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Most research models of HPV-associated squamous cervical carcinogenesis focus on stratified glycogenated squamous epithelium, a permissive environment for HPV-life-cycle completion, while immature squamous metaplastic epithelium and reserve cells as targets of HPV-infection have received less attention. Subcolumnar reserve cells of urogenital sinus origin with a CK17/p63-phenotype serve as the primary stem cell for squamous metaplasia. The area of manifest or potential squamous metaplasia, referred to as transformation zone, is the site where most squamous cancers occur after a transforming HPV infection of proliferating reserve cells and/or metaplastic epithelium. Improper use of terminology, in particular confusion of transformation zone with transition zone (synonymous: squamous-columnar junction or SCJ), as well as poorly substantiated postulates of a stem cell niche at the squamous-columnar junction with 'embryonic stem cell markers' have complicated understanding of HPV-related squamous carcinogenesis. Reserve cells as target cells and reservoirs of HPV should move into future research focus.

Background Colposcopy currently plays a vital role in the diagnosis and treatment of lower genital diseases. Exposure and biopsy are two key steps in colposcopy. When the whole transformation zone or all lesions cannot be observed, we judge colposcopy as unsatisfactory. Unsatisfactory colposcopic examination may lead to the misdiagnosis of more severe diseases. The combination of colposcopy and vaginoscopy may contribute to accurate diagnosis and clinical decisions. Case summary Here, we introduce a case of posthysterectomy deep vaginal apex not fully exposed by colposcopy, and the biopsy result was a vaginal precancerous lesion. We adopted vaginoscopy to extend the observed area and expose the lesion thoroughly, and the biopsy result was vaginal squamous cancer. Conclusion The patient received a precise diagnosis and early surgery due to the combination of colposcopy and vaginoscopy.

Objective Oral squamous cell carcinoma (OSCC) is the most common cancer in oral and maxillofacial tissue. This study aimed to investigate the expression of SLC3A2 in human OSCC tissues and its regulatory roles in OSCC. Methods The expression of SLC3A2 in human OSCC tissues was assessed using immunohistochemistry. The proliferation, migration, and invasion of oral squamous cells were evaluated after knockdown of SLC3A2. Results The expression of SLC3A2 in OSCC was higher than that in normal oral epithelial cells. SLC3A2 had higher expression levels in OSCC tissues than that in adjacent normal tissues. Upregulation of SLC3A2 was associated with advanced stages and poor survival of OSCC patients. In vitro experiments showed that knocking down of SLC3A2 was associated with reduced migration, invasion, and proliferation, but increased apoptosis of OSCC cells. Conclusion SLC3A2 exerted a harmful effect on OSCC patients by increasing migration, invasion and proliferation, and decreasing apoptosis.

PURPOSE Esophageal squamous cell cancer (ESCC) is still associated with a dismal prognosis. However, surgical series have shown that high-volume hospitals have better outcomes and that the impact of center volume on definitive chemoradiotherapy (dCRT) or CRT plus surgery (CRT + S) remains unknown. METHODS We performed a retrospective analysis of patients with locally advanced stage II-III (non-T4) ESCC treated with dCRT or CRT + S in São Paulo state, Brazil. Descriptive variables were assessed with the χ2 test after categorization of hospital volume (high-volume [HV] center, top 5 higher volume, or low-volume [LV] center). Overall survival (OS) was assessed with Kaplan-Meier curves, log-rank tests, and Cox proportional hazards. Finally, an interaction test between each facility’s treatments was performed. RESULTS Between 2000 and 2013, 1,347 patients were analyzed (77% treated with dCRT and 65.7% in HV centers) with a median follow-up of 23.7 months. The median OS for dCRT was 14.1 months (95% CI, 13.3 to 15.3 months) and for CRT + S, 20.6 months (95% CI, 16.1 to 24.9 months). In the multivariable analysis, dCRT was associated with worse OS (hazard ratio [HR], 1.38; 95% CI, 1.19 to 1.61; P < .001) compared with CRT + S. HV hospitals were associated with better OS (HR, 0.82; 95% CI, 0.71 to 0.94; P = .004) compared with LV hospitals. Importantly, CRT + S superiority was restricted to HV hospitals (dCRT v CRT + S: HR, 1.56; 95% CI, 1.29 to 1.89; P < .001), while in LV hospitals, there was no statistically significant difference (HR, 1.23; 95% CI, 0.88 to 1.43; P = .350), with a significant interaction test ( P interaction = .035). CONCLUSION Our data show that CRT + S is superior to dCRT in the treatment of ESCC exclusively in HV hospitals, which favors the literature trend to centralize the treatment of ESCC in HV centers.

Esophageal squamous cancer remains an important cause of mortality worldwide with two new immunotherapy drugs recently approved for metastatic disease.The authors review the epidemiology and genomics of esophageal squamous cell carcinoma. They also examine prior trials involving targeted agents under investigation as well immunotherapies that have been approved and novel combinations.Great advances have been made in characterizing the molecular changes in esophageal carcinoma. However, relatively few drugs have shown benefit in this disease. Targeted therapies have not shown to improve survival although many of these trials did not explore potential biomarkers. Pembrolizumab and nivolumab are now approved for esophageal squamous carcinoma but much more data are needed to understand how these agents may be used in non-metastatic settings. Novel treatments are still required as overall prognosis remains poor.

The chaperonin-containing T-complex protein 1 (CCT) subunits participate in diverse diseases. However, little is known about their expression and prognostic values in human head and neck squamous cancer (HNSC). This article aims to evaluate the effects of CCT subunits regarding their prognostic values for HNSC. We mined the transcriptional and survival data of CCTs in HNSC patients from online databases. A protein–protein interaction network was constructed and a functional enrichment analysis of target genes was performed. We observed that the mRNA expression levels of CCT1/2/3/4/5/6/7/8 were higher in HNSC tissues than in normal tissues. Survival analysis revealed that the high mRNA transcriptional levels of CCT3/4/5/6/7/8 were associated with a low overall survival. The expression levels of CCT4/7 were correlated with advanced tumor stage. And the overexpression of CCT4 was associated with higher N stage of patients. Validation of CCTs’ differential expression and prognostic values was achieved by the Human Protein Atlas and GEO datasets. Mechanistic exploration of CCT subunits by the functional enrichment analysis suggests that these genes may influence the HNSC prognosis by regulating PI3K-Akt and other pathways. This study implies that CCT3/4/6/7/8 are promising biomarkers for the prognosis of HNSC.

We encountered HPV6‐positive cervical papillary squamous cancer (PSCC) that was difficult to diagnose. The case was initially diagnosed and treated for condyloma. To the best of our knowledge, this is the first report of HPV6 infection in PSCC.

Background: The mechanisms underlying the occurrence and development of esophageal squamous cell carcinoma (ESCC) remains to be elucidated. The present study aims to investigate the roles and implications of IGF2BP1 overexpression in ESCC.Methods: IGF2BP1 protein expression in ESCC samples was assessed by immunohistochemistry (IHC), and the mRNA abundance of IGF2BP1 and INHBA was analyzed with TCGA datasets and by RNA in situ hybridization (RISH). Cell viability, migration, invasion and in vivo metastasis assays were performed to explore the roles of IGF2BP1 overexpression in ESCC. RNA immunoprecipitation sequencing (RIP-seq) and mass spectrometry were applied to identify the target RNAs and interacting proteins of IGF2BP1, respectively. RIP-PCR, RNA pulldown, immunofluorescence (IF), gene-specific m6A PCR and RNA stability assays were used to uncover the molecular mechanisms underlying the malignant phenotypes of ESCC cells caused by IGF2BP1 dysregulation. The methylation level of the IGF2BP1 promoter region was detected by methylation-specific PCR (MSP-PCR). BTYNB, a small molecular inhibitor was evaluated for its inhibitory effect on the malignant phenotypes of ESCC cells.Results: IGF2BP1 overexpression was detected in ESCC tissues and associated with the depth of tumor invasion. Knockdown of IGF2BP1 inhibited ESCC cell invasion and migration as well as tumor metastasis. Mechanistically, we observed that IGF2BP1 bound and stabilized INHBA mRNA and then enhanced the translation of INHBA, leading to the activation of Smad2/3 signaling, thus promoting malignant phenotypes. The mRNA level of INHBA was upregulated in ESCC tissues as well. Furthermore, IGF2BP1 interacted with G3BP stress granule assembly factor 1 (G3BP1) and activated the INHBA-Smad signaling. BTYNB abolished this activated signaling and significantly attenuated the malignant phenotypes of ESCC cells. In addition, IGF2BP1 mRNA expression in ESCC cells was negatively correlated with the level of its promoter methylation.Conclusions: Elevated expression of IGF2BP1 is a frequent event in ESCC tissues and might be a candidate biomarker for the disease. IGF2BP1 overexpression promotes the invasion and migration of ESCC cells by activating the INHBA-TGF-β-Smad2/3 pathway, providing a potential therapeutic target for ESCC patients with high expression of IGF2BP1.

BackgroundMetastasis are mainly responsible for the death of patients with advanced esophageal squamous cell carcinoma (ESCC). At present, there is no targeted drug for the treatment of ESCC in clinic practice. The present study aims to investigate the roles and implication of IGF2BP1 overexpression in ESCC.MethodsIGF2BP1 protein expression was assessed by immunohistochemistry (IHC), and the mRNA abundance of IGF2BP1 and INHBA were analyzed with TCGA datasets and by RNA in situ hybridization (RISH). Cell viability, migration, invasion and in vivo metastasis assays were performed to explore the roles of IGF2BP1 in ESCC. RNA immunoprecipitation sequencing (RIP-seq) and mass spectrometry were applied to identify the targets and interacting proteins of IGF2BP1, respectively. RIP-PCR, RNA-pulldown, immunofluorescence (IF), gene specific m6A PCR and RNA stability assay were used to uncover the molecular mechanism of IGF2BP1 dysregulation. The methylation level of IGF2BP1 promoter region was detected by MSP-PCR. BTYNB, a small molecular inhibitor which could block the binding of IGF2BP1 to c-Myc mRNA, was evaluated for the inhibition effect on the malignant phenotypes of ESCC cells.ResultsIGF2BP1 overexpression was detected in ESCC tissues and associated with depth of tumor invasion. Knockdown of IGF2BP1 inhibited ESCC cell invasion and migration as well as tumor metastasis. Importantly, INHBA was identified as a direct target of IGF2BP1 in ESCC cells, which had a role in promoting the malignant phenotypes. TCGA data and RISH analyses showed that the mRNA level of INHBA was upregaluted in ESCC tissues as well. Mechanistically, IGF2BP1 bound and stabilized INHBA mRNA and then enhanced its translation, leading to an activation of Smad2/3 signaling. Ras GTPase-activating protein-binding protein 1 (G3BP1) was recruited by IGF2BP1 to participate in activating the signaling process, which was inhibited by the IGF2BP1 inhibitor BTYNB. Of note, IGF2BP1 mRNA expression in ESCC cells was negatively correlated with the level of its promoter methylation.Conclusions IGF2BP1 overexpression promotes the invasion and migration of ESCC cells by up-regulating TGF-β-Smad2/3 pathway through enhancing INHBA mRNA stability and translation, providing a potential therapeutic target for ESCC treatment.

Background Although the prognosis of locally advanced cervical cancer has improved dramatically, survival for those with stage ⅢB-ⅣA disease or lymph nodes metastasis remains poor. It is believed that the incorporation of intensity-modulated radiotherapy into the treatment of cervical cancer might yield an improved loco-regional control, whereas more cycles of more potent chemotherapy after the completion of concurrent chemotherapy was associated with a diminished distant metastasis. We therefore initiated a non-randomized prospective phaseⅡ study to evaluate the feasibility of incorporating both these two treatment modality into the treatment of high risk locally advanced cervical cancer. Objectives to determine whether the incorporation of intensity-modulated radiotherapy and the addition of adjuvant paclitaxel plus cisplatin regimen into the treatment policy for patients with high risk locally advanced cervical cancer might improve their oncologic outcomes. Study Design: Patients were enrolled if they had biopsy proven stage ⅢA-ⅣA squamous cervical cancer or stage ⅡB disease with metastatic regional nodes. Intensity-modulated radiotherapy was delivered with dynamic multi-leaf collimators using 6MV photon beams. Prescription for PTV ranged from 45.0 ~ 50.0Gy at 1.8Gy ~ 2.0Gy/fraction in 25 fractions. Enlarged nodes were contoured separately and PTV-nodes were boosted simultaneously to a total dose of 50.0–65 Gy at 2.0- 2.6Gy/fraction in 25 fractions. A total dose of 28 ~ 35Gy high-dose- rate brachytherapy was prescribed to point A in 4 ~ 5 weekly fractions using an iridium- 192 source. Concurrent weekly intravenous cisplatin at 30mg/m2 was initiated on the first day of radiotherapy for over 1-hour during external-beam radiotherapy. Adjuvant chemotherapy was scheduled within 4 weeks after the completion of concurrent chemo-radiotherapy and repeated 3 weeks later. Paclitaxel 150 mg/m2 was given as a 3-hour infusion on day1, followed by cisplatin 35 mg/m2 with 1-hour infusion on day1-2 (70 mg/m2 in total). Results Fifty patients achieved complete response 4 weeks after the completion of the treatment protocol, whereas 2 patients had persistent disease. After a median follow-up period of 66 months, loco-regional (including 2 persistent disease), distant, and synchronous treatment failure occurred in 4 ,5, and 1, respectively. The 5-year disease-free survival, loco-regional recurrence-free survival, distant-metastasis recurrence-free survival was 80.5%, 90.3%, and 88.0%, respectively. Four of the patients died of the disease, and the 5-year overall survival was 92.1%. Most of the toxicities reported during concurrent chemo-radiotherapy were mild and transient. The occurrence of hematological toxicities elevated mildly during adjuvant chemotherapy, as 32% (16/50) and 4% (2/50) patients experienced grade 3–4 leukopenia and thrombocytopenia, respectively. Grade 3–4 late toxicities were reported in 3 patients. Conclusions The incorporation of intensity-modulated radiotherapy and adjuvant paclitaxel plus cisplatin chemotherapy were highly effective and well-tolerated in the treatment of high-risk locally advanced cervical cancer. The former yields an improved loco-regional control, whereas distant metastases could be effectively eradicated with mild toxicities when adjuvant regimen was prescribed.

Introduction: There is currently no standard of care for women with cervical cancer stage IB2 (FIGO 2018, >= 2 cm andObjective: To compare rates of fertility, pregnancy, life births as well as recurrence for women with cervical cancer stage IB2 treated with either NACT followed by VRT, or ART.Methods: A systematic review was performed using the PubMed database. Articles reporting the search term 'trachelectomy' as text word or as Medical Subject Headings (MeSH) were identified.Results: Ten studies were identified with a total of 338 patients. After NACT followed by VRT 39% of the women tried to conceive, 70% of these women got pregnant, of which 63% resulted in a life birth. The overall recurrence and death rate were 10% and 2.9% respectively. After ART 40% of the women tried to conceive, 21% of these women got pregnant, which resulted in a life birth rate of 42%. Recurrence and death rate after ART were 6.9%, and 3.4% respectively.Conclusion: Women with cervical cancer stage IB2 and a wish to preserve fertility treated with NACT followed by VRT have a significantly higher chance of pregnancy than women treated with ART, with comparative oncological results. (C) 2019 Elsevier Inc. All rights reserved.

Item does not contain fulltext INTRODUCTION: There is currently no standard of care for women with cervical cancer stage IB2 (FIGO 2018, >/=2 cm and

Background and Objectives: Increased osteopontin (OPN) concentrations in the plasma of patients with head and neck squamous cancer (HNSCC) have diagnostic significance, and it can indicate more aggressive biological behavior of cancer. The aim of this study was to determine OPN levels in patients with HNSCC of different primary locations and to assess its prognostic significance in metastasis development. Materials and Methods: This cohort study included 45 patients (41 male and 4 female patients) with HNSCC with different primary localization of head and neck. All patients underwent surgery—neck dissection. All patients were categorized according to the histological findings of the resected material and tumor–node–metastasis (TNM) classification system. After surgery, N categories were determined on the basis of histological features of resected material. Results: The histological findings of our patients showed: N0 in 11 patients, N1 in 8 patients, N2a in 4 patients, N2b in 14 patients and N2c in 8 patients. Plasma OPN values in all study participants ranged from 2.24 to 109.10 ng/mL. OPN levels in plasma of patients with negative nodes compared to the group of patients with positive nodes in the neck differed significantly (16.89 ng/mL to 34.08 ng/mL, respectively, p = 0.03). There were significantly lower OPN plasma levels in the group of subjects with histologically positive one lymph node in the neck (N1) compared to the group of patients with N2b histologically positive findings of resected neck material (10.4 ng/mL to 43.9 ng/mL, respectively, p = 0.02). Conclusions: The results have shown that growing N degrees of positive neck nodes classification were accompanied by growing values of plasma osteopontin. Osteopontin might be important for the development of neck metastases.

Aim: The aim of this study was to investigate the long-term outcomes of endoscopic submucosal dissection (ESD) for superficial esophageal squamous cancer. Methods: A literature search was conducted using PubMed, ProQuest and Cochrane Library databases. Primary outcomes were overall survival, disease-specific survival and recurrence-free survival at 5 years. Secondary outcomes included adverse events, recurrence and metastasis. Hazard ratios were calculated based on time to events for survival analysis, and odds radios were used to compare discrete variables. Results: A total of 3796 patients in 21 retrospective studies, including 5 comparative studies for ESD and esophagectomy were enrolled. The invasion depth was 52.0% for M1–M2, 43.2% for M3–SM1 and 4.7% for SM2 or deeper. The 5-year survival rate was: overall survival 87.3%, disease-specific survival 97.7%, and recurrence-free survival 85.1%, respectively. Pooled local recurrence of ESD was 1.8% and metastasis was 3.3%. In terms of the comparison between ESD and esophagectomy, there was no difference in the overall survival (86.4% versus 81.8%, hazard ratio = 0.66, 95% CI = 0.39–1.11) as well as disease-specific and recurrence-free survival. In addition, ESD was associated with fewer adverse events (19.8 % versus 44.0%, odds ratio = 0.3, 95% CI = 0.23–0.39). Conclusions: For superficial esophageal squamous cancer, ESD may be considered as the primary treatment of for mucosal lesions, and additional treatment should be available for submucosal invasive cancers.

Background: Discovery of methylated DNA markers (MDM) of esophageal squamous cell carcinoma (ESCC) has sparked interest in assessing these markers in tissue. We evaluated MDMs in ESCC from three geographically and ethnically distinct populations, and explored the feasibility of assaying MDMs from DNA obtained by swallowed balloon devices. Methods: MDMs were assayed in ESCC and normal tissues obtained from the populations of United States, Iran, and China, and from exfoliative cytology specimens obtained by balloons in a Chinese population. Areas under the receiver operating curve (AUC) of MDMs discriminating ESCC from normal tissues were calculated. Random forest prediction models were built, trained on U.S. cases and controls, and calibrated to U.S.-only controls (model 1) and three-country controls (model 2). Statistical tests were used to assess the relationship between dysplasia and MDM levels in balloons. Results: Extracted DNA from 333 ESCC and 322 normal tissues was analyzed, in addition to archival DNA from 98 balloons. For ESCC, model 1 validated in Iranian and Chinese tissues with AUCs of 0.90 and 0.87, and model 2 yielded AUCs of 0.99, 0.96, and 0.94 in tissues from the United States, Iran, and China, respectively. In Chinese balloons, MDMs showed a statistically significant trend of increasing levels with increasing grades of dysplasia (P < 0.004). Conclusions: MDMs accurately discriminate ESCC from normal esophagus in tissues obtained from high- and low-incidence countries. Preliminary data suggest that levels of MDMs assayed in DNA from swallowed balloon devices increase with dysplasia grade. Larger studies are needed to validate these results. Impact: MDMs coupled with minimally invasive collection methods have the potential for worldwide application in ESCC screening.

Background: Papillary thyroid carcinoma (PTC) is generally considered a relatively slow-growing, indolent cancer; however, an important subset of these cancers known as the tall cell variant (TCV), portend a more aggressive prognosis. TCV PTC is characterized by cells, which are at least twice as tall as they are wide. Patients diagnosed with TCV PTC fare worse than those with the classic variant. A less common thyroid cancer, spindle cell squamous cell carcinoma (SCSC), may arise as a primary tumor, but rarely also alongside or from a previous TCV PTC (1). It may also occur as a component of an anaplastic thyroid cancer, the most aggressive and rarest thyroid malignancy. There are three main types of anaplastic SCSC arising from TCV PTC based on histological characteristics: Type 1 is defined by the presence of both TCV and SCSC within the initial resection; type 2 refers to when the SCSC arises as a recurrence or metastasis in patients with a known history of TCV PTC; type 3 occurs when SCSC presents as a primary laryngeal SCC in patients with or without a known history of TCV. We report a case of type 2 anaplastic SCSC. Clinical Case: A 76 yr old man with hx of invasive TCV PTC (diagnosed 2011) s/p total thyroidectomy with b/l neck dissection and laryngectomy, as well as 200 mci of I-131 (in 2012), returns to clinic in 2019, with worsening unexplained weight loss (> 20 lbs). He had been lost to follow-up since 2015. Now, chest CT showed a new, necrotic, left lower lobe mass obstructing the bronchus, as well as bony erosion of the right clavicle and manubrium. Bronchoscopy of the mass was performed, and pathology was consistent with metastatic anaplastic thyroid cancer with squamous nests. Immunohistochemistry was positive for PAX-8, p40, p63 and negative for TTF-1, Napsin A, TG and PDL-1. The endobronchial tumor tissue was compared to the prior resection specimen from 2011, showing morphologic similarity to the squamoid nests. In retrospect, these nests likely represented small foci of anaplastic thyroid cancer arising in association with TCV PTC. The positive staining for PAX-8 and lack of expression for TTF-1 and Napsin A supports this interpretation and is evidence against a primary pulmonary squamous cell carcinoma. Next Gen Sequencing was positive for BRAF V600E mutation, which allowed us to offer BRAF inhibitor and MEK inhibitor therapy. Unfortunately, due to patient’s non-adherence to therapy and follow-up clinic visits, we are not able to assess his response. Conclusion: This is a case of the rarely described type 2 anaplastic SCSC and is an example of the very poor prognosis associated with TCV PTC. It is a reminder that this variant of PTC should be treated more aggressively from the time it is first identified on biopsy. Reference: (1) Gopal PP et al. The variable presentations of anaplastic spindle cell squamous carcinoma associated with tall cell variant of papillary thyroid carcinoma. Thyroid. 2011;21(5):493–499.

Background: Globally Esophageal cancer is a common cancer arising from human esophageal mucosal tissue. Epidemiological studies suggest inverse correlation between carotenoid intake and incident risk of this devastating malignancy. Methods: In an effort to examine the modulatory role of carotenoids in human esophageal carcinogenesis at a cellular level, we examined the effects of α-carotene and β-carotenes, on cell proliferation and DNA synthesis in human esophageal epithelial (HEE) cells and human esophageal squamous cancer (HESC) cells in in-vitro cultures. HEE and HESC cells were incubated with different concentrations of α- and β-carotenes both individually and in combination. Results: Both Carotenes significantly inhibited (p

Oral squamous cancers constitute a large proportion of head–neck malignancies in India. One subset of oral cancers includes lesions arising in the oral commissure and the mucosa around it. These are unique in their location and pattern of spread with even small lesions affecting oral competence, function, and cosmesis. This study was done to analyse such “pericommissural” cancers and to explore if they should be placed in a distinct subcategory of buccal cancers with different implications for management and prognostication. 25 cases of pericommissural squamous cancers were studied. Presentation, extent, differentiation, nodal metastases, and treatment outcomes were evaluated. Cancers of the pericommissure made up 8.7% of oral cancers that were treated surgically between 2013 and 2015. All cases underwent upfront surgery with neck dissection and reconstruction with local flaps. 36% cases were staged pT4; 12% cases had nodal involvement. 40% patients received adjuvant treatment. After a median follow-up of 676 days, there were no recurrences. Five patients died of unrelated causes and one patient died of a second primary in the lung. Functional and cosmetic outcomes were measured objectively as well as subjectively; patient expectations were taken into consideration and the scores were satisfactory. Pericommissural squamous cancers show a distinct behaviour and it may be helpful to place these lesions in a separate subcategory of oral cancers. Functional and cosmetic aspects are as important in their management as is disease control.

Background: The objective of this study is to evaluate the effectiveness and safety of bovine pericardium patch (BPP) repair for cervical anastomotic leakage after esophageal squamous cancer. Methods: Intractable cervical anastomotic leakage developed in 7 patients of esophageal squamous cell carcinoma undergoing cervical anastomosis. These patients received the BPP repair. The necrotic tissue around the cervical anastomosis was removed during the operation, and the defect was repaired with BPP according to the size of the leakage. Results: The operative duration was 60–90 min (median, 75 min). There were no signs of recurrent anastomotic leakage in each patient undergoing BPP repair. Oral intake was initiated 5–8 days (median, 6 days) after the BPP repair operation without any discomfort. Conclusions: The BPP repair is a safe and effective processing scheme for patients with cervical anastomotic fistula after resection of esophageal squamous cell carcinoma. This method may be recommended for appropriate patients with intractable cervical anastomotic fistula.

Oral cancers, primarily squamous cell carcinomas (SCCs), progress either slowly or aggressively. Here we assessed the role of macrophages in SCC behavior. We used mouse SCC cells derived from tumors harboring a KrasG12D activation mutation and Smad4 deletion in keratin 15–positive stem cells and a human oral SCC cell line, FaDu, which has NRAS amplification and SMAD4 deletion. SCC cells were transplanted into immune-compromised or immune-competent (syngeneic) recipients. After tumors were established, we used clodronate liposomes to ablate macrophages. We found that the number of tumor-associated macrophages (TAMs) was not affected by the presence of T cells but differed considerably among tumors derived from different SCC lines. Clodronate significantly reduced TAMs and splenic macrophages, resulting in reduced SCC volumes. Tumors with clodronate treatment did not show decreased proliferation but did exhibit increased apoptosis and reduced vascular density. FLIP (Fas-associated via death domain-like interleukin 1β–converting enzyme inhibitory protein), an apoptosis inhibitor abundantly produced in tumor cells and TAMs, was reduced in tumor cells of clodronate-treated mice. Reduced FLIP levels correlated with reductions in phosphorylated nuclear NFκB p65 and NFκB inhibitor attenuated FLIP protein levels in SCC cells. Furthermore, TGFβ1 serum levels and pSmad3 were reduced in clodronate-treated mice, but their reductions were insufficient to reverse epithelial-mesenchymal transition or TGFβ-mediated angiogenesis in endothelial cells. Consequently, metastasis was not significantly reduced by macrophage reduction. However, reduced pSmad3 correlated with reduction of its transcriptional target, vascular endothelial growth factor A, in clodronate-treated tumor cells, which correlated with reduced vascular density in clodronate-treated tumors. Taken together, our study revealed that macrophages contribute to SCC expansion through interactions with tumor cells but are dispensable for SCC metastasis. Our study provides novel insights into understanding the contributions and limitations of TAMs in SCC progression.