Metachronous Distant Metastases Research Articles

Clinicopathologic Factors Associated with Prognosis in Patients with Metastatic Squamous Cell Carcinoma of the Anal Canal: A Multicenter Cohort Study.

Due to its rarity, there is insufficient evidence for managing ASCC patients with distant metastasis. Thus far, the therapeutic strategy for distant metastasis of ASCC is less standardized and requires a more individualized approach. Therefore, it is crucial to obtain information regarding treatment outcomes and prognostic factors following the development of distant metastasis to identify optimal care strategies for better patient outcomes and predict their prognosis. In the multi-institute cohort study conducted in Japan, we retrospectively assessed 58 ASCC patients with synchronous distant metastasis and 28 ASCC patients with metachronous distant metastasis. When comparing the OS between ASCC patients with synchronous distant metastasis and metachronous distant metastasis, there was no statistically significant difference between the two groups. The OS rate at five years was 37.4% for patients with synchronous distant metastasis and 27.6%; for metachronous distant metastasis. In ASCC patients with synchronous distant metastasis, patients with distant metastasis at multiple sites exhibited extremely worse OS than those at single sites (HR: 4.56, 95% CI: 1.16-18.00, P< 0.0001). In addition, in ASCC patients with metachronous distant metastasis, early recurrence was an independent factor for predicting poor OS in the multivariate analysis (HR: 4.13, 95% CI: 1.22-13.94, P = 0.022). ASCC patients with distant metastasis at multiple sites were a worse prognosis. In addition, early recurrence was identified as an independent prognostic factor for OS among ASCC patients.

Cancer histology in metastatic lymph node predicts prognosis in patients with node-positive stage IV colorectal cancer.

Appropriate prognostic indicators are required for patients with stage IV colorectal cancer (CRC). Lymph node metastasis mainly involves four histological types of CRC. Some metastatic lymph nodes (mLNs) showing cribriform carcinoma are associated with distant metastasis in patients with node-positive CRC and are correlated with recurrence and survival in stage III disease. However, the significance of mLN histology in the prognosis of patients with node-positive stage IV disease remains unclear. We enrolled 449 consecutive patients with CRC who underwent primary tumor resection with lymph node dissection between January 2011 and November 2018. This study included 88 patients with node-positive stage IV CRC and synchronous or metachronous distant metastases. We retrospectively investigated the association between cancer histology in the mLNs based on our classification and cancer-specific survival (CSS) in patients with node-positive stage IV CRC. Kaplan-Meier analysis showed that CSS was better in patients with CRC and all the mLNs showing tubular-type carcinoma. In contrast, patients with at least some mLNs showing poorly differentiated-type carcinoma had poor prognosis. Multivariate analysis showed that "all mLNs showing tubular-type carcinoma" was an independent good prognostic factor for CSS in patients with node-positive stage IV CRC. In addition, "at least some mLNs showing poorly differentiated-type carcinoma" was an independent poor prognostic factor for CSS in patients with node-positive stage IV disease. The histological type of the mLN may indicate a better or poor prognosis for patients with stage IV CRC.

Deep learning radiomics-based prediction model of metachronous distant metastasis following curative resection for retroperitoneal leiomyosarcoma: a bicentric study

BackgroundCombining conventional radiomics models with deep learning features can result in superior performance in predicting the prognosis of patients with tumors; however, this approach has never been evaluated for the prediction of metachronous distant metastasis (MDM) among patients with retroperitoneal leiomyosarcoma (RLS). Thus, the purpose of this study was to develop and validate a preoperative contrast-enhanced computed tomography (CECT)-based deep learning radiomics model for predicting the occurrence of MDM in patients with RLS undergoing complete surgical resection.MethodsA total of 179 patients who had undergone surgery for the treatment of histologically confirmed RLS were retrospectively recruited from two tertiary sarcoma centers. Semantic segmentation features derived from a convolutional neural network deep learning model as well as conventional hand-crafted radiomics features were extracted from preoperative three-phase CECT images to quantify the sarcoma phenotypes. A conventional radiomics signature (RS) and a deep learning radiomics signature (DLRS) that incorporated hand-crafted radiomics and deep learning features were developed to predict the risk of MDM. Additionally, a deep learning radiomics nomogram (DLRN) was established to evaluate the incremental prognostic significance of the DLRS in combination with clinico-radiological predictors.ResultsThe comparison of the area under the curve (AUC) values in the external validation set, as determined by the DeLong test, demonstrated that the integrated DLRN, DLRS, and RS models all exhibited superior predictive performance compared with that of the clinical model (AUC 0.786 [95% confidence interval 0.649–0.923] vs. 0.822 [0.692–0.952] vs. 0.733 [0.573–0.892] vs. 0.511 [0.359–0.662]; both P < 0.05). The decision curve analyses graphically indicated that utilizing the DLRN for risk stratification provided greater net benefits than those achieved using the DLRS, RS and clinical models. Good alignment with the calibration curve indicated that the DLRN also exhibited good performance.ConclusionsThe novel CECT-based DLRN developed in this study demonstrated promising performance in the preoperative prediction of the risk of MDM following curative resection in patients with RLS. The DLRN, which outperformed the other three models, could provide valuable information for predicting surgical efficacy and tailoring individualized treatment plans in this patient population.Trial registration: Not applicable.

An approach to the management of recurrent metastatic squamous cell carcinoma of the anus: A case report

Introduction: Anal squamous cell carcinoma (ASCC) is an uncommon gastrointestinal cancer that is increasingly curable when diagnosed in early stages. Distant metastases are relatively uncommon. New technologies have been introduced for the early detection of disease recurrence across all solid tumors, but their role in ASCC has not been well described. We present a case of isolated metachronous metastasis to the lung from primary ASCC, without primary recurrence and the application of circulating tumor DNA (ctDNA) technology in management. Case Report: The patient is a 63-year-old female who presented with altered bowel habits, rectal bleeding and was found to have a 3×2 cm mass fixed to the anal sphincter on colonoscopy. Biopsy showed moderately differentiated invasive squamous cell carcinoma. Imaging revealed inguinal lymphadenopathy but was negative for distant metastases. She underwent definitive chemoradiotherapy without complications. Post-treatment surveillance scans were negative for residual disease or distant metastasis. Two years later, positron emission tomography (PET)/computed tomography (CT) scans revealed a 0.5 cm sub-pleural nodule which when repeated three months later grew to 0.7 cm. The nodule was then surgically resected. Histology was positive for metastatic squamous cell carcinoma, similar to the primary tumor. Given the dearth of data related to treatment in the setting of resected isolated metastatic disease we pursued ctDNA testing which was negative. Given this finding along with the clinical presentation, time to metastasis (two years) and absence of other evidence of recurrence we opted to monitor expectantly rather than administer systemic chemotherapy. Conclusion: Anal squamous cell carcinoma with metachronous distant metastasis is an unusual phenomenon. Treatment with chemotherapy in completely resected metastatic disease is controversial. Use of ctDNA technology may have a role in aiding in this complex decision making.

Patterns of recurrence in head and neck squamous cell carcinoma to inform personalized surveillance protocols.

Development of evidence-based post-treatment surveillance guidelines in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is limited by comprehensive documentation of patterns of recurrence and metastatic spread. A retrospective analysis of patients diagnosed with R/M HNSCC at a National Cancer Institute-designated cancer center between 1998- 2019 was performed (n=447). Univariate and multivariate analysis identified patterns of recurrence and predictors of survival. Median overall survival (mOS) improved over time (6.7months in 1998-2007 to 11.8months in 2008-2019, p= .006). Predictors of worse mOS included human papillomavirus (HPV) negativity (hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.2-2.6), high neutrophil/lymphocyte ratio (HR, 2.1 [1.4-3.0], disease-free interval (DFI) ≤6months (HR, 1.4 [1.02-2.0]), and poor performance status (Eastern Cooperative Oncology Group, ≥2; HR, 1.91.1-3.4). In this cohort, 50.6% of recurrences occurred within 6months of treatment completion, 72.5% occurred within 1year, and 88.6% occurred within 2years. Metachronous distant metastases were more likely to occur in patients with HPV-positive disease (odds ratio [OR], 2.3 [1.4-4.0]), DFI >6months (OR, 2.4 [1.5-4.0]), and body mass index ≥30 (OR, 2.3 [1.1-4.8]). Oligometastatic disease treated with local ablative therapy was associated with improved survival over polymetastatic disease (HR, 0.36; 95% CI, 0.24-0.55). These data regarding patterns of distant metastasis in HNSCC support the clinical utility of early detection of recurrence. Patterns of recurrence in this population can be used to inform individualized surveillance programs as well as to risk-stratify eligible patients for clinical trials. After treatment for head and neck cancer (HNC), patients are at risk of recurrence at prior sites of disease or at distant sites in the body. This study includes a large group of patients with recurrent or metastatic HNC and examines factors associated with survival outcomes and recurrence patterns. Patients with human papillomavirus (HPV)-positive HNC have good survival outcomes, but if they recur, this may be in distant regions of the body and may occur later than HPV-negative patients. These data argue for personalized follow-up schedules for patients with HNC, perhaps incorporating imaging studies or novel blood tests.

Molecular Urothelial Tumor Cell Subtypes Remain Stable During Metastatic Evolution

Urothelial cancer (UC) care is moving toward precision oncology. For tumor biology–driven treatment of metastatic UC (mUC), molecular subtypes play a crucial role. However, it is not known whether subtypes change during metastatic evolution. To address this, we analyzed a UC progression cohort (N = 154 patients) with 138 matched primary tumors (PRIM) and synchronous or metachronous distant metastasis (MET) by immunohistochemistry, and mRNA sequencing in a subgroup of 20 matched pairs. Protein-based tumor cell subtypes and histomorphology remained stable during metastatic progression (concordance: 94%, 95% confidence interval [CI] 88–97%). In comparison, transcriptome-based molecular consensus subtypes exhibited higher heterogeneity between PRIM and MET (concordance: 45%, 95% CI 23–69%), with switches particularly occurring between luminal and stroma-rich tumors. Of note, all tumors classified as stroma rich showed luminal tumor cell differentiation. By an in-depth analysis, we found a negative correlation of luminal gene and protein expression with increasing desmoplastic stroma content, suggesting that luminal tumor cell differentiation of “stroma-rich tumors” is superimposed by gene expression signals stemming from the stromal compartment. Immunohistochemistry allows tumor cell subtyping into luminal, basal, or neuroendocrine classes that remain stable during metastatic progression. These findings expand our biological understanding of UC MET and have implications for future subtype-stratified clinical trials in patients with mUC. Patient summaryUrothelial carcinomas (UCs) occur in different appearances, the so-called molecular subtypes. These molecular subtypes will gain importance for the therapy of metastatic UCs in the future. We could demonstrate that the subtype remains stable during metastasis, which is highly relevant for future studies.

Clinicomics-guided distant metastasis prediction in breast cancer via artificial intelligence

BackgroundBreast cancer has become the most common malignant tumour worldwide. Distant metastasis is one of the leading causes of breast cancer-related death. To verify the performance of clinicomics-guided distant metastasis risk prediction for breast cancer via artificial intelligence and to investigate the accuracy of the created prediction models for metachronous distant metastasis, bone metastasis and visceral metastasis.MethodsWe retrospectively enrolled 6703 breast cancer patients from 2011 to 2016 in our hospital. The figures of magnetic resonance imaging scanning and ultrasound were collected, and the figures features of distant metastasis in breast cancer were detected. Clinicomics-guided nomogram was proven to be with significant better ability on distant metastasis prediction than the nomogram constructed by only clinical or radiographic data.ResultsThree clinicomics-guided prediction nomograms on distant metastasis, bone metastasis and visceral metastasis were created and validated. These models can potentially guide metachronous distant metastasis screening and lead to the implementation of individualized prophylactic therapy for breast cancer patients.ConclusionOur study is the first study to make cliniomics a reality. Such cliniomics strategy possesses the development potential in artificial intelligence medicine.

Prognostic of recurrence and survival in poorly differentiated thyroid cancer.

The prognosis of poorly differentiated thyroid carcinomas (PDTC) defined by the Turin criteria is variable. The aim of this study on 51 PDTC patients was to determine clinical, histological and molecular prognostic factors associated with recurrence in patients with localized disease at initial treatment and with overall survival in patients with distant metastases. Of 40 patients for whom next-generation sequencing (NGS) by ThyroSeq v3 was able to be performed on historical samples, we identified high-risk molecular signature (TERT, TP53 mutations) in 24 (60%) cases, intermediate risk signature in 9 (22.5%) cases and low-risk signature in 7 (17.5%) cases. Potentially actionable mutations were identified in 10% of cases. After a median follow-up of 57.5 months, recurrence occurred in 11 (39%) of the 28 patients with localized disease. The American Thyroid Association (ATA) high risk of relapse, high mitotic count, high molecular risk signature and CD163 expression were associated with recurrence (P = 0.009, 0.01, 0.049, 0.03 respectively). After a median follow-up of 49.5 months, thyroid cancer-related death occurred in 53% of the patients with distant metastases. There was no significant prognostic factor associated with death in univariate analysis. However, none of the patients with intermediate ATA risk of recurrence and none of the patients with low-risk molecular signature died from the disease. In addition, high molecular-risk signature was associated with the presence of synchronous or metachronous distant metastasis (P = 0.007) and with poor overall survival (P = 0.01). In conclusion, ATA risk of relapse and high mitotic count was associated with higher rate of recurrence in localized PDTC. High molecular-risk signature was associated with the presence of distant metastasis and poor overall survival. Further studies are needed to determine if molecular testing adds to ATA risk stratification or response to therapy in predicting outcomes.

Spatial and Temporal Heterogeneity of Tumor-Infiltrating Lymphocytes in Advanced Urothelial Cancer.

Checkpoint inhibitors targeting PD-(L)1 induce objective responses in 20% of patients with metastatic urothelial cancer (UC). CD8+ T cell infiltration has been proposed as a putative biomarker for response to checkpoint inhibitors. Nevertheless, data on spatial and temporal heterogeneity of tumor-infiltrating lymphocytes in advanced UC are lacking. The major aims of this study were to explore spatial heterogeneity for lymphocyte infiltration and to investigate how the immune landscape changes during the disease course. We performed multiplex immunohistochemistry to assess the density of intratumoral and stromal CD3+, CD8+, FoxP3+ and CD20+ immune cells in longitudinally collected samples of 49 UC patients. Within these samples, spatial heterogeneity for lymphocyte infiltration was observed. Regions the size of a 0.6 tissue microarray core (0.28 mm2) provided a representative sample in 60.6 to 71.6% of cases, depending on the cell type of interest. Regions of 3.30 mm2, the median tumor surface area in our biopsies, were representative in 58.8 to 73.8% of cases. Immune cell densities did not significantly differ between untreated primary tumors and metachronous distant metastases. Interestingly, CD3+, CD8+ and FoxP3+ T cell densities decreased during chemotherapy in two small cohorts of patients treated with neoadjuvant or palliative platinum-based chemotherapy. In conclusion, spatial heterogeneity in advanced UC challenges the use of immune cell infiltration in biopsies as biomarker for response prediction. Our data also suggests a decrease in tumor-infiltrating T cells during platinum-based chemotherapy.

Oncologic outcomes according to the level of disease burden in patients with metachronous distant metastases from uterine cervical cancer: a Korean Radiation Oncology Group study (KROG 18-10).

ObjectiveThis study aimed to evaluate the oncologic outcomes according to disease burden in uterine cervical cancer patients with metachronous distant metastases.MethodsBetween 2005 and 2015, 163 patients with metachronous distant metastases from uterine cervical cancer after receiving a definitive therapy were evaluated at seven institutions in Korea. Low metastatic burden was defined as less than 5 metastatic sites, whereas high metastatic burden was others. Each metastasis site was divided based on the lymph node (LN) and organs affected. The overall survival (OS) and progression-free survival (PFS) were assessed. Cox proportional hazards models, including other clinical variables, were used to evaluate the survival outcomes.ResultsThe median follow-up duration was 22.2 months (range: 0.3–174.8 months). Para-aortic LNs (56.4%), lungs (26.4%), supraclavicular LNs (18.4%), and peritoneum (13.5%) were found to be the common metastasis sites. Among 37 patients with a single metastasis, 17 (45.9%) had LN metastases and 20 (54.1%) had organ metastases. The 1- and 2-year OS rates were 73.9% and 55.0%, respectively, whereas the PFS rates were 67.2% and 42.9%, respectively. SCC Ag after recurrence and high metastatic burden were significant factors affecting the OS (p=0.004 and p<0.001, respectively). Distant organ recurrence, short disease-free interval (≤2 years), and high metastatic burden were unfavorable factors for PFS (p=0.003, p=0.011, and p=0.002, respectively).ConclusionA favorable oncologic outcome can be expected by performing salvage treatments in selected patients with a long disease-free interval, low metastatic burden, and/or lymphatic-only metastasis.

Patient Age Is Significantly Related to Distant Metastasis of Papillary Thyroid Microcarcinoma.

ObjectiveDistant metastasis in papillary thyroid microcarcinoma (PTMC) is rare but fatal, and its relationship with patient age remains unclear. The objective of this study was to examine the association between age at diagnosis and metachronous distant metastasis in PTMC.MethodsConsecutive patients who underwent thyroidectomy for PTC measuring 10 mm or less at a tertiary hospital from January 2000 to December 2016 were enrolled. Patients who had evidence of distant metastasis at diagnosis or underwent postoperative radioiodine (RAI) ablation were excluded. A Cox proportional hazards model with restricted cubic splines (RCS) was applied to examine the association between age at diagnosis and distant metastasis.ResultsA total of 4,749 patients were evaluated. The median age was 44 years (range, 8–78 years), and 3,700 (78%) were female. After a median follow-up of 65 months, 21 distant metastases (20 lung, 1 liver) were recognized. A univariate Cox proportional model using a 5-knot RCS revealed a significant overall (p = 0.01) and a potential nonlinear association (p = 0.08) between distant metastasis and age at diagnosis. In multivariate analysis, age at diagnosis, extrathyroidal extension (ETE), and lymph node metastasis (pN+) were independent risk factors for distant metastasis. Compared with the middle-aged group (30–45 years old), younger and older patients had a higher risk of distant metastasis [HR, 95% CI, p-value, age ≤ 30, 4.54 (0.91–22.60), 0.06, age > 45, 6.36 (1.83–22.13), <0.01].ConclusionAge at diagnosis is associated with metachronous distant metastasis of PTMC, and patients with younger or older age have a higher risk of distant metastasis than middle-aged patients.

The Association of Metastasis Pattern and Management of Metastatic Disease with Oncological Outcomes in Patients with Malignant Peripheral Nerve Sheath Tumors: A Multicenter Cohort Study.

Simple SummaryAround 40% of patients with MPNSTs develop distant metastasis (DM) within five years. Identification of MPNST patients more likely to develop DM and the identification of prognostic factors after DM diagnosis may guide clinical decision-making and may result in a better balance between quantity and quality of life. This study aimed to identify clinicopathologic and treatment-related factors associated with the development of DM and with overall survival (OS) after DM diagnosis. NF1, high grade, tumor size, triton and R2 resections were independent risk factors for the development of DM. This is the first study that reveals that NF1 status is also independently associated with worse survival after DM diagnosis with a median survival difference of more than 6 months between NF1 and no-NF1 patients. Purpose: This multicenter cohort study aimed to identify clinicopathologic and treatment-related factors associated with the development of distant metastasis (DM) and with overall survival (OS) after DM diagnosis in patients with malignant peripheral nerve sheath tumors (MPNST). Methods: All patients diagnosed with primary MPNST from 1988 to 2019 who were surgically treated for the primary tumor were included. Multivariable Cox regression analyses were performed to identify factors associated with DM and OS after DM diagnosis. Results: A total of 383 patients were included in this analysis, of which 150 developed metastatic disease. No differences in clinicopathologic characteristics and clinical outcome were found between patients with synchronous and metachronous DM. Neurofibromatosis type 1 (NF1), high grade, tumor size, triton and R2 resections were independent risk factors for the development of DM. NF1 and more than two metastasis sites were independently associated with worse OS after DM diagnosis. Metastasectomy, chemotherapy and the metastatic site category ‘other’ were associated with prolonged survival after DM diagnosis. Conclusions: This analysis provides important insights into clinicopathologic and treatment factors associated with outcomes in metastatic MPNST. Moreover, NF1-status is associated with a higher risk of DM; it is also independently associated with worse survival in metastatic MPNST.

Long-Term Outcomes and Causes of Death among Medullary Thyroid Carcinoma Patients with Distant Metastases.

Simple SummaryThe prognostic significance of metastatic sites, and immediate cause of death in MTC patients with distant metastasis remains unclear. In this study, we calculated the time from metastasis to death, and we found that long-term oncologic outcomes were differ from initial metastatic site; the hazard ratio for bone metastatic sites (HR: 5.42; p = 0.044) and multisite metastasis (HR: 6.11; p = 0.006) were significantly higher than for lung metastasis. Complications due to the progression of distant metastasis were the most common cause of death, followed by complications related to chemotherapy and airway obstruction.Distant metastasis is a poor prognostic factor in medullary thyroid carcinoma (MTC), but the significance of differentiating the characteristics according to the site of distant metastasis remains unclear. This study aimed to evaluate the clinical characteristics and long-term oncologic outcomes in MTC patients with distant metastasis. We identified 46 MTC patients with distant metastasis between 1994 and 2019. Clinical characteristics were compared based on the timing of the detection of distant metastasis. Additionally, survival rates following the detection of distant metastasis were evaluated to compare the clinical significance of metastatic site. The detailed causes of death were also investigated. Of the 46 patients, 15 patients (32.6%) had synchronous distant metastasis and 31 patients (67.4%) had metachronous distant metastasis. There was no clinical difference between these two groups except regarding initial surgical extent. The lung (52.2%) was the most common metastatic site, followed by the bone (28.3%), mediastinum (19.6%), liver (17.4%), adrenal gland (4.3%), brain (4.3%), kidney (2.2%), and pancreas (2.2%). Patients with bone metastasis and multisite metastasis had significantly worse prognoses than those with lung metastasis (hazard ratio: 5.42; p = 0.044 and hazard ratio: 6.11; p = 0.006). Complications due to the progression of distant metastasis, airway obstruction due to tracheal invasion, and complications related to chemotherapy were leading causes of death. In conclusion, there was no difference in clinical characteristics according to the timing of distant metastasis. Oncological outcomes differed by metastatic site.

Dissemination patterns and chronology of distant metastasis affect survival of patients with head and neck squamous cell carcinoma

ObjectivesTo define metastatic categories based on their prognostic significance. We hypothesized that oligometastasis in patients with head and neck squamous cell carcinoma (HNSCC) is associated with better post-distant metastasis disease specific survival (post-DM DSS) compared to patients with polymetastasis. Furthermore, the impact on survival of synchronous versus metachronous distant metastasis (DM) occurrence was assessed. Materials and methodsRetrospective cohort study in which patients with DM were stratified into three groups: oligometastasis (maximum of 3 metastatic foci in ≤2 anatomic sites), explosive metastasis (≥4 metastatic foci at one anatomic site) and explosive-disseminating metastasis (spread to ≥3 anatomic sites or >3 metastatic foci in 2 anatomic sites). In addition, patients were divided into synchronous versus metachronous DM. ResultsBetween January 1, 2006 and December 31, 2013, a total of 2687 patients with HNSCC were identified, of which 324 patients developed DM. In this group, 115 (35.5%) patients had oligometastasis, 64 (19.8%) patients had explosive metastasis and 145 (44.8%) patients had explosive-disseminating metastasis. Their median post-DM DSS were 4.7 months, 4.1 months and 1.7 months respectively (p < .001). Synchronous DM was associated with more favorable survival rates in univariable and multivariable analyses than metachronous DM with recurrence of the index tumor (6-month post-DM DSS probability of 0.51 vs 0.17, p < .001). ConclusionOligometastasis in HNSCC signifies a better prognosis than a polymetastatic pattern. Metachronous DM occurrence with recurrence of the primary index tumor is associated with an unfavorable prognosis.

T stage-dependent lymph node and distant metastasis and the accuracy of lymph node assessment in rectal cancer

Summary Objective To analyze data obtained in a representative number of patients with primary rectal cancer with respect to lymph node diagnostics and related tumor stages. Methods In pT2-, pT3-, and pT4 rectal cancer lesions, the impact of investigated lymph nodes on the frequency of pN+ status, the cumulative risk of metachronous distant metastases, and overall survival was studied by means of a prospective multicenter observational study over a defined period of time. Results From 2000 to 2011, the proportion of surgical specimens with ≥ 12 investigated lymph nodes increased significantly, from 73.6% to 93.2% (p &lt; 0.001; the number of investigated lymph nodes from 16.2 to 20.8; p &lt; 0.001). Despite this, the percentage of pN+ rectal cancer lesions varied only non-significantly (39.9% to 45.9%; p = 0.130; median, 44.1%). For pT2-, pT3-, and pT4 rectal cancer lesions, there was an increasing proportion of pN+ findings correlating significantly with the number of investigated lymph nodes up to n = 12 investigated lymph nodes. Only in pT3 rectal cancer was there a significant increase in pN+ findings in case of &gt; 12 lymph nodes (p = 0.001), but not in pT2 (p = 0.655) and pT4 cancer lesions (p = 0.256). For pT3pN0cM0 rectal cancer, the risk of metachronous distant metastases and overall survival did not depend on the number of investigated lymph nodes. Conclusion In rectal cancer, at least n = 12 lymph nodes are to be minimally investigated. The investigation of fewer lymph nodes is associated with a higher risk of false-negative pN0 findings. In particular, in pT3 rectal cancer, the investigation of more than 12 lymph nodes lowers the risk of false-negative pN0 findings. An upstaging effect by the investigation of a possibly maximal number of lymph nodes could not be detected.

Gut vascular barrier impairment leads to intestinal bacteria dissemination and colorectal cancer metastasis to liver.

Metastasis is facilitated by the formation of a "premetastatic niche," which is fostered by primary tumor-derived factors. Colorectal cancer (CRC) metastasizes mainly to the liver. We show that the premetastatic niche in the liver is induced by bacteria dissemination from primary CRC. We report that tumor-resident bacteria Escherichia coli disrupt the gut vascular barrier (GVB), an anatomical structure controlling bacterial dissemination along the gut-liver axis, depending on the virulence regulator VirF. Upon GVB impairment, bacteria disseminate to the liver, boost the formation of a premetastatic niche, and favor the recruitment of metastatic cells. In training and validation cohorts of CRC patients, we find that the increased levels of PV-1, a marker of impaired GVB, is associated with liver bacteria dissemination and metachronous distant metastases. Thus, PV-1 is a prognostic marker for CRC distant recurrence and vascular impairment, leading to liver metastases.

T3 versus T4a staging challenges in deeply invasive colonic adenocarcinomas and correlation with clinical outcomes

Despite the latest 8th edition American Joint Committee on Cancer Staging Manual guidelines, disagreement still exists among pathologists regarding staging deeply invasive colonic adenocarcinomas ≤1 mm to the serosal surface. In this retrospective study, 151 untreated colonic adenocarcinomas staged initially as either pT3 or pT4a and with available 5-year follow-up data were retrieved and re-categorized: Group 1 (38 cases): pT4a with tumor at the serosa; Group 2 (49 cases): tumor ≤1 mm from the serosa, with intervening reactive fibrosis (40/49) or inflammation (9/49); Group 3 (64 cases): pT3 tumor >1 mm from the serosa. Clinical outcomes were analyzed. Groups 1 and 2 tumors showed significantly lower 5-year recurrence-free survival and lower overall survival rates (log-rank p < 0.001 for both), when compared with Group 3 tumors. Even after adjusting for adjuvant therapy and nodal metastases, the proportional hazards ratios for the risk of death (p < 0.001) and risk of recurrence (p = 0.005) showed significantly higher risk in Groups 1 and 2 compared with Group 3. The synchronous nodal (p = 0.012) and metachronous distant metastases (p = 0.004) were also significantly more in Groups 1 and 2 versus Group 3. Colonic adenocarcinomas ≤1 mm from the serosal surface behaved more akin to “bona fide” pT4a tumors at the serosal surface in our study with regards to clinical outcomes. We recommend these tumors be staged as pT4a rather than pT3, as supported by outcome data in our study. We hope this will also ensure reproducibility and consistency in staging these tumors across institutions.

Late-onset distant metastases confer poor prognosis in patients with well-differentiated thyroid cancer.

Distant metastases from well-differentiated thyroid carcinoma (WDTC) occasionally occur over a wide range of time intervals after primary thyroid surgery. The prognostic impact of the timing of distant metastasis onset remains unclear. We retrospectively reviewed the clinicopathologic features and clinical outcomes of 57 patients with WDTC and distant metastases, and evaluated the mutational profiles of BRAF, RAS, and TERT promoter genes. All patients underwent thyroidectomy and radioactive iodine (RAI) ablation using the same treatment protocol. Synchronous distant metastases were defined as those detected within 12 months of the primary WDTC diagnosis. Metachronous metastases were considered early- and late-onset diseases if detected 1-5 and ≥5 years after the primary diagnosis, respectively. In all patients, the 5- and 10-year cancer-specific survival (CSS) rates after the diagnosis of distant metastasis were 86% and 57%, respectively. Late-onset (≥5 years) metachronous distant metastasis was associated with age of ≥55 years (P=0.043) and patients refractory to RAI therapy (P=0.026). TERT promoter mutations were associated with RAI refractivity (P=0.026). BRAF V600E and RAS mutations had no prognostic significance. Bone metastasis (P=0.002) and the onset time of distant metastasis (P=0.004) were associated with poor CSS. There was no significant difference in CSS between patients with synchronous distant metastases and those with early-onset (1-5 years) metachronous distant metastases. In the multivariate analysis, bone metastasis [hazard ratio (HR) =10.24; 95% confidence interval (CI): 1.25-83.74; P=0.030] and late-onset (≥5 years) metachronous distant metastasis (HR =5.20; 95% CI: 1.01-26.63; P=0.048) were independent predictors for worse CSS. The prognosis of patients with WDTC was poorer for late metachronously detected metastases than for synchronous or early metachronous metastases. Patients with distant metastasis occurring 5 years later after primary thyroid diagnosis should, therefore, be more carefully treated.

Distant metastasis prediction via a multi-feature fusion model in breast cancer.

This study aimed to develop a model that fused multiple features (multi-feature fusion model) for predicting metachronous distant metastasis (DM) in breast cancer (BC) based on clinicopathological characteristics and magnetic resonance imaging (MRI). A nomogram based on clinicopathological features (clinicopathological-feature model) and a nomogram based on the multi-feature fusion model were constructed based on BC patients with DM (n=67) and matched patients (n=134) without DM. DM was diagnosed on average (17.31±13.12) months after diagnosis. The clinicopathological-feature model included seven features: reproductive history, lymph node metastasis, estrogen receptor status, progesterone receptor status, CA153, CEA, and endocrine therapy. The multi-feature fusion model included the same features and an additional three MRI features (multiple masses, fat-saturated T2WI signal, and mass size). The multi-feature fusion model was relatively better at predicting DM. The sensitivity, specificity, diagnostic accuracy and AUC of the multi-feature fusion model were 0.746 (95% CI: 0.623-0.841), 0.806 (0.727-0.867), 0.786 (0.723-0.841), and 0.854 (0.798-0.911), respectively. Both internal and external validations suggested good generalizability of the multi-feature fusion model to the clinic. The incorporation of MRI factors significantly improved the specificity and sensitivity of the nomogram. The constructed multi-feature fusion nomogram may guide DM screening and the implementation of prophylactic treatment for BC.

Validation of the Brandwein Gensler Risk Model in Patients of Oral Cavity Squamous Cell Carcinoma in North India.

India has one of the highest incidences of oral squamous cell carcinoma (OSCC), with 75,000-80,000 new cases a year. The outcome in early oral cancer is better, but a significant proportion (12-14%) of these patients still relapses and dies due to locoregional or distant recurrences. Several clinicopathological and molecular factors have been used to prognosticate and predict outcomes in these patients of OSCC. The present study aims to validate Brandwein Gensler (BG) risk predictive model in surgically treated OSCC patients in a tertiary care centre in North India. All oral cavity cancer patients, treated in the Department of Surgical Oncology, King George's Medical University, between 2013 and 2017, were reviewed. Patients with histologically diagnosed OSCC, aged > 18years undergoing primary surgical resection were included in the study. The final histopathological evaluation was done by a dedicated pathologist to categorize patients according to BG model risk categories. This model comprises of three factors, lymphocytic host response, perineural invasion and worst pattern of invasion, scored by the method described by Brandwein Gensler et al. The sum of these scores is used to define low, moderate and high risk categories. The study, conducted during 2013-2017, included 149 patients. Median age was 45years (range 25-75years). Tobacco use was noted in 143 patients. Buccal mucosa was the most common site (51%). Surgical margins were clear (> 5mm) in 97.9% cases. Postoperative radiotherapy was given in 47.7% patients. Locoregional recurrences (LRR) (primary site and neck) were documented in 17 of the 149 patients (11.4%). There was no synchronous or metachronous distant metastasis noted in any of the study patients. Six patients had disease specific mortality. Among the 17 patients with LRR, majority (11) belonged to the high risk category of the BG risk model. Adjuvant radiotherapy had been administered in 10 of these 11 recurrent patients belonging to the high risk category. The Brandwein Gensler risk model is predictive of locoregional recurrences (p = 0.02) for OSCC undergoing primary surgery. It can be used to devise strategies to prevent recurrences or identification of recurrences at an earlier point for salvage. The benefit of further escalation of adjuvant therapy in the high risk category needs further studies, as 90% patients in this group recurred despite complete adjuvant treatment.