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1.
Eur Arch Otorhinolaryngol ; 280(1): 409-417, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36036273

ABSTRACT

PURPOSE: To explore the clinical characteristics, prognostic factors, and value of adjuvant therapy for major salivary duct carcinoma (SDC). METHODS: Data of SDC patients who received surgery was obtained from Surveillance, Epidemiology, and End Results (SEER) database (2004-2016). Kaplan-Meier and Cox regression analyses were performed to assess prognostic factors. Propensity score matching (PSM) was done to evaluate the clinical value of adjuvant therapy. RESULTS: A total of 287 patients were enrolled. The 5-year overall survival (OS) and disease-specific survival (DSS) rates were 53.8% and 70.8%, respectively. In the univariate analysis, tumor size, T, N, TNM staging, SEER combined staging, number of regional lymph nodes examined, and number of positive lymph nodes were associated with OS and DSS. Age and primary surgical methods were also related to OS. Among patients with negative lymph nodes, patients with tumor size > 4 cm had significantly worse prognosis (P = 0.009). Multivariate analysis showed that age > 75 years, T3-4, and positive lymph nodes were independent risk factors for SDC. After PSM, the prognostic factors were age, tumor site, and T and N stage. Postoperative radiotherapy could improve OS in patients with tumor size > 4 cm (P = 0.049). CONCLUSIONS: Advanced age, submandibular gland lesions, T3-4 stage, and lymph node involvement were independent prognostic factors for SDC. In patients with tumors > 4 cm, adjuvant radiotherapy improved the OS of SDC patients.


Subject(s)
Carcinoma, Ductal , Salivary Gland Neoplasms , Humans , Aged , Cohort Studies , Prognosis , Salivary Glands/pathology , Combined Modality Therapy , Salivary Gland Neoplasms/pathology , Neoplasm Staging , Carcinoma, Ductal/therapy , Carcinoma, Ductal/pathology , Radiotherapy, Adjuvant , SEER Program
2.
Cancer ; 128(3): 509-518, 2022 02 01.
Article in English | MEDLINE | ID: mdl-34661906

ABSTRACT

BACKGROUND: Salivary duct carcinoma (SDC) and adenocarcinoma, not otherwise specified (adeno-NOS), are rare salivary gland cancers. Data on the efficacy of systemic therapy for these diseases are limited. METHODS: Data were retrospectively collected from patients seen at The University of Texas MD Anderson Cancer Center during 1990 to 2020. Objective response rate (ORR) was assessed per RECIST v1.1. Recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS) were assessed by Kaplan-Meier method. Cox regression model was performed to identify predictors of survival. RESULTS: The analysis included 200 patients (110 with SDC and 90 with adeno-NOS); 77% had androgen-receptor-positive tumors and 47% had HER2-positive (2+-3+) tumors. Most patients without metastasis at diagnosis underwent surgery (98%) and postoperative radiotherapy (87%). Recurrence rate was 55%, and the median RFS was 2 years. Nodal involvement and positive surgical margins were associated with recurrence (P < .005). Among patients with stage IVA-B disease, addition of systemic therapy to local therapy increased OS (P = .049). The most-used palliative-systemic-therapy regimen was platinum doublet ± trastuzumab. For first-line therapy, the ORR and median PFS were 33% and 5.76 months, respectively, and for second-line therapy the ORR and median PFS were 25% and 5.3 months, respectively. ORR and PFS were higher with HER2-targeting agents. Median OS was 5 years overall and 2 years for metastatic disease. Older age and higher stage were associated with worse OS. CONCLUSION: Adding systemic therapy to local therapy may improve outcomes of patients with locoregionally advanced SDC or adeno-NOS. Except for HER2-targeted therapy, response to palliative systemic therapy is limited. These findings may be used as a benchmark for future drug development.


Subject(s)
Adenocarcinoma , Carcinoma, Ductal , Salivary Gland Neoplasms , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Carcinoma, Ductal/pathology , Carcinoma, Ductal/therapy , Humans , Receptor, ErbB-2 , Retrospective Studies , Salivary Ducts/pathology , Salivary Ducts/surgery , Salivary Gland Neoplasms/pathology
3.
Am J Surg Pathol ; 46(2): 233-240, 2022 02 01.
Article in English | MEDLINE | ID: mdl-34619708

ABSTRACT

Prostatic duct adenocarcinoma, characterized by pseudostratified columnar epithelium, has historically been considered invasive carcinoma, although it may commonly have an intraductal component. Usual (acinar) intraductal carcinoma of the prostate (IDC-P) is a noninvasive high-risk lesion typically associated with high-grade, high-stage prostate cancer. Whereas there have been rare biopsy studies of pure acinar IDC-P or IDC-P associated with only low-grade carcinoma, there have been no analogous series of IDC-P with cribriform or papillary ductal morphology on biopsy unassociated with invasive high-grade carcinoma. We identified 14 patients with biopsies showing IDC-P with ductal morphology, defined as prostatic duct adenocarcinoma confined to glands/ducts with immunohistochemically proven retention of basal cells. Our series includes 12 patients with pure IDC-P and 2 patients with concurrent low-volume Grade Group 1 invasive cancer in unassociated cores. Three patients underwent radical prostatectomy: 2/3 had high-grade cancer in their resection specimen (Grade Group 3, Grade Group 5), including 1 with advanced stage and nodal metastases; 1/3 had Grade Group 1 organ-confined carcinoma and spatially distinct IDC-P with ductal morphology. Five men had only follow-up biopsies: 2/5 had cancer (Grade Group 2, Grade Group 4); 1/5 had IDC-P (on 2 repeat biopsies); and 2/5 had benign transurethral resection of the prostate. In all 5 cases with invasive cancer, the invasive portion was comprised purely of acinar morphology; no invasive ductal component was identified. Five patients did not have follow-up biopsies and were treated with radiation therapy±androgen deprivation. One patient had no follow-up information. In an analogous situation to acinar IDC-P, we propose that rarely there is a precursor form of ductal adenocarcinoma that can exist without concurrent invasive high-grade carcinoma and propose the term "IDC-P with ductal morphology," consistent with the terminology for acinar prostate adenocarcinoma. Until more evidence is accumulated, we recommend reporting and treating patients with IDC-P with ductal morphology in a manner analogous to those with acinar IDC-P. As with pure IDC-P with acinar morphology, we would also recommend not grading pure IDC-P with ductal morphology. Finally, we propose a new addition to the diagnostic criteria of IDC-P to include intraductal lesions with ductal morphology consisting of papillary fronds or cribriform lesions lined by cytologically atypical pseudostratified epithelium.


Subject(s)
Adenocarcinoma, Papillary/pathology , Carcinoma, Ductal/pathology , Prostatic Neoplasms/pathology , Adenocarcinoma, Papillary/classification , Adenocarcinoma, Papillary/therapy , Biopsy , Carcinoma, Ductal/classification , Carcinoma, Ductal/therapy , Humans , Male , Neoplasm Grading , Neoplasm Invasiveness , Predictive Value of Tests , Prostatic Neoplasms/classification , Prostatic Neoplasms/therapy , Terminology as Topic , Treatment Outcome
4.
Immunol Invest ; 51(5): 1498-1514, 2022 Jul.
Article in English | MEDLINE | ID: mdl-34486463

ABSTRACT

Although immune checkpoint inhibitors (ICIs) have emerged as new therapeutic options for refractory cancer, they are only effective in select patients. Tumor antigen-pulsed dendritic cell (DC) vaccine therapy activates tumor-specific cytotoxic T lymphocytes, making it an important immunotherapeutic strategy. Salivary ductal carcinoma (SDC) carries a poor prognosis, including poor long-term survival after metastasis or recurrence. In this study, we reported a case of refractory metastatic SDC that was treated with a tumor lysate-pulsed DC vaccine followed by a single injection of low-dose nivolumab, and a durable complete response was achieved. We retrospectively analyzed the immunological factors that contributed to these long-lasting clinical effects. First, we performed neoantigen analysis using resected metastatic tumor specimens obtained before treatment. We found that the tumor had 256 non-synonymous mutations and 669 class I high-affinity binding neoantigen peptides. Using synthetic neoantigen peptides and ELISpot analysis, we found that peripheral blood mononuclear leukocytes cryopreserved before treatment contained pre-existing neoantigen-specific T cells, and the cells obtained after treatment exhibited greater reactivity to neoantigens than those obtained before treatment. Our results collectively suggest that the rapid and long-lasting effect of this combination therapy in our patient may have resulted from the presence of pre-existing neoantigen-specific T cells and stimulation and expansion of those cells following tumor lysate-pulsed DC vaccine and ICI therapy.


Subject(s)
Cancer Vaccines , Carcinoma, Ductal , Carcinoma , Antigens, Neoplasm , Cancer Vaccines/therapeutic use , Carcinoma, Ductal/therapy , Dendritic Cells , Humans , Leukocytes, Mononuclear , Nivolumab/therapeutic use , Peptides , Retrospective Studies , Salivary Ducts/metabolism
5.
Eur Arch Otorhinolaryngol ; 279(1): 327-333, 2022 Jan.
Article in English | MEDLINE | ID: mdl-33763743

ABSTRACT

PURPOSE: Salivary gland tumors are rare and include benign and malignant entities with different behavior and prognosis. Salivary gland carcinoma accounts for 0.2% of all cancers and 5-9% of head and neck carcinomas. We aim to describe the clinicopathological characteristics and discuss the immunohistochemical findings of salivary ductal carcinoma. METHODS: We obtained 17 cases (2.3%) of salivary ductal carcinoma (SDC) from 727 patients with parotid tumors at our cancer center from a database covering a 22-year period (1996-2018). Two pathologists confirmed the diagnosis and excluded 6 cases. Eleven cases were assessed by immunohistochemistry (IHC) for HER2, estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), mammaglobin, P53, GATA3, S100, cytokeratins (7,8,14,18, and 20), P63, PAX8, calponin, and SOX10. RESULTS: Eleven SDC cases were in advanced stage, and 80% had metastasis. All cases were surgically treated, and 40% received different adjuvant chemotherapy regimens. we found that most patients were dead of disease. The histological and immunohistochemical analysis showed that 70% of cases were high-grade, 40% were positive for HER2, and 50% for AR. Moreover, a high Ki-67 proliferative index was detected in all cases. We observed luminal differentiation in 50% of cases. CONCLUSION: SDC is a rare entity and survival is very poor. It is histologically similar to ductal carcinoma of the breast. However, important differences exist that help to distinguish them in case of synchronous cancers. The clinical behavior of SDC seems to be more aggressive and IHC analysis is useful for designing therapies.


Subject(s)
Carcinoma, Ductal , Lacrimal Apparatus , Parotid Neoplasms , Salivary Gland Neoplasms , Biomarkers, Tumor , Carcinoma, Ductal/therapy , Humans , Immunohistochemistry
6.
Int Urol Nephrol ; 54(1): 89-95, 2022 Jan.
Article in English | MEDLINE | ID: mdl-34797483

ABSTRACT

AIM: To compare cancer-specific mortality (CSM) rates between radical prostatectomy (RP) vs. external beam radiotherapy (RT) in patients with ductal carcinoma (DC) of the prostate. MATERIALS AND METHODS: Within the Surveillance, Epidemiology, and End Results (SEER) database (2004-2016), we identified 369 DC patients, of whom 303 (82%) vs. 66 (18%) were treated with RP vs. RT, respectively. Kaplan-Meier plots and uni- and stepwise multivariate Cox regression models addressed CSM in the unmatched population. After propensity score matching (PSM) and inverse probability of treatment weighting (IPTW), Kaplan-Meier curve and Cox regression models tested the effect of RP vs RT on CSM. RESULTS: Overall, RT patients were older, harbored higher PSA values, higher clinical T and higher Gleason grade groups. 5-year CSM rates were respectively 4.2 vs. 10% for RP vs. RT (HR 0.40, 95% CI 0.16-0.99, p = 0.048, favoring RP). At step-by-step multivariate Cox regression, after adding possible confounders, the central tendency of the HR for RP vs. RT approached 1. PSM resulted into 124 vs. 53 patients treated respectively with RP vs. RT. After PSM, as well as after IPTW, the protective effect of RP was no longer present (HR 1.16, 95% CI 0.23-5.73, p = 0.9 and 0.97, 95% CI 0.35-2.66, p = 0.9, respectively). CONCLUSIONS: Although CSM rate of ductal carcinoma RP patients is lower of that of RT patients, this apparent benefit disappears after statistical adjustment for population differences.


Subject(s)
Carcinoma, Ductal/mortality , Carcinoma, Ductal/therapy , Prostatic Neoplasms/mortality , Prostatic Neoplasms/therapy , Aged , Carcinoma, Ductal/radiotherapy , Humans , Male , Middle Aged , Prostatectomy/methods , Prostatic Neoplasms/radiotherapy , Retrospective Studies , Survival Rate
7.
Curr Oncol Rep ; 23(9): 110, 2021 07 16.
Article in English | MEDLINE | ID: mdl-34272624

ABSTRACT

PURPOSE OF REVIEW: This review will discuss current understanding and management approaches of Intraductal carcinoma of the prostate (IDC-P). IDC-P is a histological finding characterized by neoplastic cells that expand but do not invade prostate ducts. RECENT FINDINGS: The presence of IDC-P on a prostate biopsy is almost always associated with an invasive disease component and is independently associated with worse clinical outcomes in both early and late disease. These tumors are enriched for mutations in homologous DNA recombination repair (HRR) leading to high genomic instability. Multiparametric MRI with targeted biopsy may aid in diagnosis. Given the poor clinical outcomes associated with this histologic entity, its presence in biopsies should warrant consideration of aggressive management.


Subject(s)
Carcinoma, Ductal/genetics , DNA Mismatch Repair/genetics , Genetic Predisposition to Disease/genetics , Microsatellite Instability , Mutation , Prostatic Neoplasms/genetics , Carcinoma, Ductal/pathology , Carcinoma, Ductal/therapy , Humans , Male , Neoplasm Grading , Prostatic Neoplasms/pathology , Prostatic Neoplasms/therapy , Signal Transduction/genetics
9.
Nat Rev Urol ; 18(6): 337-358, 2021 06.
Article in English | MEDLINE | ID: mdl-33824525

ABSTRACT

Ductal adenocarcinoma (DAC) is the most common variant histological subtype of prostate carcinoma and has an aggressive clinical course. DAC is usually characterized and treated as high-risk prostatic acinar adenocarcinoma (PAC). However, DAC has a different biology to that of acinar disease, which often poses a challenge for both diagnosis and management. DAC can be difficult to identify using conventional diagnostic modalities such as serum PSA levels and multiparametric MRI, and the optimal management for localized DAC is unknown owing to the rarity of the disease. Following definitive therapy for localized disease with radical prostatectomy or radiotherapy, the majority of DACs recur with visceral metastases at low PSA levels. Various systemic therapies that have been shown to be effective in high-risk PAC have limited use in treating DAC. Although current understanding of the biology of DAC is limited, genomic analyses have provided insights into the pathology behind its aggressive behaviour and potential future therapeutic targets.


Subject(s)
Carcinoma, Ductal/diagnosis , Carcinoma, Ductal/therapy , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/therapy , Humans , Male
10.
Int J Surg Pathol ; 29(7): 726-730, 2021 Oct.
Article in English | MEDLINE | ID: mdl-33683973

ABSTRACT

Salivary duct carcinoma of the parotid gland is a highly aggressive epithelial malignancy morphologically resembling high-grade, invasive, and in situ breast carcinoma. It can occasionally present with variable morphology making it diagnostically challenging in cases with unusual morphological components. Ancillary testing, particularly androgen receptor (AR) positivity on immunohistochemistry, can be very helpful in cases that demonstrate extensive squamous morphology, since AR positivity is uncommon in both the primary salivary gland and metastatic squamous cell carcinomas to the parotid. In this report, we describe a case of salivary duct carcinoma that showed only a squamous cell carcinoma component on the initial primary tumor site biopsy, as well as in subsequent contralateral neck lymph node and skin metastases. Apart from the variable morphology, the typical salivary duct and squamous cell carcinoma tumor components also showed significant immunohistochemical differences, including differential staining of human epidermal growth factor receptor 2/neu. The associated diagnostic pitfalls, distinct immunoprofiles of the tumor components, helpful adjuncts for making the correct diagnosis, and associated therapeutic implications are discussed.


Subject(s)
Carcinoma, Ductal/diagnosis , Carcinoma, Squamous Cell/diagnosis , Neoplasms, Complex and Mixed/diagnosis , Parotid Gland/pathology , Parotid Neoplasms/diagnosis , Aged , Biomarkers, Tumor/analysis , Biomarkers, Tumor/antagonists & inhibitors , Biomarkers, Tumor/genetics , Biopsy , Carcinoma, Ductal/genetics , Carcinoma, Ductal/pathology , Carcinoma, Ductal/therapy , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/therapy , Chemoradiotherapy/methods , DNA Mutational Analysis , Diagnosis, Differential , Fatal Outcome , Female , Humans , Immunohistochemistry , Mutation , Neoplasms, Complex and Mixed/genetics , Neoplasms, Complex and Mixed/pathology , Neoplasms, Complex and Mixed/therapy , Palliative Care/methods , Parotid Neoplasms/genetics , Parotid Neoplasms/pathology , Parotid Neoplasms/therapy
11.
Surg Pathol Clin ; 14(1): 111-126, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33526216

ABSTRACT

Salivary duct carcinoma (SDC) is a rare, aggressive salivary gland malignancy with significant mortality. Morphologically, most tumors are characterized by apocrine differentiation with a typical immunophenotype of androgen receptor positive/gross cystic disease fluid protein positive/estrogen receptor negative/progesterone receptor negative. Several morphologic variants of SDC exist, representing diagnostic pitfalls. Several differential diagnoses should be considered because prognosis, treatment, and management may be different from SDC. For SDC, current treatment strategies are aggressive and commonly include surgical excision with lymph node dissection and adjuvant radiotherapy. Continued research is examining the utility of androgen deprivation therapy and targeted molecular therapy.


Subject(s)
Carcinoma, Ductal/pathology , Salivary Gland Neoplasms/pathology , Carcinoma, Ductal/diagnosis , Carcinoma, Ductal/therapy , Diagnosis, Differential , Humans , Immunophenotyping , Neoplasm Metastasis , Prognosis , Receptors, Androgen/analysis , Salivary Gland Neoplasms/diagnosis , Salivary Gland Neoplasms/therapy
13.
J. health med. sci. (Print) ; 7(1): 15-23, ene.-mar. 2021. tab, ilus
Article in Spanish | LILACS | ID: biblio-1380259

ABSTRACT

El carcinoma del conducto salival es un tumor epitelial maligno agresivo, que involucra principalmente a la glándula parótida, con características histológicas semejantes al carcinoma ductal de glándula mamaria. El propósito de este trabajo fue presentar los resultados clínico-patológicos de cinco casos de carcinoma del conducto salival primario de glándula parótida y evaluar la expresión de Ki67. Histológicamente, el carcinoma del conducto salival presentó nidos epiteliales con patrones papilar, sólido y cribiforme, comedonecrosis tanto en la lesión primaria como en los nodos linfoides metastásicos y, además, invasión perineural. Se demostró con Ki 67 una alta proliferación celular en cuatro (80 %) de los cinco casos estudiados. Se concluyó que: el carcinoma del conducto salival es una lesión maligna de mal pronóstico, raramente informado en la literatura odontológica, con características histológicas semejantes a las del carcinoma ductal de alto grado de la mama; la comedonecrosis es un signo específico de esta enfermedad; puede desarrollarse "de novo" o en un adenoma pleomórfico preexistente; su diagnóstico diferencial histopatológico es fundamental para planificar su tratamiento y determinar su pronóstico, a pesar de su tratamiento quirúrgico y radioterapia postoperatoria es un tumor agresivo con alta proliferación celular, infiltración perineural, recurrencias y metástasis.


Salivary duct carcinoma is an aggressive malignant epithelial tumor, primarily involving the parotid gland, with histologic features similar to ductal carcinoma of the breast. The purpose of this work was to report the clinicopathological results of five cases of primary salivary duct carcinoma of the parotid gland and evaluate the expression of Ki67. Histologically, salivary duct carcinoma presented epithelial nests with papillary, solid, and cribriform patterns, with comedonecrosis in both the primary lesion and the metastatic limph nodes, and perineural invasion. A high cell proliferation was demonstrated with Ki67 in four (80 %) of the five cases studied. We concluded that: salivary duct carcinoma is a malignant lesion with a poor prognosis, rarely reported in the dental literature, with histological characteristics similar to those of high-grade ductal carcinoma of the breast; comedonecrosis is a specific sign of this disease; may develop "de novo" or in a pre-existing pleomorphic adenoma; its differential histopathological diagnosis is essential to plan its treatment and determine its prognosis; despite its surgical treatment and postoperative radiotherapy, it is an aggressive tumor with high cell proliferation, perineural infiltration, recurrences and metastasis.


Subject(s)
Humans , Male , Female , Middle Aged , Aged , Salivary Gland Neoplasms/pathology , Biomarkers, Tumor/genetics , Carcinoma, Ductal/pathology , Salivary Gland Neoplasms/genetics , Salivary Gland Neoplasms/therapy , Immunohistochemistry/methods , Ki-67 Antigen , Carcinoma, Ductal/genetics , Carcinoma, Ductal/therapy
14.
World J Urol ; 39(4): 1161-1170, 2021 Apr.
Article in English | MEDLINE | ID: mdl-32591899

ABSTRACT

PURPOSE: To retrospectively review our 20 year experience of multidisciplinary management of non-metastatic ductal prostate cancer (dPC), a rare but aggressive histological subtype of prostate cancer whose optimal therapeutic approach is still controversial. METHODS: Histologically confirmed dPC patients undergoing primary, curative treatment [radical prostatectomy (RP), external beam radiotherapy (EBRT), and androgen deprivation therapy (ADT)] were included, and percentage of ductal and acinar pattern within prostate samples were derived. Survival outcomes were assessed using the subdistribution hazard ratio (SHR) and Fine-and-Gray model. RESULTS: From January 1997 to December 2016, 81 non-metastatic dPC fitted selection criteria. Compared to surgery alone, SHR for progression-free survival and cancer-specific mortality were 2.8 (95% CI 0.6-13.3) and 1.3 (95% CI 0.1-16.2) for exclusive EBRT, 2.7 (95% CI 0.6-13.0) and 6.5 (95% CI 0.6-69.8) for adjuvant EBRT, 4.9 (95% CI 0.7-35.5) and 5.8 (95% CI 0.5-65.6) for salvage EBRT post-prostatectomy recurrence, and 3.2 (95% CI 0.7-14.0) and 3.9 (95% CI 0.3-44.1) for primary ADT (P = 0.558; P = 0.181), respectively. Comparing multimodal treatment and monotherapy confirmed the above trends. Local recurrence more typically occurred in pure dPC patients, mixed histology more frequently produced metastatic spread (29.6% relapse in total, P = 0.026). CONCLUSION: Albeit some limitations affected the study, our findings support the role of local treatment to achieve better disease control and improve quality of life. Different behavior, with typical local growth in pure dPC, higher distant metastatization in the mixed form, might influence treatment response. Given its poor prognosis, we recommend multidisciplinary management of dPC.


Subject(s)
Adenocarcinoma/therapy , Carcinoma, Ductal/therapy , Patient Care Team/trends , Prostatic Neoplasms/therapy , Aged , Aged, 80 and over , Humans , Male , Medical Oncology , Middle Aged , Retrospective Studies , Treatment Outcome , Urology
15.
Oral Oncol ; 110: 105018, 2020 11.
Article in English | MEDLINE | ID: mdl-33039794

ABSTRACT

OBJECTIVES: Salivary duct carcinoma (SDC) is a rare and aggressive subtype of salivary gland cancer. Androgen receptor (AR) (96%) and HER2 (29-46%) expression, and a high propensity for regional lymph node metastases are hallmarks of the disease. We hypothesized that c-MET, E-cadherin, PSMA tumor and PSMA neovascular expression may be prognostic factors in SDC. MATERIALS AND METHODS: Expression levels of these proteins were established on tissue microarrays containing 165 primary SDC tumor specimens. Association with survival was studied with Kaplan-Meier curves, and univariable and multivariable Cox regression models. Furthermore, association with lymph node status, AR and HER2 expression, and gender was studied. RESULTS: We found that patients with high PSMA tumor expression showed a significantly longer overall survival (OS) (median 83 vs. 43 months, P = 0.022), a trend towards a longer DFS (median 51 vs. 22 months, P = 0.094), and significantly reduced hazard ratio for death in the univariable Cox regression model (HR 0.46, P = 0.034). In the multivariable model only a high number of tumor-positive lymph nodes and high age (>80) at diagnosis were prognostic for poor OS. High PSMA tumor expression was also significantly associated with low N-stage (P = 0.001) and expression was higher in women versus men (P = 0.029). High PSMA tumor expression and E-cadherin loss were significantly associated with strong and weak AR-expression, respectively (P = 0.033 and P = 0.007). None of the factors were significantly associated with HER2 expression. CONCLUSION: c-MET, E-cadherin, and tumor and neovascular PSMA expression are no independent prognostic factors in SDC.


Subject(s)
Cadherins/genetics , Carcinoma, Ductal/etiology , Proteasome Endopeptidase Complex/metabolism , Proto-Oncogene Proteins c-met/genetics , Salivary Gland Neoplasms/etiology , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor , Cadherins/metabolism , Carcinoma, Ductal/diagnosis , Carcinoma, Ductal/mortality , Carcinoma, Ductal/therapy , Disease Susceptibility , Female , Gene Expression , Humans , Immunohistochemistry , In Situ Hybridization , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Staging , Prognosis , Proportional Hazards Models , Proto-Oncogene Mas , Proto-Oncogene Proteins c-met/metabolism , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Salivary Gland Neoplasms/diagnosis , Salivary Gland Neoplasms/mortality , Salivary Gland Neoplasms/therapy
16.
Nat Immunol ; 21(10): 1152-1159, 2020 10.
Article in English | MEDLINE | ID: mdl-32807942

ABSTRACT

Pancreatic ductal adenocarcinoma carries a dismal prognosis, and outcomes have improved little with modern therapeutics. Checkpoint-based immunotherapy has failed to elicit responses in the vast majority of patients with pancreatic cancer. Alongside tumor cell-intrinsic mechanisms associated with oncogenic KRAS-induced inflammation, the tolerogenic myeloid cell infiltrate has emerged as a critical impediment to adaptive antitumor immune responses. Furthermore, the discovery of an intratumoral microbiome and the elucidation of host-microbe interactions that curtail antitumor immunity also present opportunities for intervention. Here we review the mechanisms of immunotherapy resistance in pancreatic ductal adenocarcinoma and discuss strategies to directly augment T cell responses in parallel with myeloid cell- and microbiome-targeted approaches that may enable immune-mediated control of this malignancy.


Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Carcinoma, Ductal/immunology , Immune Checkpoint Inhibitors/therapeutic use , Immunotherapy/methods , Myeloid-Derived Suppressor Cells/immunology , Pancreatic Neoplasms/immunology , T-Lymphocytes/immunology , Adaptive Immunity , Animals , Carcinoma, Ductal/therapy , Humans , Immune Tolerance , Immunomodulation , Microbiota , Pancreatic Neoplasms/therapy , T-Lymphocytes/transplantation , Tumor Microenvironment
17.
J Immunol Res ; 2020: 7503605, 2020.
Article in English | MEDLINE | ID: mdl-32537471

ABSTRACT

The study aimed to clarify the potential immune-related targets and mechanisms of Qingyihuaji Formula (QYHJ) against pancreatic cancer (PC) through network pharmacology and weighted gene co-expression network analysis (WGCNA). Active ingredients of herbs in QYHJ were identified by the TCMSP database. Then, the putative targets of active ingredients were predicted with SwissTargetPrediction and the STITCH databases. The expression profiles of GSE32676 were downloaded from the GEO database. WGCNA was used to identify the co-expression modules. Besides, the putative targets, immune-related targets, and the critical module genes were mapped with the specific disease to select the overlapped genes (OGEs). Functional enrichment analysis of putative targets and OGEs was conducted. The overall survival (OS) analysis of OGEs was investigated using the Kaplan-Meier plotter. The relative expression and methylation levels of OGEs were detected in UALCAN, human protein atlas (HPA), Oncomine, DiseaseMeth version 2.0 and, MEXPRESS database, respectively. Gene set enrichment analysis (GSEA) was conducted to elucidate the key pathways of highly-expressed OGEs further. OS analyses found that 12 up-regulated OGEs, including CDK1, PLD1, MET, F2RL1, XDH, NEK2, TOP2A, NQO1, CCND1, PTK6, CTSE, and ERBB2 that could be utilized as potential diagnostic indicators for PC. Further, methylation analyses suggested that the abnormal up-regulation of these OGEs probably resulted from hypomethylation, and GSEA revealed the genes markedly related to cell cycle and proliferation of PC. This study identified CDK1, PLD1, MET, F2RL1, XDH, NEK2, TOP2A, NQO1, CCND1, PTK6, CTSE, and ERBB2 might be used as reliable immune-related biomarkers for prognosis of PC, which may be essential immunotherapies targets of QYHJ.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Ductal/therapy , Drugs, Chinese Herbal/therapeutic use , Immunotherapy/methods , Pancreatic Neoplasms/therapy , Biomarkers, Tumor/genetics , CDC2 Protein Kinase/genetics , Carcinoma, Ductal/mortality , Computational Biology , DNA Methylation , Databases, Factual , Gene Regulatory Networks , Humans , Pancreatic Neoplasms/mortality , Phospholipase D/genetics , Proto-Oncogene Proteins c-met/genetics , Survival Analysis , Transcriptome , Up-Regulation
18.
Cancer Cytopathol ; 128(10): 693-703, 2020 10.
Article in English | MEDLINE | ID: mdl-32421944

ABSTRACT

Salivary duct carcinoma (SDC) is an aggressive subtype of primary salivary gland carcinoma, often with an advanced stage at presentation and high rates of metastasis and recurrence. It most commonly arises in the parotid gland of older men and microscopically resembles high-grade breast ductal carcinoma. While 50 years have lapsed since the first report of this entity, recent intensive studies have shed light on its biologic, genetic, and clinical characteristics. The diagnosis of SDC is aided by the immunohistochemical expression of androgen receptor (AR) coupled with its characteristic histomorphology. Fine-needle aspiration typically reveals cytologic features of high-grade carcinoma, and ancillary studies using cell block material can facilitate the specific diagnosis of SDC. In surgical specimens, certain histologic features are important prognostic factors, including nuclear pleomorphism, mitotic counts, vascular invasion, and the morphology at the invasion front. Several clinical studies have shown promising results using targeted therapy for AR and human epidermal growth factor receptor 2 (HER2), and the latest version of the National Comprehensive Cancer Network guidelines recommends the evaluation of AR and HER2 status before treatment. Recent molecular analyses have revealed multiple heterogeneous alterations in well-known oncogenes and tumor suppressor genes, including TP53, HRAS, PIK3CA, PTEN, and BRAF. Clinical trials of drugs targeting these genes may broaden the treatment options for SDC in the near future.


Subject(s)
Biomarkers, Tumor/genetics , Carcinoma, Ductal/pathology , Molecular Targeted Therapy , Salivary Gland Neoplasms/pathology , Animals , Carcinoma, Ductal/genetics , Carcinoma, Ductal/therapy , Humans , Salivary Gland Neoplasms/genetics , Salivary Gland Neoplasms/therapy
19.
Theranostics ; 10(5): 2273-2283, 2020.
Article in English | MEDLINE | ID: mdl-32089741

ABSTRACT

Rationale: Treatment options for recurrent and/or metastatic (R/M) adenoid cystic carcinoma (ACC) and salivary duct carcinoma (SDC), major subtypes of salivary gland cancer, are limited. Both tumors often show overexpression of prostate-specific membrane antigen (PSMA). In prostate cancer, PSMA-ligands labeled with 68Ga or 177Lu are used for imaging and therapy, respectively. Primary aim of this study in R/M ACC and SDC patients was to systematically investigate 68Ga-PSMA-uptake by PET/CT imaging to determine if PSMA radionuclide therapy could be a treatment option. Methods: In a prospective phase II study, PET/CT imaging was performed 1 h post injection of 68Ga-PSMA-HBED-CC in 15 ACC patients and 10 SDC patients. Maximum standardized uptake values (SUV) were determined in tumor lesions. Immunohistochemical PSMA expression was scored in primary tumors and metastatic tissue. Standard imaging (MRI or CT) was performed for comparison. Results: In ACC patients, SUVmax ranged from 1.1 to 30.2 with a tumor/liver-ratio >1 in 13 out of 14 evaluable patients (93%). In SDC patients, SUVmax ranged from 0.3 to 25.9 with a tumor/liver-ratio >1 in 4 out of 10 patients (40%). We found a large intra-patient inter-metastatic variation in uptake of 68Ga-PSMA, and immunohistochemistry did not predict ligand uptake in ACC and SDC. Finally, PSMA-PET detected additional bone metastases compared to CT in 2 ACC patients with unexplained pain. Conclusion: In 93% of ACC patients and 40% of SDC patients we detected relevant PSMA-ligand uptake, which warrants to study PSMA radionuclide therapy in these patients. Additionally, our data provide arguments for patient selection and treatment timing. Finally, PSMA-PET imaging has added diagnostic value compared to CT in selected patients.


Subject(s)
Carcinoma, Adenoid Cystic/diagnostic imaging , Carcinoma, Ductal/metabolism , Edetic Acid/analogs & derivatives , Oligopeptides/pharmacokinetics , Positron Emission Tomography Computed Tomography/methods , Adult , Aged , Antigens, Surface/metabolism , Carcinoma, Ductal/therapy , Edetic Acid/administration & dosage , Edetic Acid/pharmacokinetics , Edetic Acid/therapeutic use , Female , Gallium Isotopes , Gallium Radioisotopes , Glutamate Carboxypeptidase II/metabolism , Humans , Magnetic Resonance Imaging/methods , Male , Middle Aged , Neoplasm Metastasis/diagnostic imaging , Neoplasm Metastasis/pathology , Neoplasm Recurrence, Local/diagnostic imaging , Neoplasm Recurrence, Local/pathology , Oligopeptides/administration & dosage , Oligopeptides/therapeutic use , Prospective Studies , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Radiopharmaceuticals/administration & dosage , Radiopharmaceuticals/pharmacokinetics , Radiopharmaceuticals/therapeutic use , Salivary Ducts/pathology , Salivary Gland Neoplasms/pathology
20.
Cancer Radiother ; 24(2): 135-137, 2020 Apr.
Article in French | MEDLINE | ID: mdl-31992517

ABSTRACT

We report a rare case of salivary duct carcinoma and we study its clinical and evolutionary features. A 64-year-old patient was referred for right peripheral facial paralysis. MRI showed suspected formation of the right parotid gland. Treatment included total parotidectomy and ipsilateral neck lymph node dissection. The histology concluded to a ductal carcinoma of the parotid with lymph node metastasis. Radiation therapy has been indicated. Salivary duct carcinoma of the parotid gland is a highly aggressive and uncommon tumor. Treatment of localized forms is based on surgery and radiotherapy.


Subject(s)
Carcinoma, Ductal , Parotid Neoplasms , Carcinoma, Ductal/complications , Carcinoma, Ductal/diagnostic imaging , Carcinoma, Ductal/pathology , Carcinoma, Ductal/therapy , Facial Paralysis/etiology , Humans , Lymph Node Excision , Lymphatic Metastasis , Magnetic Resonance Imaging , Male , Middle Aged , Parotid Neoplasms/complications , Parotid Neoplasms/diagnostic imaging , Parotid Neoplasms/pathology , Parotid Neoplasms/therapy
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