Effects of neoadjuvant chemotherapy vs chemoradiotherapy in the treatment of esophageal adenocarcinoma: A systematic review and meta-analysis.

BACKGROUND: Neoadjuvant therapy is an essential modality for reducing the clinical stage of esophageal cancer; however, the superiority of neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT) is unclear. Therefore, a discussion of these two modalities is necessary. AIM: To investigate the benefits and complications of neoadjuvant modalities. METHODS: To address this concern, predefined criteria were established using the PICO protocol. Two independent authors performed comprehensive searches using predetermined keywords. Statistical analyses were performed to identify significant differences between groups. Potential publication bias was visualized using funnel plots. The quality of the data was evaluated using the Risk of Bias Tool 2 (RoB2) and the GRADE approach. RESULTS: Ten articles, including 1928 patients, were included for the analysis. Significant difference was detected in pathological complete response (pCR) [P < 0.001; odds ratio (OR): 0.27; 95%CI: 0.16-0.46], 30-d mortality (P = 0.015; OR: 0.4; 95%CI: 0.22-0.71) favoring the nCRT, and renal failure (P = 0.039; OR: 1.04; 95%CI: 0.66-1.64) favoring the nCT. No significant differences were observed in terms of survival, local or distal recurrence, or other clinical or surgical complications. The result of RoB2 was moderate, and that of the GRADE approach was low or very low in almost all cases. CONCLUSION: Although nCRT may have a higher pCR rate, it does not translate to greater long-term survival. Moreover, nCRT is associated with higher 30-d mortality, although the specific cause for postoperative complications could not be identified. In the case of nCT, toxic side effects are suspected, which can reduce the quality of life. Given the quality of available studies, further randomized trials are required.

Trending of small bowel adenocarcinoma research from 2000 to 2022: A bibliometric analysis.

Small bowel adenocarcinoma (SBA) is a rare tumor entity with a relatively poor prognosis. Diagnosis and management of SBA are still challenging despite recent advancement of diagnostic methods and publication of guidelines. This study aimed to analyze and visualize the trending of SBA research in the past 22 years in the 21st century through bibliometric analysis. Our study collected 1270 publication records of SBA from 2000 Jan 1st to 2022 December 31 from Web of Science and used VOSviewer and CiteSpace to analyze countries, institutions, journals, authors, references and keywords to present the latest trends in SBA research. The USA was the most productive country in terms of the total number of publications (n = 418). The Mayo Clinic (n = 22) and University of Texas MD Cancer Center (n = 22) were the institutions with top publications. The "World Journal Of Gastroenterology" (n = 30) had the largest publications. Overman Michael J (n = 17) was the most active and prolific author. The "small bowel adenocarcinoma" was the most frequent keyword. Our bibliometric analysis provides a comprehensive overview of the trends and gaps in the research of SBA. Despite the challenges faced, researchers from USA, Japan and China have made significant contributions to the field of SBA research, and further research is necessary to develop evidence-based guidelines, and advance the understanding and management of SBA.

A degradome-related signature for predicting the prognosis and immunotherapy benefit in stomach adenocarcinoma based on machine learning procedure.

Stomach adenocarcinoma (STAD) is one of the subtype of gastric cancer with high invasiveness, extreme heterogeneity, high morbidity, and high mortality. The degradome is the most abundant class of cellular enzymes that play an essential role in regulating cellular activity and carcinogenesis. An integrative machine learning procedure including 10 methods was performed to develop a prognostic degradome-based prognostic signature (DPS) in TCGA, GSE15459, GSE26253, and GSE62254 datasets. Investigations of the DPS concerning immune infiltration, immunotherapy benefits, and drug priority were orchestrated. The DPS developed by Enet [alpha = 0.3] method was regarded as the optimal prognostic model. The DPS had a stable and powerful performance in predicting the clinical outcome of STAD and served as an independent risk factor in training and testing cohorts. The C-index of DPS was higher than that of age, sex, and clinical stage. STAD patients with low DPS scores had a higher abundance of B cells, CD8+ T cells, higher cytolytic scores, and T cell co-stimulation scores. Moreover, low DPS score indicated a lower tumor immune dysfunction and exclusion score, lower T cell dysfunction and exclusion score, higher PD1&CTLA4 immunophenoscore, and higher tumor mutation burden score in STAD, demonstrating a better immunotherapy response. STAD patients with a high DPS score had a lower IC50 value of common chemotherapy and targeted therapy regimens (Cisplatin, Docetaxel, Gefitinib, etc). Our study developed an optimal DPS for STAD. The DPS could predict the prognosis, risk stratification and guide treatment for STAD patients.

Immune signature of small bowel adenocarcinoma and the role of tumor microenvironment.

In this editorial we comment on the article published "Clinical significance of programmed cell death-ligand expression in small bowel adenocarcinoma is determined by the tumor microenvironment". Small bowel adenocarcinoma (SBA) is a rare gastrointestinal neoplasm and despite the small intestine's significant surface area, SBA accounts for less than 3% of such tumors. Early detection is challenging and the reason arises from its asymptomatic nature, often leading to late-stage discovery and poor prognosis. Treatment involves platinum-based chemotherapy with a 5-fluorouracil combination, but the lack of effective chemotherapy contributes to a generally poor prognosis. SBAs are linked to genetic disorders and risk factors, including chronic inflammatory conditions. The unique characteristics of the small bowel, such as rapid cell renewal and an active immune system, contributes to the rarity of these tumors as well as the high intratumoral infiltration of immune cells is associated with a favorable prognosis. Programmed cell death-ligand 1 (PD-L1) expression varies across different cancers, with potential discrepancies in its prognostic value. Microsatellite instability (MSI) in SBA is associated with a high tumor mutational burden, affecting the prognosis and response to immunotherapy. The presence of PD-L1 and programmed cell death 1, along with tumor-infiltrating lymphocytes, plays a crucial role in the complex microenvironment of SBA and contributes to a more favorable prognosis, especially in the context of high MSI tumors. Stromal tumor-infiltrating lymphocytes are identified as independent prognostic indicators and the association between MSI status and a favorable prognosis, emphasizes the importance of evaluating the immune status of tumors for treatment decisions.

Machine learning-based cell death signature for predicting the prognosis and immunotherapy benefit in stomach adenocarcinoma.

Stomach adenocarcinoma (STAD) is a one of most common malignancies with high mortality-to-incidence ratio. Programmed cell death (PCD) exerts vital functions in the progression of cancer. The role of PCD-related genes (PRGs) in STAD are not fully clarified. Using TCGA, GSE15459, GSE26253, GSE62254 and GSE84437 datasets, PCD-related signature (PRS) was constructed with an integrative procedure including 10 machine learning methods. The role of PRS in predicting the immunotherapy benefits was evaluated by several predicting score and 3 immunotherapy datasets (GSE91061, GSE78220, and IMvigor210). The model developed by Lasso + CoxBoost algorithm having a highest average C-index of 0.66 was considered as the optimal PRS. As an independent risk factor for STAD patients, PRS had a good performance in predicting the overall survival rate of patients, with an AUC of 1-, 3-, and 5-year ROC curve being 0.771, 0.751 and 0.827 in TCGA cohort. High PRS score demonstrated a lower gene set score of some immune-activated cells and immune-activated activities. Patient with high PRS score had a higher TIDE score, higher immune escape score, lower PD1&CTLA4 immunophenoscore, lower TMB score, lower response rate and poor prognosis, indicating a less immunotherapy response. The IC50 value of some drugs correlated with chemotherapy and targeted therapy was higher in high PRS score group. Our investigation developed an optimal PRS in STAD and it acted as an indicator for predicting the prognosis, stratifying risk and guiding treatment for STAD patients.

A prospective phase II clinical trial of total neoadjuvant therapy for locally advanced gastric cancer and gastroesophageal junction adenocarcinoma.

To investigate the safety and efficacy of the neoadjuvant chemoradiotherapy (NCRT) followed by neoadjuvant consolidation chemotherapy (NCCT) and surgery for locally advanced gastric cancer (GC) or gastroesophageal junction (GEJ) adenocarcinoma. Patients diagnosed as locally advanced GC or Siewert II/III GEJ adenocarcinoma with clinical stage T3-4 and/or N positive were prospectively enrolled. Patients underwent NCRT (45 Gy/25 fractions) with concurrent S-1, followed by NCCT (4 to 6 cycles of the SOX regimen) 2 to 4 weeks after NCRT. Gastric cancer radical resection with D2 lymph node dissection was performed 4 to 6 weeks after the total neoadjuvant therapy. The study was conducted from November 2019 to January 2023, enrolling a total of 46 patients. During the NCRT, all patients completed the treatment without dose reduction or delay. During the NCCT, 32 patients (69.6%) completed at least 4 cycles of chemotherapy. Grade 3 or higher adverse events in NCRT (5 cases) were non-hematological. During the course of NCCT, a notable occurrence of hematological toxicities was observed, with grade 3 or higher leukopenia (9.7%) and thrombocytopenia (12.2%) being experienced. A total of 28 patients (60.9%) underwent surgery, achieving R0 resection in all cases. A significant proportion of cases (71.4%) exhibited pathological downstaging to ypT0-2, while 10 patients (35.7%) demonstrated a pathologic complete response (pCR). The total neoadjuvant therapy comprising NCRT followed by NCCT and surgery demonstrates a low severe adverse reactions and promising efficacy, which could be considered as a viable treatment for locally advanced GC or GEJ adenocarcinoma.Trial registration: Clinicaltrials.gov (registration number: NCT04062058); the full date of first trial registration was 20/08/2019.

LOAd703, an oncolytic virus-based immunostimulatory gene therapy, combined with chemotherapy for unresectable or metastatic pancreatic cancer (LOKON001): results from arm 1 of a non-randomised, single-centre, phase 1/2 study.

BACKGROUND: Pancreatic ductal adenocarcinoma is characterised by low immunogenicity and an immunosuppressive tumour microenvironment. LOAd703, an oncolytic adenovirus with transgenes encoding TMZ-CD40L and 4-1BBL, lyses cancer cells selectively, activates cytotoxic T cells, and induces tumour regression in preclinical models. The aim of this study was to evaluate the safety and feasibility of combining LOAd703 with chemotherapy for advanced pancreatic ductal adenocarcinoma. METHODS: LOKON001 was a non-randomised, phase 1/2 study conducted at the Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA, and consisted of two arms conducted sequentially; the results of arm 1 are presented here. In arm 1, patients 18 years or older with previously treated or treatment-naive unresectable or metastatic pancreatic ductal adenocarcinoma were treated with standard 28-day cycles of intravenous nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 (up to 12 cycles) and intratumoural injections of LOAd703 every 2 weeks. Patients were assigned using Bayesian optimal interval design to receive 500 µL of LOAd703 at 5 × 1010 (dose 1), 1 × 1011 (dose 2), or 5 × 1011 (dose 3) viral particles per injection, injected endoscopically or percutaneously into the pancreatic tumour or a metastasis for six injections. The primary endpoints were safety and treatment-emergent immune response in patients who received at least one dose of LOAd703, and antitumour activity was a secondary endpoint. This study was registered with ClinicalTrials.gov, NCT02705196, arm 2 is ongoing and open to new participants. FINDINGS: Between Dec 2, 2016, and Oct 17, 2019, 23 patients were assessed for eligibility, leading to 22 patients being enrolled. One patient withdrew consent, resulting in 21 patients (13 [62%] men and eight [38%] women) assigned to a dose group (three to dose 1, four to dose 2, and 14 to dose 3). 21 patients were evaluable for safety. Median follow-up time was 6 months (IQR 4-10), and data cutoff was Jan 5, 2023. The most common treatment-emergent adverse events overall were anaemia (96 [8%] of 1237 events), lymphopenia (86 [7%] events), hyperglycaemia (70 [6%] events), leukopenia (63 [5%] events), hypertension (62 [5%] events), and hypoalbuminaemia (61 [5%] events). The most common adverse events attributed to LOAd703 were fever (14 [67%] of 21 patients), fatigue (eight [38%]), chills (seven [33%]), and elevated liver enzymes (alanine aminotransferase in five [24%], alkaline phosphatase in four [19%], and aspartate aminotransferase in four [19%]), all of which were grade 1-2, except for a transient grade 3 aminotransferase elevation occurring at dose 3. A maximum tolerated dose was not reached, thereby establishing dose 3 as the highest-evaluated safe dose when combined with nab-paclitaxel plus gemcitabine. Proportions of CD8+ effector memory cells and adenovirus-specific T cells increased after LOAd703 injections in 15 (94%) of 16 patients for whom T-cell assays could be performed. Eight (44%, 95% CI 25-66) of 18 patients evaluable for activity had an objective response. INTERPRETATION: Combining LOAd703 with nab-paclitaxel plus gemcitabine in patients with advanced pancreatic ductal adenocarcinoma was feasible and safe. To build upon this novel chemoimmunotherapeutic approach, arm 2 of LOKON001, which combines LOAd703, nab-paclitaxel plus gemcitabine, and atezolizumab, is ongoing. FUNDING: Lokon Pharma, the Swedish Cancer Society, and the Swedish Research Council.

Mesonephric-like adenocarcinoma of the ovary.

Mesonephric-like adenocarcinoma is a new class of rare subtypes of the female reproductive system. Its clinical symptoms are similar to other types of ovarian tumors. The diagnosis is based on pathological and immunohistochemical methods. The main treatment option is surgery combined with chemotherapy. Few cases have been reported at home and abroad. We reported a case of a 45-year-old woman with a cystic solid mass in the left adnexa. The postoperative pathological diagnosis was mesonephric-like adenocarcinoma of the left ovary and mature cystic teratoma (partial infiltration of the small intestine). This case had no specific clinical symptoms. Immunohistochemical findings showed positive results of GATA3, TTF1, CD10, ER, and PR. Paclitaxel and carboplatin chemotherapy were given after the operation. Currently, no specific criteria are available for diagnosis and treatment of the disease. This article aims to improve the understanding of clinicians in this disease and create a basis for clinical diagnosis and treatment.

Sinonasal adenocarcinoma presented as a giant anterior cranial fossa mass: a case report and review of the literature.

BACKGROUND: Intestinal adenocarcinoma accounts for less than 0.1-4% of all malignancies in the region. It is common among woodworkers and leather workers. Sinonasal adenocarcinoma usually arises from the ethmoid sinus (40%) or nasal cavity (25%). Extension to nearby structures is common, but intracranial spread is very rare. These tumors are usually treated with surgery, with a reported 5-year survival rate of 59% to 80%. CASE PRESENTATION: This is a 60-year-old Black African male patient who presented with globalized headache, nasal obstruction with snoring during sleep, anosmia, change in mentation, sometimes agitation and left-side visual loss of one-year duration with worsening his above symptoms over the last one month. He couldn't smell soap bilaterally; in his left eye he could see only hand movement at nearly 30 cm. On brain magnetic resonance imaging, there was a T1 hypo- and T2 hyper-intense anterior cranial fossa mass arising from the left ethmoid sinuses and sphenoid sinuses and compressing the left optic structures, and brain computed tomography demonstrated heterogeneous hypo- to isodense mass. Complete tumor excision achieved and discharged with significant improvement and linked to oncology unit for radiotherapy. CONCLUSION: The management of these patients is multidisciplinary, involving neurosurgeons, otolaryngologists, oncologists, and maxillofacial surgeons. Surgical resection is the main treatment strategy, followed by radiotherapy, particularly intensity-modulated therapy. Chemotherapy is used in highly advanced, metastatic, and unresectable tumors.

Multicenter analysis on the value of standard (chemo)radiotherapy in elderly patients with locally advanced adenocarcinoma of the esophagus or gastroesophageal junction.

BACKGROUND: To assess the tolerability and oncological results of chemoradiation in elderly patients with locally advanced adenocarcinoma of the esophagus or gastroesophageal junction. METHODS: This multi-center retrospective analysis included 86 elderly patients (≥ 65 years) with esophageal or gastroesophageal junction adenocarcinoma (median age 73 years; range 65-92 years) treated with definitive or neoadjuvant (chemo)radiotherapy. The treatment was performed at 3 large comprehensive cancer centers in Germany from 2006 to 2020. Locoregional control (LRC), progression-free survival (PFS), distant metastasis-free survival (DMFS), overall survival (OS), and treatment-associated toxicities according to CTCAE criteria v5.0 were analyzed, and parameters potentially relevant to patient outcomes were evaluated. RESULTS: Thirty-three patients (38%) were treated with neoadjuvant chemoradiation followed by surgery, while the remaining patients received definitive (chemo)radiation. The delivery of radiotherapy without dose reduction was possible in 80 patients (93%). In 66 patients (77%), concomitant chemotherapy was initially prescribed; however, during the course of therapy, 48% of patients (n = 32) required chemotherapy de-escalation due to treatment-related toxicities and comorbidities. Twenty-nine patients (34%) experienced higher-grade acute toxicities and 14 patients (16%) higher-grade late toxicities. The 2-year LRC, DMFS, PFS, and OS amounted to 72%, 49%, 46%, and 52%, respectively. In multivariate analysis, neoadjuvant chemoradiation followed by surgery was shown to be associated with significantly better PFS (p = 0.006), DMFS (p = 0.006), and OS (p = 0.004) compared with all non-surgical treatments (pooled definitive radiotherapy and chemoradiation). No such advantage was seen over definitive chemoradiation. The majority of patients with neoadjuvant therapy received standard chemoradiotherapy without dose reduction (n = 24/33, 73%). In contrast, concurrent chemotherapy was only possible in 62% of patients undergoing definitive radiotherapy (n = 33/53), and most of these patients required dose-reduction or modification of chemotherapy (n = 23/33, 70%). CONCLUSIONS: In our analysis, omission of chemotherapy or adjustment of chemotherapy dose during definitive radiotherapy was necessary for the overwhelming majority of elderly esophageal cancer patients not eligible for surgery, and hence resulted in reduced PFS and OS. Therefore, optimization of non-surgical approaches and the identification of potential predictive factors for safe administration of concurrent chemotherapy in elderly patients with (gastro)esophageal adenocarcinoma is required.

Association between microsatellite status and characteristics and outcomes of early-onset compared to late-onset rectal cancer.

BACKGROUND: Microsatellite instability (MSI) is an important prognosticator for colorectal cancer (CRC). The present study aimed to assess the impact of MSI status on the characteristics and outcomes of early-onset compared to late-onset rectal cancer. METHODS: This retrospective cohort study used data from the US National Cancer Database (2004-2019) to assess the baseline characteristics, treatment patterns, short-term outcomes, and overall survival (OS) of early-onset rectal adenocarcinoma affecting patients < 50 years compared to late-onset rectal adenocarcinoma according to the MSI status. RESULTS: The present study included 48,407 patients (59.9% male) with rectal cancer, 17.3% of patients were < 50 years and 6.3% had MSI-H tumors. In the early-onset group, patients with MSI-H tumors had a lower mean age (41.5 vs 43 years, p < 0.001) and presented less often with stage IV disease (22.1% vs 17.7%, p = 0.03) and liver metastasis (9.1% vs 13.5%, p = 0.011) than patients with MSS tumors. In the late-onset group, patients with MSI-H and MSS tumors had similar demographics, disease stage, and metastatic pattern, yet MSI-H patients more often received neoadjuvant radiation therapy (58.9% vs 55.1%, p = 0.009) and neoadjuvant systemic therapy (40% vs 36.2%, p = 0.005). In both age groups, MSI-H tumors were associated with more pathologic T3-4 stage and were more likely mucinous and poorly differentiated carcinomas than MSS tumors. The median OS of MSI-H tumors was similar to MSS tumors (108.09 vs 102.31 months, p = 0.1), whether in the early-onset (139.5 vs 134.2 months, p = 0.821) or late-onset groups (106.1 vs 104.3 months, p = 0.236). CONCLUSIONS: In both age groups, MSI-H rectal cancers were more often mucinous and poorly differentiated carcinomas and had pT3-4 stage more often than MSS cancers. MSI-H rectal cancers tend to present less often with distant metastases and nodal involvement than MSS cancers only in early-onset, but not in late-onset rectal cancers. The association between MSI status and survival was not notable in this study, whether in the early-onset or late-onset groups.

The yield of diagnostic laparoscopy with peritoneal lavage in gastric adenocarcinoma: A retrospective cohort study.

INTRODUCTION: Diagnostic laparoscopy (DL) with peritoneal lavage has been adopted as a standard staging procedure for patients with gastric cancer (GC). Evaluation of the value of DL is important given ongoing improvements in diagnostic imaging and treatment. As contemporary data from European centres are sparse, this retrospective cohort study aimed to assess the yield of DL in patients with potentially curable gastric cancer, and to identify predictive factors for peritoneal metastases. METHODS: Patients with adenocarcinoma of the stomach, treated between January 2016 and December 2018, were identified from institutional databases of two high volume European Upper-GI centres. Patients who underwent a DL with peritoneal lavage for potentially curable disease after clinical staging with imaging (cT1-4N0-3M0) were included. The primary outcome was the proportion of patients with a positive DL, defined as macroscopic metastatic disease, positive peritoneal cytology washings (PC+) or locally irresectable disease. RESULTS: Some 80 of 327 included patients (24.5%) had a positive DL, excluding these patients from neoadjuvant treatment (66 of 327; 20.2%) and/or surgical resection (76 of 327; 23.2%). In 34 of 327 patients (10.3%), macroscopic metastatic disease was seen, with peritoneal deposits in 30 of these patients. Only 16 of 30 patients with peritoneal disease had positive cytology. Some 41 of 327 patients (12.5%) that underwent DL had PC+ in the absence of macroscopic metastases and five patients (1.5%) had an irresectable primary tumour. Diffuse type carcinoma had the highest risk of peritoneal dissemination, irrespective of cT and cN categories. CONCLUSION: The diagnostic yield of staging laparoscopy is high, changing the management in approximately one quarter of patients. DL should be considered in patients with diffuse type carcinoma irrespective of cT and cN categories.

Recurrent ectopic primary breast adenocarcinoma of the vulva with a 19-year follow-up period.

We present a case of an ectopic breast adenocarcinoma of the vulva with metastatic local recurrence and a total follow-up period of 19 years, the longest documented in the literature to our knowledge. Following surgical excision, radiation therapy and hormonal treatment after the recurrence, the patient has remained disease free. This case demonstrates the potential for malignant transformation in accessory breast tissue and highlights the importance of close surveillance and regular physical examinations in patients with a history of ectopic breast malignancy.

Prognostic Value of Immune Cells Subsets Within the Tumor Microenvironment in Patients With Rectal Adenocarcinoma.

BACKGROUND/AIM: One-third of newly diagnosed colorectal cancer cases are rectal cancers. Multimodal treatment regimens including surgery, radiotherapy, and chemotherapy improve local control and survival outcome and decrease tumor relapse for patients with rectal adenocarcinoma (READ). However, stratification of patients to predict their responses is urgently needed to improve therapeutic responses. PATIENTS AND METHODS: Immunostainings of CD3+, CD8+, and CD45RO+ immune cell subsets within the tumor microenvironment were evaluated using immunohistochemistry in two hundred seventy-nine READ patients. RESULTS: In this study, we found that examination of the adaptive immune response by quantifying CD3+, CD8+, and CD45RO+ immune cell subsets, provides improved and independent prognostic value for patients with READ. Regardless of conventional clinical and pathologic parameters, the densities of T cell subsets were strongly related to a better prognosis in patients with READ. High density of intratumoral immune cells is associated with absence of nodal metastasis, lymphovascular invasion, and perineural invasion. Moreover, high tumor-infiltrating lymphocyte (TIL) subsets were associated with favorable survival outcome in patients with READ, especially high-risk patients with advanced READ. CONCLUSION: Immune cell subsets including CD3, CD8, and CD45RO within the tumor microenvironment were independent prognostic factors for patients with READ.

Genetic and therapeutic landscapes in cohort of pancreatic adenocarcinomas: next-generation sequencing and machine learning for full tumor exome analysis.

About 7% of all cancer deaths are caused by pancreatic cancer (PCa). PCa is known for its lowest survival rates among all oncological diseases and heterogenic molecular profile. Enormous amount of genetic changes, including somatic mutations, exceeds the limits of routine clinical genetic laboratory tests and further stagnates the development of personalized treatments. We aimed to build a mutational landscape of PCa in the Russian population based on full exome next-generation sequencing (NGS) of the limited group of patients. Applying a machine learning model on full exome individual data we received personalized recommendations for targeted treatment options for each clinical case and summarized them in the unique therapeutic landscape.

Bone metastatic cancer of unknown primary at initial presentation

Introduction Cancer of unknown primary (CUP) is a challenging malignancy. The purpose of this study was to investigate the clinical characteristics and prognosis of bone metastatic CUP using the population-based Surveillance, Epidemiology, and End Results (SEER) database. Methods From the SEER database, we identified 1908 patients with bone metastatic CUP at initial presentation between 2010 and 2018. Histology was subdivided following International Classification of Diseases for Oncology codes as Adenocarcinoma, Squamous cell, Neuroendocrine, or Carcinoma not otherwise specified (NOS). Cox proportional hazard modeling was applied using factors of age, sex, ethnicity, histological subtype, and therapeutic intervention. Results Among the 1908 patients, histology was Neuroendocrine in 240 patients, Squamous cell in 201 patients, Adenocarcinoma in 810 patients and NOS in 657 patients. In each subtype, patients tended to be predominantly male and white. Chemotherapy was introduced for 28% of patients and radiation for 34% in the entire cohort. Survival in patients with bone metastatic CUP was unfavorable, with a median survival of 2 months. Among the histological subtypes, Adenocarcinoma showed shorter survival than the other groups. In addition, treatment interventions such as chemotherapy and radiation therapy prolonged survival, particularly for Squamous cell, Adenocarcinoma and NOS, but not for Neuroendocrine. Discussion Bone metastatic CUP showed extremely poor prognosis, but treatment interventions such as chemotherapy and radiation generally offered survival benefits. Further randomized clinical research is needed to confirm the present results (AU)

Real-time ex vivo monitoring of NK cell migration toward obesity-associated oesophageal adenocarcinoma following modulation of CX3CR1.

Oesophagogastric adenocarcinomas (OAC) are poor prognosis, obesity-associated cancers which may benefit from natural killer (NK) cell-based immunotherapies. Cellular immunotherapies encounter two key challenges to their success in OAC, namely recruitment to extratumoural tissues such as the omentum at the expense of the tumour and an immunosuppressive tumour microenvironment (TME) which can hamper NK cell function. Herein, we examined approaches to overcome the detrimental impact of obesity on NK cells and NK cell-based immunotherapies. We have demonstrated that NK cells migrate preferentially to the chemotactic signals of OAC patient-derived omentum over tumour in an ex vivo model of immune cell migration. We have identified CX3CR1 modulation and/or tumour chemokine profile remodelling as approaches to skew NK cell migration towards tumour. We also report targetable immunosuppressive facets of the obese OAC TME which dampen NK cell function, in particular cytotoxic capabilities. These data provide insights into approaches to therapeutically overcome key challenges presented by obesity and will inform superior design of NK cell-based immunotherapies for OAC.

Impact of histological subtypes on clinical outcome of endocervical adenocarcinoma.

OBJECTIVE: This multicenter study aimed to investigate the disparity in clinical features and prognosis among different histopathologic subtypes of endocervical adenocarcinoma (EA) based on the 2014 World Health Organization (WHO) classification. METHODS: We retrieved and analyzed data from the Chinese Four C Database between 2004 and 2018. 672EA patients with radical hysterectomies from 32 institutions were retrospectively reviewed. Clinicopathologic characteristics, five-year overall survival (OS), and disease-free survival (DFS) were compared based on histological subtypes. RESULTS: The 5-year DFS and OS rates for usual, endometrioid, mucinous, gastric, villoglandular, clear cell/serous/mesonephric EAs were as follows: 81.3 %, 89.1 %, 63.0 %, 35.6 %, 88.6 %, 79.9 %, respectively (P < 0.0001); 87.4 %, 96.6 %, 74.7 %, 34.0 %, 96.7 %, 86.3 %, respectively (P < 0.0001). Gastric- and mucinous-type exhibited a higher frequency of lymph node metastasis, deep stromal invasion, uterine corpus invasion, and recurrence than the usual -type (recurrence rate:50.00 % vs 29.90 % vs 15.50 %, P < 0.0001). Multivariate analysis revealed gastric-type was significantly associated with inferior DFS (HR,3.018; 95 % CI, 1.688-5.397; P < 0.0001) and OS(HR, 4.114; 95 % CI, 2.002-8.453; P < 0.0001). Furthermore, compared to the usual -type, mucinous-type demonstrated significantly worse DFS (HR, 1.773; 95 % CI,1.123-2.8; P = 0.014) and OS (HR, 2.168; 95 % CI,1.214-3.873; P = 0.009) whereas endometrioid-type was an identified as independent factor for better DFS (HR, 0.365; 95 % CI,0.143-0.928; P = 0.034). Villoglandular subtype displayed similar features and favorable prognosis as the usual type. CONCLUSIONS: Relevant clinical features and prognosis varied significantly among histological subtypes of EA, thus offering valuable guidance for the development of subtype-specific treatment strategies to optimize EA management.

Correlation of primary tumor volume and histopathologic response following neoadjuvant treatment of esophageal adenocarcinoma.

INTRODUCTION: In esophageal cancer, histopathologic response following neoadjuvant therapy and transthoracic esophagectomy is a strong predictor of long-term survival. At the present, it is not known whether the initial tumor volume quantified by computed tomography (CT) correlates with the degree of pathologic regression. METHODS: In a retrospective analysis of a consecutive patient cohort with esophageal adenocarcinoma, tumor volume in CT prior to chemoradiotherapy or chemotherapy alone was quantified using manual segmentation. Primary tumor volume was correlated to the histomorphological regression based on vital residual tumor cells (VRTC) (Cologne regression scale, CRS: grade I, >50% VRTC; grade II, 10-50% VRTC; grade III, <10% VRTC and grade IV, complete response without VRTC). RESULTS: A total of 287 patients, 165 with neoadjuvant chemoradiotherapy according to the CROSS protocol and 122 with chemotherapy according to the FLOT regimen, were included. The initial tumor volume for patients following CROSS and FLOT therapy was measured (CROSS: median 24.8 ml, IQR 13.1-41.1 ml, FLOT: 23.4 ml, IQR 10.6-37.3 ml). All patients underwent an Ivor-Lewis esophagectomy. 180 patients (62.7 %) were classified as minor (CRS I/II) and 107 patients (37.3 %) as major or complete responder (CRS III/IV). The median tumor volume was calculated as 24.2 ml (IQR 11.9-40.3 ml). Ordered logistic regression revealed no significant dependence of CRS from tumor volume (OR = 0.99, p-value = 0.99) irrespective of the type of multimodal treatment. CONCLUSION: The initial tumor volume on diagnostic CT does not aid to differentiate between potential histopathological responders and non-responders to neoadjuvant therapy in esophageal cancer patients. The results emphasize the need to establish other biological markers of prediction.