia , Etoposídeo/administração & dosagem , Idoso , Pessoa de Meia-Idade , Perfilação da Expressão Gênica/métodos , Adulto , Estadiamento de NeoplasiasRESUMO
Background: Programmed death-ligand 1 (PD-L1) expression has been recognized as a potential biomarker for various cancers, yet its diagnostic and prognostic significance in urothelial bladder cancer (BCa) requires further investigation. Methods: In this prospective single-center study, we aimed to assess the feasibility and diagnostic adequacy of PD-L1 expression analysis using cytoinclusion in BCa patients. We enrolled consecutive patients undergoing endoscopic transurethral resection of bladder tumor (TURBT), repeat TURBT, or robot-assisted radical cystectomy. Urinary and tissue specimens were collected from these patients for cytoinclusion and histopathological analysis to evaluate PD-L1 expression. Results: Out of 29 patients, PD-L1 expression was detected from cytoinclusion in 42.8% (3 out of 7), 10% (1 out of 10), and 66.8% (8 out of 12) of patients with negative/papilloma, low-grade, and high-grade tumors, respectively. Conversely, histopathological analysis identified PD-L1 expression in 57.2% (4 out of 7), 30% (3 out of 10), and 83.3% (10 out of 12) of patients with negative/papilloma, low-grade, and high-grade tumors, respectively. The diagnostic concordance between cytoinclusion and histopathology was 85.7%, 80%, and 83.3% in patients with negative/papilloma, low-grade, and high-grade tumors, respectively. Conclusions: Our study underscores the promise of cytoinclusion as a minimally invasive method for quantifying urinary PD-L1 percentages. This approach could serve as both a potential prognostic and diagnostic indicator, easily obtainable from urine samples. Standardizing this technique could facilitate its widespread use as a valuable tool.
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Introduction: Rearranged during transfection (RET) gene rearrangements occur in 1%-2% of non-small cell lung cancer (NSCLC). Because of the results of the study LIBRETTO-001, selpercatinib has been approved as the first-line treatment for patients with RET fusion-positive advanced NSCLC. Selpercatinib demonstrated to be well tolerated. Despite this, gastrointestinal adverse events (AEs) are frequently reported, and no clinical-radiological and endoscopic features and their impact in terms of treatment discontinuations, interruptions, and dose reductions have been described so far. Case report: A 37-year-old never-smoker woman was treated in our institution with selpercatinib for a RET fusion-positive NSCLC. After 9 months of treatment, the patient referred abdominal pain of grade (G) 2, associated with nausea of G2, bilious vomiting of G3, and weight loss of G1. At computed tomography scan, the presence of important bowel wall thickening, free ascitic fluid, mesenteric congestion, and stranding was detected. The patient underwent an anterograde enteroscopy extended to jejunum with detection of lymphocytic duodenitis with sub-mucosal edema. Selpercatinib treatment was temporary interrupted with complete resolution of the symptoms and then re-administered with dose reduction, without relapsed of the gastrointestinal toxicity after 120 days. Conclusion: To our knowledge, this is the first case report of a patient with NSCLC treated with selpercatinib outside a clinical study who developed severe gastrointestinal toxicity characterized by small bowel edema and lymphocytic duodenitis, leading to treatment interruption and dose reduction. The gastrointestinal AE has been described by a radiological, endoscopic, and histopathological point of view. Further investigations are needed to better identify pathological mechanisms of gastrointestinal toxicity for an appropriate AE management.
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Background: Paratesticular fibrous pseudotumor (PFP) is a rare intrascrotal benign fibrous mass of uncertain aetiology, usually arising between testicular tunica layers and is supposed to be related to inflammatory reactive conditions. Because of morphological similarities to IgG4-related sclerosing fibro-inflammatory lesions, some authors recently postulated that PFP might belong to the IgG4-related disease (IgG4-RD) family. Considering the rarity of this lesion, only few cases have been reported in literature about the correlation between IgG4-RD and PFP. Management of PFP could be extremely challenging: due to the lack of typical clinical signs and the non-specific radiological characteristics, misapprehension does occur in the majority of cases, mainly because these intrascrotal mass may mimic testicular neoplasm, therefore leading to radical orchidectomy rather than a desirable testis-sparing surgery. Case Description: Herein we report two cases of young males treated for PFP with histological feature of IgG4-RD. Patients underwent testicular sparing surgery. At 2-year follow-up no evidence of local or distant relapse nor testicular disorder was observed in both patients. An up-to-date review of the literature about the correlation between PFP and the IgG4-RD was carried out. Conclusions: PFP is an extremely rare condition with uncertain etiology being part of IgG4-RD family. Preoperative imaging mimics malignancy hence diagnosis is usually made by specimen analysis. Intraoperative frozen section is fundamental in order to guarantee conservative treatment that is feasible and safe after mid-term follow-up.