Aggressive Lymph Node Research Articles

Simultaneous bilateral video-assisted thoracic surgery is safe and feasible for multiple primary lung cancers

BackgroundThe treatment for bilateral synchronous multiple primary lung cancers (MPLC) remains challenging. Simultaneous bilateral video-assisted thoracic surgery (VATS) may be an optimal treatment with curative intent, but its safety and feasibility are controversial.MethodsOne hundred and fifty-eight patients who underwent simultaneous bilateral VATS (simultaneous group) and 79 who underwent two-staged bilateral VATS (two-staged group) were included in this study. Their medical records were retrospectively reviewed and analyzed.ResultsThe majority of patients were female and non-smokers. The most common surgical plan was lobectomy and contralateral wedge resection in both groups. There was no significant difference in the postoperative complication rate between the simultaneous groups and two-staged group (13.3% vs. 11.4%, p = 0.73). Patients who underwent simultaneous bilateral resection had shorter hospital stays, shorter anesthesia time and less chest drainage compared with those who underwent two-staged resection. Advanced TNM stage, complicated surgical plan and aggressive lymph node resection were risk factors for postoperative complications in simultaneous bilateral VATS. Patients in two groups had similar overall survival and disease free survival (p = 0.2).ConclusionsSimultaneous bilateral VATS for bilateral lung nodule resection is as safe and feasible as two-staged bilateral VATS. Patients who underwent simultaneous bilateral resection had similar or even better outcomes compared to that of the two-staged group. Simultaneous bilateral VATS is potentially an optimal treatment option for patients with erarly cTNM stage and good physical condition.

Functional loss of tumor suppressor genes detected by loss of heterozygosity, but not driver mutations, predicts aggressive lymph node status in papillary thyroid carcinoma

BackgroundRecognizing aggressive tumor biology is essential to optimizing patient management for papillary thyroid carcinomas (PTC). Aggressive lymph node (ALN) status is one feature that influences decision-making. We evaluated genomic deletions in regions of tumor suppressor genes, detected by loss of heterozygosity (LOH) analysis, to understand causal alterations linked to thyroid cancer aggressiveness and to serve as a molecular diagnostic biomarker for ALN status. MethodsWe analyzed 105 primary PTC enriched for patients with ALN (64% with, 36% without). We also analyzed 39 positive lymph nodes (79% with, 21% without ALN). LOH was determined using a panel of 25 polymorphic microsatellite alleles targeting 10 genomic loci harboring common tumor suppressor genes. Additionally, ThyGeNEXT® and ThyraMIR® assays were performed. ResultsLOH was detected in 43/67 primary PTC from patients with ALN status, compared with only 5/38 primary PTC without ALN (minimal metastatic burden) (P=0.0000003). This is further supported by post hoc analyses of paired primary and metastatic samples. Paired samples from patients with ALN are more likely to harbor LOH, compared to the ALN negative group (P=0.0125). Additionally, 12/31 paired samples from patients with ALN demonstrated additional or different LOH loci in metastatic samples compared to the primary tumor samples. No association was seen between ALN and mutational, translocation, or microRNA data. ConclusionsLOH detected in primary PTC significantly predicts ALN status. Analysis of paired primary and metastatic samples from patients with / without ALN status further supports this relationship. The acquisition of LOH at additional loci is common in lymph nodes from patients with ALN status. Simple summaryA subset of patients with papillary thyroid carcinoma (PTC) will develop recurrent disease. One known predictor of recurrence is the American Thyroid Association category “Aggressive Lymph Node” (ALN) disease, considering metastatic burden. Loss of heterozygosity (LOH) — chromosomal loss in regions of tumor suppressor genes — has yet to be investigated as a possible mechanism driving ALN status in PTC. The ability to predict ALN status prior to surgery can guide the extent of surgery and postoperative treatment options. We found that paired samples from patients with ALN are more likely to harbor LOH, compared to patients without ALN disease. 38% of patients with ALN demonstrated additional or different LOH loci in metastatic samples compared to the primary tumor samples. LOH complements current molecular analysis of thyroid cancer when searching for evidence of aggressive biology.

Histological transformation to signet-ring cell carcinoma in a patient with clinically aggressive poorly differentiated adenocarcinoma of the ascending colon after response to chemotherapy plus cetuximab: a case report

BackgroundAlteration of chemosensitivity or tumor aggressiveness in response to chemotherapy has been reported, and liquid biopsy assessment during chemotherapy for colorectal cancers has confirmed the acquisition of mutations in various oncogenes. However, the occurrence of histological transformation seems to be extremely rare in colorectal cancers, and the few existing case reports of this transformation are from lung cancer and breast cancer. In this report, we describe the histological transformation of clinically aggressive scirrhous-type poorly differentiated adenocarcinoma of the ascending colon to signet-ring cell carcinoma in almost all recurrent tumors that were confirmed by autopsy after response to chemotherapy plus cetuximab.Case presentationA 59-year-old woman visited our hospital with whole abdominal pain and body weight loss and was diagnosed with scirrhous-type poorly differentiated adenocarcinoma of the ascending colon with aggressive lymph node metastases. The intrinsic chemosensitivity of the tumors was evident upon initiation of mFOLFOX6 plus cetuximab therapy, and right hemicolectomy was performed, and the tumor obviously remained in the peripancreatic area, paraaortic region, or other retroperitoneal areas. The ascending colon tumors mainly consisted of poorly differentiated adenocarcinoma and were not associated with signet-ring cell components except for minute clusters in a few lymphatic emboli in the main tumor. Chemotherapy was continued, and metastases were eliminated at 8 months after the operation; this response was maintained for an additional 4 months. Discontinuation of chemotherapy plus cetuximab resulted in immediate tumor recurrence and rapid expansion, and the patient died of the recurrent tumor 1 year and 2 months after the operation. Autopsy specimens revealed that almost all of the recurrent tumors exhibited transformation and consisted of signet-ring cell histology.ConclusionThis case might suggest that various oncogene mutations or epigenetic changes resulting from chemotherapy, especially regimens that include cetuximab, contribute to the transformation of non-signet-ring cell colorectal carcinoma to signet-ring cell carcinoma histology and can promote the aggressive clinical progression characteristic of signet-ring cell carcinoma.

Less demand on stem cell marker-positive cancer cells may characterize metastasis of colon cancer.

CD44 and CD133 are stem cell markers in colorectal cancer (CRC). CD44 has distinctive isoforms with different oncological properties like total CD44 (CD44T) and variant CD44 (CD44V). Clinical significance of such markers remains elusive. Sixty colon cancer were examined for CD44T/CD44V and CD133 at mRNA level in a quantitative PCR, and clarified for their association with clinicopathological factors. (1) Both CD44T and CD44V showed higher expression in primary colon tumors than in non-cancerous mucosas (p<0.0001), while CD133 was expressed even in non-cancerous mucosa and rather decreased in the tumors (p = 0.048). (2) CD44V expression was significantly associated with CD44T expression (R = 0.62, p<0.0001), while they were not correlated to CD133 at all in the primary tumors. (3) CD44V/CD44T expressions were significantly higher in right colon cancer than in left colon cancer (p = 0.035/p = 0.012, respectively), while CD133 expression were not (p = 0.20). (4) In primary tumors, unexpectedly, CD44V/CD44T/CD133 mRNA expressions were not correlated with aggressive phenotypes, but CD44V/CD44T rather significantly with less aggressive lymph node metastasis/distant metastasis (p = 0.040/p = 0.039, respectively). Moreover, both CD44V and CD133 expressions were significantly decreased in liver metastasis as compared to primary tumors (p = 0.0005 and p = 0.0006, respectively). Our transcript expression analysis of cancer stem cell markers did not conclude that their expression could represent aggressive phenotypes of primary and metastatic tumors, and rather represented less demand on stem cell marker-positive cancer cells.

Relationship between the number of lymph nodes dissected and prognosis in muscle-invasive bladder cancer in the era of neoadjuvant chemotherapy.

Many studies have shown a good prognostic association with a large number of lymph node dissections. However, most of these studies did not include patients who have received neoadjuvant chemotherapy. The purpose of this study was to verify the relationship between survival outcomes and the number of lymph nodes removed during radical cystectomy in patients with muscle-invasive bladder cancer in the era of neoadjuvant chemotherapy. This retrospective study considered patients who were diagnosed with clinical ≥T2N0M0 muscle-invasive bladder cancer and treated with radical cystectomy at the Nagoya University Hospital and affiliated hospitals from January 2004 to December 2019. We excluded patients who had a history of upper tract urothelial cancer or non-urothelial carcinoma. The association between prognosis and the number of lymph nodes removed was investigated. We retrospectively enrolled a total of 477 patients. The mean number of lymph nodes dissected was 14. Two hundred and twenty-six patients (47.4%) received neoadjuvant chemotherapy. More extensive lymphadenectomy (≥15 lymph nodes) correlated with better 5-year overall survival across all patients (68% vs. 57%, p = 0.01). In patients who received neoadjuvant chemotherapy, there was no difference in overall survival according to the number of dissected lymph nodes (66% vs. 71%, p = 0.433). In patients who did not receive neoadjuvant chemotherapy, ≥15 lymph nodes dissected was associated with significantly better overall survival (70.3% vs. 46.9%, p < 0.01). No association between more aggressive lymph node dissection and prognosis was found in patients who underwent neoadjuvant chemotherapy. Conversely, extended lymph node dissection is desirable for patients who have not received neoadjuvant chemotherapy.

Tall cell variant papillary thyroid carcinoma impacts disease-free survival at the 10 % cut-point on multivariate analysis

IntroductionThe diagnosis of tall cell variant papillary thyroid carcinoma (TCV-PTC) corresponds to the feature of “aggressive histology” within the framework of the American Thyroid Association (ATA) Risk of Recurrence (ROR) guidelines. Using the current World Health Organization (WHO) definition for TCV-PTC (tall cells with height at least twice the width, distribution ≥ 30 %), we examined the impact of this diagnosis on disease-free survival (DFS). MethodsThe study cohort consisted of 347 patients treated for primary papillary thyroid carcinoma (PTC). Current ATA guidelines were followed for the extent of surgery and the administration of adjuvant radioiodine therapy. Clinical surveillance included ultrasound examination and biochemical parameters according to ATA standards. The outcome was measured as time from surgery to first disease recurrence (DR) versus time from surgery until the last documented disease-free encounter (no evidence of disease, NED). Disease-free patients with fewer than 6 months of follow-up were excluded from this cohort. Structural recurrences are documented by histology or cytology whereas biochemical recurrences are documented by rising serum thyroglobulin in the absence of structural disease. All slides on all patients were examined by two pathologists with the substantial interobserver agreement (Kappa = 73 %). The primary tumors are categorically classified either as (1) TCV-PTC (definition above), (2) Papillary thyroid carcinoma with tall cell features (PTC-TCF) (≥ 10 % < 30 % tall cells), or (3) Control (< 10 % tall cells). Tumor size is categorized as either (1) ≤ 10 mm, (2) 11–29 mm, or (3) ≥ 30 mm. Degree of ETE is categorized as either intrathyroidal, microscopic ETE, histologic spread to strap muscles, or pT4 disease. Results185 patients are classified as TCV-PTC (≥ 30 % tall cells), 62 as PTC-TCF (≥ 10 % < 30 % tall cells), and 100 as control group (< 10 % tall cells). TCV-PTC is associated with ≥ 30 mm size (p = .0246) and invasion of strap muscles and/or pT4 (p = .0325). There was no relationship between TCV-PTC and aggressive lymph node (ALN) status defined by ATA. Overall follow-up ranged from two months (one patient death) to 203 months (mean 40.8, median 33.0). DR occurred in 61 patients (mean 31.4 months, range 0 –184, 59 structural recurrences, 2 biochemical recurrences). Three models for TCV-PTC were examined: Model 1 - Tall cells ≥ 10% versus control, Model 2 - TCV-PTC versus TCF-PTC versus control, and Model 3 - TCV-PTC versus control. Kaplan Meier curves demonstrated decreased DFS with ALN status (p = .0001), ETE (p = .0295), and TCV-PTC (Model 1, p = .041). On multivariate analysis, TCV-PTC (Model 1) remained significantly predictive when adjusted for ALN (p = .0059). ETE dropped out of the model. ConclusionTCV-PTC is significantly associated with larger tumors and a greater degree of ETE. The diagnosis of TCV-PTC significantly impacts DFS at the 10 % cut-point on multivariate analysis.

The Impact of Race on C-MYC Expression and Resulting Prognostic Implications in Head and Neck Squamous Cell Carcinoma

<h3>Background</h3> Epidemiological data identifies race-based disparities in Black patients for head and neck squamous carcinoma (HNSCC) screening, detection, treatment, and survival. Although socioeconomic and environmental factors play a role in the existing racial disparities, HNSCC incidence and survival rates in the Black population cannot be attributed to these factors alone. Analyzing the molecular profiles of HNSCC tumors has the potential to help elucidate the mechanisms behind these disparities. The overexpression of the proto-oncogene C-MYC across racial demographics is of particular interest in this study given its association with poor outcomes in HNSCC. <h3>Materials and Methods</h3> To investigate the effect of race on survival of head and neck cancer, we examined HNSCC samples from 49 Black and 446 white patients in The Cancer Genome Atlas (TCGA). We used cox proportional hazard models and Kaplan Meier curves to identify the effect of race on HNSCC survival outcome. We then characterized the extent to which molecular alterations in Black patients impact their clinical outcomes. <h3>Results</h3> We found that Black patients lived significantly less disease-free months and had a poorer overall survival than white patients. Black patients showed a higher frequency of human papillomavirus (HPV)-negative than HPVpositive tumors compared to white patients. Black patients were found to suffer higher rates of metastasis and more aggressive lymph node involvement. Lastly, we found a significant enrichment of MYC signaling and amplifications in the tumors of Black patients compared to white patients. <h3>Conclusions</h3> This project uncovers novel data toward gaining an understanding of the racial disparities in HNSCC and advances the research aimed at eliminating these disparities. Unique tumor mutations and molecular signatures such as C-MYC could be used for more targeted, individualized screening, diagnostic, and treatment modalities to reduce outcome disparities in the Black population.

Focal neuroendocrine carcinoma mixed with adenocarcinoma of the gallbladder with aggressive lymph node metastasis in a patient who did not meet the mixed neuroendocrine\u2013non-neuroendocrine neoplasm criteria

A 70-year-old Japanese woman who was treated for interstitial pneumonia (IP) with steroid therapy developed cholecystitis. A serial computed-tomography (CT) imaging showed irregular thickness of the fundus wall of the gallbladder and two rapidly enlarged lymph nodes (LNs): number (no.) 12 and no. 8a. Positron-emission tomography-computed tomography (PET-CT) scan showed an abnormal uptake at the site of the gallbladder tumor and those LNs. We subsequently performed open radical cholecystectomy and LN dissection of the no. 12 and 8a LNs, following complete remission of IP. The histology showed gallbladder adenocarcinoma, with a single focus of neuroendocrine carcinoma (NEC) component of less than 30%; Ki-67 index > 80%, synaptophysin (Syn) (+), chromogranin A (CgA) (+), and clusters of differentiation (CD) 56 (+) (T2bN1M0, Stage IIIB). LN no. 8a was diffusely metastatic with NEC components. LN no. 12c, which was adjacent to the cystic duct, revealed necrosis without apparent tumor cells, but was highly suspicious for tumor necrosis. The final diagnosis was adenocarcinoma of the gallbladder with focal NEC (< 30%), which did not meet the criteria for mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN). Postoperatively, she completed 4 cycles of adjuvant chemotherapy for NEC (Cisplatin plus Etoposide), and no recurrence was observed after 12 months.

Abstract 2205: Molecular subtypes of head and neck cancer in patients with African ancestry

Abstract Epidemiological data identifies disparities in black patients for head and neck squamous carcinoma (HNSCC) screening, detection, treatment, and survival. Although socioeconomic and environmental factors play a role in the existing racial disparities, HNSCC incidence and survival rates in the black population cannot be attributed to these factors alone. To investigate the role race plays in the genomics of head and neck cancer, we examined HNSCC samples from 49 black and 446 white patients in the Cancer Genome Atlas (TCGA). We used computationally-derived ancestry identifications to correlate race with HNSCC molecular features. We then characterized the extent to which genomic alterations in black patients impact their clinical outcomes. We found that black patients lived significantly fewer disease-free months and had a poorer overall survival than white patients. Black patients showed a higher frequency of human papillomavirus (HPV)-negative than HPV-positive tumors compared to white patients. Black patients were found to suffer higher rates of metastasis and more aggressive lymph node involvement. Differences in patient primary tumor site were also identified, with black patients having a higher prevalence of tumors in the larynx and lower prevalence of tumors in the tongue compared to white patients. We also found higher frequencies of RUNX1T1, KMT2D, and UNC13C mutations and lower frequency of PIK3CA mutations in black patients. We found a significant enrichment of MYC signaling and amplifications in the tumors of black patients compared to white patients. Novel data uncovered by this project brings us closer to understanding the racial disparities in HNSCC, and advances research aimed at eliminating those disparities. Unique tumor mutations and molecular signatures show promising clinical utility in providing more targeted, individualized screening diagnostic, and treatment modalities to reduce outcome disparities in the black population. Citation Format: Nadia Mezghani, Alexandria G. Yao, Alison M. Taylor, Fatemeh Momen-Heravi. Molecular subtypes of head and neck cancer in patients with African ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2205.

Neuroendocrine Neoplasms of the Gallbladder: A Clinicopathological Analysis of 13 Patients and a Review of the Literature.

Objectives Mixed neuroendocrine–non-neuroendocrine neoplasms (MiNENs) are rare gallbladder neuroendocrine neoplasms (GB-NENs). This study is aimed at investigating the clinicopathological features of GB-NENs and identifying prognostic factors related to overall survival (OS) of GB-MiNENs. Methods The clinical data and pathological features of 13 patients with GB-NENs in our hospital were retrospectively reviewed. Additionally, 41 GB-MiNENs cases reported in English literature were reviewed and survival analysis was performed. Results The mean age of thirteen patients (6 males and 7 females) with GB-NENs was 57.2 years (range: 35-75 years). Two patients were diagnosed with NET grade 1 (G1), two patients with NEC (large cell/small cell = 1/1), and nine patients with MiNENs. Of these 9 patients with MiNENs, 8 had composite tumors and 1 had amphicrine carcinoma. Microscopically, the adenocarcinoma component was located in the surface mucosa, and the neuroendocrine component was in the area of deep invasion, liver infiltration, and lymph node metastasis. Total analysis of 41 GB-MiNENs showed that patients were mainly elderly women (female/male ratio, 2.4 : 1.0; median age, 60 years). Kaplan-Meier's analysis demonstrated that liver metastasis and TNM stage III-IV were associated with decreased OS (P < 0.05), whereas age, sex, tumor size, grade of the neuroendocrine component, lymph node metastasis, and adjuvant chemotherapy were not significantly prognostic indicators of OS. Multivariate analysis identified liver metastasis (hazard ratio = 4.262, 95%confidence interval = 1.066‐17.044, P = 0.040) as an independent unfavorable prognostic factor. Conclusions GB-MiNENs were the most common type of GB-NENs in our case series, and neuroendocrine components exhibited more aggressive lymph node metastasis and local invasion than adenocarcinoma. Liver metastasis was a poor prognostic indicator in GB-MiNENs patients.

Novel interventional radiological management for lymphatic leakages after gynecologic surgery: lymphangiography and embolization.

Post-operative lymphatic leakage is a common complication of a radical gynecologic surgery involving aggressive lymph node dissection. Its manifestation varies from asymptomatic lymphoceles to life-threatening chylous ascites. In the past, nuclear medicine lymphoscintigraphy was the sole imaging modality for the confirmation of the leakage, of which application is limited due to its poor spatial resolution. While a conservative treatment with percutaneous drainage was the mainstream treatment method, surgical exploration was the last resort for the recalcitrant leakages. Recently, there have been a series of innovations in the field of interventional radiology, including intranodal Lipiodol® lymphangiography, dynamic magnetic resonance (MR) lymphangiography, lymphatic embolization, and mesenteric lymph node lymphangiography. Intranodal Lipiodol® lymphangiography provides very reliable and secure access to the lymphatic system, while requiring only fundamental skills and equipment available to all interventional radiologists. Besides, Lipiodol® is being received a spotlight for its potential therapeutic effects on refractory lymphatic leakage. Dynamic MR lymphangiography plays a vital role in the diagnosis and management of non-traumatic lymphatic diseases, as well as in the post-operative lymphatic leakage with its superior contrast, spatial and temporal resolution. Lymphatic embolization is a technique of using N-BCA glue, a liquid embolic agent, for lymphatic leakages. It can be further described as lymphopseudoaneurysm (LPA) embolization or lymph node embolization, according to which structure is being embolized. Lymphatic embolization opened a new realm of possibilities in the field of interventional lymphology, resulting in the development of treatment approaches for chylous ascites and lymphoceles. Mesenteric lymph node lymphangiography offers the opacification of the upstream mesenteric chylous lymphatic system and can detect lymphatic leakage from the intestinal trunk or the more proximal parts of the mesenteric lymphatic system. With the advent of these latest interventional radiological techniques, more comprehensive approaches to the management of recalcitrant post-operative lymphatic leakages have been enabled.

Downregulation of CDH16 in Papillary Thyroid Cancer and Its Potential Molecular Mechanism Analysed by qRT-PCR, TCGA and in silico Analysis.

ObjectiveThyroid cancer has the highest prevalence among the cancer types that affect the endocrine system; however, its molecular mechanisms are not yet determined. Cadherin-16 (CDH16) plays an important role in the tumorigenesis of human cancers, but its influence on papillary thyroid cancer (PTC) is poorly investigated. This study aimed to explore the role of CDH16 in PTC.MethodsWe performed quantitative real-time polymerase chain reaction to investigate CDH16 expression in PTC. The clinical significance of CDH16 expression in PTC was then evaluated using The Cancer Genome Atlas (TCGA) database. Bioinformatics analysis was also conducted to determine the potential molecular mechanisms of CDH16.ResultsCDH16 was remarkably downregulated in PTC tumors compared with that in corresponding normal thyroid tissues in the local and TCGA cohorts. This downregulation was associated with unfavorable clinicopathological features, including histological type, high tumor stage, aggressive lymph node metastasis (LNM), and advanced clinical stage. In addition, logistic analyses revealed that the reduced expression of CDH16 can aggravate the risk of LNM in PTC. Bioinformatics analysis indicated that the co-expressed CDH16 genes mainly participated in signaling the cancer-related pathways.ConclusionCDH16 is involved in PTC progression and acts as an LNM-related gene in PTC.

Abstract 2622: Plasma growth diefferentiation factor-15 is and independen marker for aggressive disease in endometrial cancer

Abstract Objective: Better biomarkers are needed in order to identify patients with endometrial carcinoma at risk of recurrence and who may profit from a more aggressive treatment regimen. Our objective was to explore the applicability of plasma growth differentiation factor 15 (GDF-15) as a marker for recurrent disease, as well as a marker for poor prognosis and lymph node metastases. Methods: EDTA-blood samples were obtained from 235 patients with endometrial cancer before primary surgery. For 36 of these patients, matching blood samples were collected at time of recurrence. Blood samples were also collected from 78 patients with endometrial hyperplasia. Plasma GDF-15 was measured by an enzyme-linked immunosorbent assay (ELISA). Preoperative pelvic MRI scans for 141 patients were investigated in parallel for imaging variables. Results: Preoperative plasma level of GDF-15 was significantly higher for patients who experienced recurrence (1780 ng/L; 95% CI; 518-9475 ng/L) than for patients who did not develop recurrent disease (1236 ng/L; 95% CI; 307-7030 ng/L) (p&amp;lt;0.001). Plasma levels of GDF-15 at recurrence (2818 ng/L, 95% CI 2088-3548 ng/L) were significantly higher than plasma levels of GDF-15 measured at time of primary diagnosis (1857 ng/L, 95% CI; 1317-2398 ng/L) (p=0.001). High plasma level GDF-15 independently predicts recurrent disease (OR=3.14; 95% CI 2.10-4.76) and lymph node metastases (OR=2.64; 95% CI 1.52-4.61). Patients with high plasma level of GDF-15 had significantly larger tumor volume (p=0.008). Conclusion: Elevated plasma level of GDF-15 is associated with aggressive disease and lymph node metastasis in endometrial carcinoma. GDF-15 may be helpful in indicating recurrent disease. Citation Format: Hilde Engerud. Plasma growth diefferentiation factor-15 is and independen marker for aggressive disease in endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2622.

Abstract 3912: The PI3K/mTOR dual inhibitor PF-04691502 shows antitumor activity in Sezary cells and in a xenograft mouse model

Abstract Introduction: Cutaneous T-cell Lymphomas (CTCLs) are extranodal non-Hodgkin’s lymphomas deriving from neoplastic transformation of T lymphocytes that home to the skin. Mycosis fungoides (MF) is the most diffuse form, usually having an indolent course but presenting in some cases as an aggressive disease with a poor prognosis. Sézary syndrome (SS) is a rare and aggressive variant, with erythroderma, leukemia, and lymph node involvement. Despite recent advances, CTCLs are still incurable cancers and the clinical symptoms are highly disabling. Among the landscape of genomic alterations identified in CTCL, we and others have described alterations of the PI3K pathway members (loss of PTEN, LKB1 and PDCD4, and gain of p70S6K). As a consequence, several SS patients show hyper-activation of PI3K/AKT/mTOR pathway. Hence, inhibition of this pathway represents a potential therapeutic choice against CTCL. Objective: In this work, we investigated the therapeutic potential of the dual-PI3K/mTOR inhibitor PF-04691502 (hereafter PF-502) against CTCL. Materials and Methods: PF-502 therapeutic efficacy was evaluated in four CTCL cell lines and in patient-derived SS cells, for its ability to inhibit cell growth, to induce apoptosis and to inhibit chemotaxis toward the chemokine SDF-1. Moreover, to evaluate PF-502 therapeutic effects in vivo we used a xenograft mouse model, consisting of nude mice transplanted with the CTCL-derived HH cell line. Results: PF-502 inhibited the cell growth of all the CTCL cell lines (0.07-0.32 µM, IC50 range), and of tumor cells derived from six SS patients (2.3 µM, mean IC50). The mechanism of action of PF-502 in CTCL cell lines was a combination of apoptosis induction and G1 block, while in SS patients it was mostly based on a strong apoptosis induction. Of note, PF-502 showed an only modest effect in T-lymphocytes from 3 healthy donors. PF-502 inhibited also cell migration toward the chemokine SDF-1, in both the systems. This result might have an important clinical implication because we have recently demonstrated that malignant lymphocytes are activated by the skin microenvironment. Thus, blocking the homing to the skin could affect the disease course. Finally, PF-502 has a robust antitumor activity in the xenograft mouse model, by reducing tumor volume (400 mm3 in treated mice vs 936 mm3 in controls) as well as tumor weight (0.2 g in treated mice vs 0.56 g in controls). Moreover, the Kaplan-Meier curve, in these mice, revealed that PF-502 treatment prolongs survival (P&amp;lt;0.005). Conclusions: Our results strongly support the therapeutic potential of targeting PI3K/AKT/mTOR pathway in CTCL. Citation Format: Antonella Bresin, Cristina Cristofoletti, Francesca Monzo, Elisabetta Caprini, Mauro Helmer Citterich, Alessandra Frezzolini, Alessandro Monopoli, Roberto Benucci, Maria Cantonetti, Enrico Scala, Giandomenico Russo, Maria Grazia Narducci. The PI3K/mTOR dual inhibitor PF-04691502 shows antitumor activity in Sezary cells and in a xenograft mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3912.

Histopathologic differentiation as a prognostic factor in patients with carcinoma of the hepatopancreatic ampulla of Vater.

ObjectivePeriampullary carcinomas are a group of neoplasms with variable histopathology that originate from the anatomical junction of different epithelial types including the bile duct, pancreatic duct, and duodenal mucosa. This study was performed to determine whether the histopathologic type of these tumors should be considered an independent prognostic factor.MethodsWe analyzed the specimen histopathology of 37 patients who underwent radical cephalic pancreatoduodenectomy for carcinoma of the ampulla of Vater during a 5-year period. We excluded patients with other tumors with an indication for Whipple’s procedure and those in whom R0 resection was not achieved.ResultsThe carcinomas of the hepatopancreatic ampulla were intestinal in 23 (62%) patients, pancreatobiliary in 13 (35%), and mixed type in 1 (3%). The analysis demonstrated significantly more advanced local tumor spread, a more aggressive lymph node metastasizing pattern, and more frequent lymphatic and perineural invasion in patients with pancreatobiliary than intestinal and mixed type tumors.ConclusionPancreatobiliary type of ampullary carcinoma is associated with a poorer prognosis than intestinal and mixed types because of its more aggressive behavior. Histopathology should be regarded as an independent predictor of survival and may have therapeutic and prognostic implications for patients.

Safety and feasibility of laparoscopic gastrectomy accompanied by D1+ lymph node dissection for early gastric cancer in elderly patients.

The age of patients with gastric cancer has increased worldwide. The aim of this study was to investigate the safety and feasibility of laparoscopic gastrectomy (LG) for early gastric cancer in elderly patients. We retrospectively investigated 221 consecutive patients who underwent LG for early gastric cancer during a 5-year period (January 2010 to December 2014). We divided the patients into two groups: elderly patients (≥75 years old) and younger patients (<75 years old). We compared these two groups with respect to clinical characteristics, histopathological findings, intraoperative factors, and postoperative outcomes. The preoperative characteristics were similar in both groups. Except for the number of harvested lymph nodes (42.0 vs 34.9; P = 0.0016), the short-term operative outcomes, including postoperative complications and histopathological findings, were comparable between the two groups. Although significantly fewer lymph nodes were harvested in the elderly group, the overall survival and relapse-free survival rates did not significantly differ between the groups. Postoperative complications, such as acute cholecystitis and internal hernia, occurred during the long-term postoperative period after LG, and these unexpected complications were more frequently observed in elderly patients. All elderly patients required additional emergent surgeries for delayed complications. The outcomes of LG for early gastric cancer in elderly patients seem to be reasonable. Aggressive lymph node dissection may be omissible in elderly patients with acceptable results. LG can be a safe and feasible procedure in elderly patients. However, the higher rate of delayed but urgent complications during the long-term postoperative period must be considered.

Overexpression of Plasminogen Activator Inhibitor-1 in Advanced Gastric Cancer with Aggressive Lymph Node Metastasis.

PurposeThe purpose of this study is to investigate differentially expressed genes using DNA microarray between advanced gastric cancer (AGC) with aggressive lymph node (LN) metastasis and that with a more advanced tumor stage but without LN metastasis.Materials and MethodsFive sample pairs of gastric cancer tissue and normal gastric mucosa were taken from three patients with T3N3 stage (highN) and two with T4N0 stage (lowN). Data from triplicate DNA microarray experiments were analyzed, and candidate genes were identified using a volcano plot that showed ≥ 2-fold differential expression and were significant by Welch's t test (p < 0.05) between highN and lowN. Those selected genes were validated independently by reverse-transcriptase–polymerase chain reaction (RT-PCR) using five AGC patients, and tissue-microarray (TMA) comprising 47 AGC patients.ResultsCFTR, LAMC2, SERPINE2, F2R, MMP7, FN1, TIMP1, plasminogen activator inhibitor-1 (PAI-1), ITGB8, SDS, and TMPRSS4 were commonly up-regulated over 2-fold in highN. REG3A, CD24, ITLN1, and WBP5 were commonly down-regulated over 2-fold in lowN. Among these genes, overexpression of PAI-1 was validated by RT-PCR, and TMA showed 16.7% (7/42) PAI-1 expression in T3N3, but none (0/5) in T4N0 (p=0.393).ConclusionDNA microarray analysis and validation by RT-PCR and TMA showed that overexpression of PAI-1 is related to aggressive LN metastasis in AGC.

Matrix metalloproteinase-7 mRNA and protein expression in gastric carcinoma: a meta-analysis.

Messenger RNA (mRNA) acts as template for protein synthesis. The matrix metalloproteinase-7 (MMP-7) protein and its mRNA expression have been suggested to be involved in the development of various diseases and cancers. We aimed to study associations between the MMP-7 protein and mRNA expression in gastric carcinoma (GC) patients. We searched in the Science Citation Index, the Cochrane Library, PubMed, Embase, CINAHL, Current Contents Index, and several Chinese databases. Studies were pooled and odds ratios and their corresponding 95 % confidence intervals were calculated. Subgroup analyses and publication bias detection were also conducted. Statistical analysis was performed via Version 12.0 STATA software. An updated meta-analysis based on 16 independent cohort studies was performed to investigate this association. The study suggests that significant differences in MMP-7 protein levels were observed in tumor-node-metastasis (TNM) I-II vs. III-IV (odds radio (OR) =3.19, 95 % confidence interval (95%CI) =1.59 ∼ 6.41, P=0.001), in T1-2 vs. T3-4 invasive grade (OR=1.82, 95%CI=1.07 ∼ 3.12, P=0.028), and in distant metastasis-positive vs. metastasis-negative samples (OR=3.14, 95%CI=1.05 ∼ 9.35, P=0.040). Increased MMP-7 mRNA levels were found to be significantly correlated with invasive grade (T3-4 vs. T1-2: OR=5.61, 95%CI=2.64 ∼ 11.95, P<0.001) and in the lymph node (LN) metastasis (positive vs. negative: OR=7.08, 95%CI=4.20 ∼ 11.93, P<0.001) group. Country subgroup analysis yielded significantly different estimates in the protein expression of MMP-7 of all experimental groups. MMP-7 mRNA levels were increased in LN metastasis-positive GC in contrast to metastasis-negative in China and Korea (all P<0.05); this was not shown in Japan (P>0.05). Higher protein and mRNA levels of MMP-7 were statistically associated with aggressive LN metastasis, advanced TNM stage, and invasion in GC patients; MMP-7 can thus potentially serve as a useful biomarker in determining GC progression and prognosis.

Tumor-derived interleukin-1 promotes lymphangiogenesis and lymph node metastasis through M2-type macrophages.

Tumors formed by a highly metastatic human lung cancer cell line are characterized by activated signaling via vascular endothelial growth factor (VEGF)-C through its receptor (VEGFR-3) and aggressive lymph node metastasis. In this study, we examined how these highly metastatic cancers acquired aggressive lymph node metastasis. Compared with their lower metastatic counterparts, the highly metastatic tumors formed by this cell line expressed higher amounts of interleukin (IL)-1α, with similarly augmented expression of IL-1α and IL-1β by tumor stromal cells and of VEGF-A and VEGF-C by tumor-associated macrophages. These tumor-associated macrophages were mainly of the M2 type. Administration of a macrophage-targeting drug suppressed the production of these potent angiogenic and lymphangiogenic factors, resulting in decreased tumor growth, angiogenesis, lymphangiogenesis, and lymph node metastasis. In Matrigel plug assays, the highly metastatic cells formed tumors that were extensively infiltrated by M2-type macrophages and exhibited enhanced angiogenesis and lymphangiogenesis. All of these responses were suppressed by the IL-1 receptor (IL-1R) antagonist anakinra. Thus, the IL-1α-driven inflammatory activation of angiogenesis and lymphangiogenesis seems to provide a highly metastatic tumor microenvironment favorable for lymph node metastasis through cross-talk with macrophages. Accordingly, the IL-1R/M2-type macrophage axis may be a good therapeutic target for patients with this form of lung cancer.

Salvage chemoradiotherapy for locally advanced esophageal carcinomas

'Salvage chemoradiotherapy (CRT)' was introduced in 2005 to treat thoracic esophageal carcinomas deemed unresectable based on the intraoperative findings. The therapeutic concept is as follows: the surgical plan is changed to an operation that aims to achieve curability by the subsequent definitive CRT. For this purpose, the invading tumor is resected as much as possible, and systematic lymph node dissection is performed except for in the area around the bilateral recurrent nerves. The definitive CRT should be started as soon as possible and should be performed as planned. We hypothesized that this treatment would be feasible and provide good clinical effects. We herein verified this hypothesis. Twenty-seven patients who received salvage CRT were enrolled in the study, and their clinical course, therapeutic response, and prognosis were evaluated. The patients who had poor oral intake because of esophageal stenosis were able to eat solid food soon after the operation. The radiation field could be narrowed after surgery, and this might have contributed to the high rate of finishing the definitive CRT as planned. As a result, the overall response rate was 74.1%, and 48.1% of the patients had a complete response. No patient experienced fistula formation. The 1-, 3-, and 5-year overall survival rates were 66.5%, 35.2%, and 35.2%, respectively. Salvage CRT had clinical benefits, such as the fact that patients became able to have oral intake, that fistula formation could be prevented, that the adverse events associated with the definitive CRT could be reduced, and that prognosis of the patients was satisfactory. Although the rate of recurrent nerve paralysis was relatively high even after the suspension of aggressive bilateral recurrent nerve lymph node dissection, and the rate of the progressive disease after the definitive CRT was high, salvage CRT appears to provide some advantages for the patients who would otherwise not have other treatment options following a non-curative and residual operation.