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Leading-strand DNA replication by polymerase epsilon (Polϵ) across single-strand breaks (SSBs) causes single-ended double-strand breaks (seDSBs), which are repaired via homology-directed repair (HDR) and suppressed by fork reversal (FR). Although previous studies identified many molecules required for hydroxyurea-induced FR, FR at seDSBs is poorly understood. Here, we identified molecules that specifically mediate FR at seDSBs. Because FR at seDSBs requires poly(ADP ribose)polymerase 1 (PARP1), we hypothesized that seDSB/FR-associated molecules would increase tolerance to camptothecin (CPT) but not the PARP inhibitor olaparib, even though both anti-cancer agents generate seDSBs. Indeed, we uncovered that Polϵ exonuclease and CTF18, a Polϵ cofactor, increased tolerance to CPT but not olaparib. To explore potential functional interactions between Polϵ exonuclease, CTF18, and PARP1, we created exonuclease-deficient POLE1exo-/-, CTF18-/-, PARP1-/-, CTF18-/-/POLE1exo-/-, PARP1-/-/POLE1exo-/-, and CTF18-/-/PARP1-/- cells. Epistasis analysis indicated that Polϵ exonuclease and CTF18 were interdependent and required PARP1 for CPT tolerance. Remarkably, POLE1exo-/- and HDR-deficient BRCA1-/- cells exhibited similar CPT sensitivity. Moreover, combining POLE1exo-/- with BRCA1-/- mutations synergistically increased CPT sensitivity. In conclusion, the newly identified PARP1-CTF18-Polϵ exonuclease axis and HDR act independently to prevent fork collapse at seDSBs. Olaparib inhibits this axis, explaining the pronounced cytotoxic effects of olaparib on HDR-deficient cells.
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Proteínas Aviárias , DNA Polimerase II , Replicação do DNA , DNA Polimerase II/metabolismo , Poli(ADP-Ribose) Polimerase-1/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Humanos , Animais , Galinhas , Proteínas Aviárias/metabolismoRESUMO
Several studies have developed various artificial intelligence (AI) models for immunohistochemical analysis of programmed death ligand 1 (PD-L1) in patients with non-small cell lung carcinoma; however, none have focused on specific ways by which AI-assisted systems could help pathologists determine the tumor proportion score (TPS). In this study, we developed an AI model to calculate the TPS of the PD-L1 22C3 assay and evaluated whether and how this AI-assisted system could help pathologists determine the TPS and analyze how AI-assisted systems could affect pathologists' assessment accuracy. We assessed the 4 methods of the AI-assisted system: (1 and 2) pathologists first assessed and then referred to automated AI scoring results (1, positive tumor cell percentage; 2, positive tumor cell percentage and visualized overlay image) for final confirmation, and (3 and 4) pathologists referred to the automated AI scoring results (3, positive tumor cell percentage; 4, positive tumor cell percentage and visualized overlay image) while determining TPS. Mixed-model analysis was used to calculate the odds ratios (ORs) with 95% CI for AI-assisted TPS methods 1 to 4 compared with pathologists' scoring. For all 584 samples of the tissue microarray, the OR for AI-assisted TPS methods 1 to 4 was 0.94 to 1.07 and not statistically significant. Of them, we found 332 discordant cases, on which the pathologists' judgments were inconsistent; the ORs for AI-assisted TPS methods 1, 2, 3, and 4 were 1.28 (1.06-1.54; P = .012), 1.29 (1.06-1.55; P = .010), 1.28 (1.06-1.54; P = .012), and 1.29 (1.06-1.55; P = .010), respectively, which were statistically significant. For discordant cases, the OR for each AI-assisted TPS method compared with the others was 0.99 to 1.01 and not statistically significant. This study emphasized the usefulness of the AI-assisted system for cases in which pathologists had difficulty determining the PD-L1 TPS.
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Antígeno B7-H1 , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas , Aprendizado Profundo , Imuno-Histoquímica , Neoplasias Pulmonares , Patologistas , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Antígeno B7-H1/análise , Imuno-Histoquímica/métodos , Biomarcadores Tumorais/análise , Feminino , Masculino , Reprodutibilidade dos TestesRESUMO
Neoadjuvant therapies are used for locally advanced non-small cell lung carcinomas, whereby pathologists histologically evaluate the effect using resected specimens. Major pathological response (MPR) has recently been used for treatment evaluation and as an economical survival surrogate; however, interobserver variability and poor reproducibility are often noted. The aim of this study was to develop a deep learning (DL) model to predict MPR from hematoxylin and eosin-stained tissue images and to validate its utility for clinical use. We collected data on 125 primary non-small cell lung carcinoma cases that were resected after neoadjuvant therapy. The cases were randomly divided into 55 for training/validation and 70 for testing. A total of 261 hematoxylin and eosin-stained slides were obtained from the maximum tumor beds, and whole slide images were prepared. We used a multiscale patch model that can adaptively weight multiple convolutional neural networks trained with different field-of-view images. We performed 3-fold cross-validation to evaluate the model. During testing, we compared the percentages of viable tumor evaluated by annotator pathologists (reviewed data), those evaluated by nonannotator pathologists (primary data), and those predicted by the DL-based model using 2-class confusion matrices and receiver operating characteristic curves and performed a survival analysis between MPR-achieved and non-MPR cases. In cross-validation, accuracy and mean F1 score were 0.859 and 0.805, respectively. During testing, accuracy and mean F1 score with reviewed data and those with primary data were 0.986, 0.985, 0.943, and 0.943, respectively. The areas under the receiver operating characteristic curve with reviewed and primary data were 0.999 and 0.978, respectively. The disease-free survival of MPR-achieved cases with reviewed and primary data was significantly better than that of the non-MPR cases (P<.001 and P=.001), and that predicted by the DL-based model was almost identical (P=.005). The DL model may support pathologist evaluations and can offer accurate determinations of MPR in patients.
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Carcinoma Pulmonar de Células não Pequenas , Aprendizado Profundo , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/terapia , Terapia Neoadjuvante , Amarelo de Eosina-(YS) , Hematoxilina , Reprodutibilidade dos Testes , Neoplasias Pulmonares/terapiaRESUMO
BACKGROUND: Catastrophic thinking among patients with chronic pain impairs their quality of life and increases anxiety levels. Further, severe pain causes high emotional brain sensitivity and unpleasant feelings. However, the effects of emotional changes on catastrophic thinking in patients with chronic pain remain unclear. AIMS: We hypothesised that emotional brain activity during mild pain stimuli would affect catastrophic thinking in these patients. We aimed to examine the relationship between unpleasant emotional brain activation and catastrophic thinking due to pain stimuli in patients with chronic pain. DESIGN: This was a prospective observational study. PARTICIPANTS: We included patients with chronic pain and healthy individuals. METHODS: The impact of emotional brain activity on catastrophic thinking was evaluated, specifically, the skin conductance response and oxygenated haemoglobin levels using near-infrared spectroscopy. After receiving three different pain stimuli, the participants were evaluated using the Numeric Rating Scale, Pain Catastrophising Scale, and McGill Pain Questionnaire. RESULTS: There were 28 patients in the chronic pain group and 33 patients in the healthy group. There was no between-group difference in oxygenated haemoglobin levels during pain stimulation. The chronic pain group showed a higher Pain Catastrophising Scale score and skin conductance response than the healthy group (p < .05). In the chronic pain group, oxygenated haemoglobin levels after pain stimuli were significantly associated with the Pain Catastrophising Scale score and skin conductance response (p < .05). CONCLUSIONS: Brain activity of unpleasant emotions may influence catastrophic thinking in patients with chronic pain.
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Dor Crônica , Humanos , Dor Crônica/complicações , Dor Crônica/psicologia , Qualidade de Vida , Emoções , Catastrofização/psicologia , Encéfalo , HemoglobinasRESUMO
ABSTRACT: The diagnosis of pilomatricoma, the most common matrical tumor, is generally straightforward; however, it exhibits diverse histology associated with various morphological stages and several clinical variants, and matrical differentiation can occur in various neoplastic diseases. A 56-year-old man was admitted to our hospital to resect an 11.0-cm skin tumor on his right shoulder. Because of its large size and surface irregularities, including multiple erosions and ulcers, cutaneous malignancies were clinically suspected. Histologically, the tumor formed numerous nodules with marked matrical differentiation in the superficial to deep dermis. Although the tumor was macroscopically asymmetrical and irregular, each nodule was microscopically round-shaped and consisted of basaloid cells without marked atypia, atypical mitoses, or lymphovascular invasion. Immunohistochemically, the tumor cells were positive for beta-catenin, LEF-1, and PHLDA-1, consistent with their pilomatrical differentiation. We diagnosed the case as a giant pilomatrical tumor with uncertain malignant potential, considering its "contradictory" features, namely, the worrisome histoarchitecture, such as the asymmetrical silhouette, but bland-looking cytological appearance. Unlike typical pilomatrical tumors, this tumor contained numerous epidermal components with features similar to those of the dermal components, resulting in a unique macroscopic and histological appearance. Our case broadens the known histological diversity of pilomatrical tumors.
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Pilomatrixoma/patologia , Neoplasias Cutâneas/patologia , Diferenciação Celular , Doenças do Cabelo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
A 67-year-old man presented with abdominal distention and vomiting.Computed tomography revealed bowel obstruction due to a cecal tumor.We performed laparoscopic ileocecal resection after decompression with an ileus tube. Intraoperative findings included multiple disseminated nodules on the mesenterium surrounding the cecal tumor.The histopathologic diagnosis was poorly differentiated adenocarcinoma, which consisted of glandular proliferation of atypical epithelial cells and dispersed infiltration of goblet cells. Immunohistochemistry showed positively stained neuroendocrine markers, such as CD56, chromogranin, and synaptophysin.The patient was diagnosed with goblet cell carcinoid of the appendix and treated with combination chemotherapy of bevacizumab, fluorouracil, folinic acid, and oxaliplatin.He remained free from progression for over 1 and half years with this treatment.Subsequent chemotherapy was ineffective, and he passed away.There is no established chemotherapy regimen for goblet cell carcinoid, which has the aspects of both adenocarcinoma and neuroendocrine tumors.However, the present case suggested the efficacy of the mFOLFOX6 regimen in combination with bevacizumab for appendiceal goblet cell carcinoid.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Apêndice , Apêndice , Tumor Carcinoide , Idoso , Neoplasias do Apêndice/tratamento farmacológico , Bevacizumab , Tumor Carcinoide/tratamento farmacológico , Fluoruracila , Humanos , Leucovorina , Masculino , Compostos OrganoplatínicosRESUMO
Most lung carcinomas are subtyped by their morphologies; however, immunohistochemistry is usually performed when it is difficult to determine. The most reliable antibodies for distinguishing lung adenocarcinoma from squamous cell carcinoma are thyroid transcription factor-1 (TTF-1) and p40 (ΔNp63). In general, these markers are mutually exclusive in their expression of lung primary carcinoma; however, a few cases of non-small cell lung carcinoma (NSCLC) with coexpression of both markers have been reported. Examining a tissue microarray of 229 squamous cell carcinomas and 346 adenocarcinomas, we found one case of NSCLC with coexpression of TTF-1 and p40. Herein, we present a 71-year-old man, who had a mass lesion in the left lung apex. A transbronchial lung biopsy was performed, revealing NSCLC. He underwent left upper segmentectomy and lymph node dissection. Macroscopically, the mass showed a white-to-tan solid tumor on the cut surface. Microscopically, the tumor was composed of polygonal tumor cells which had round and vesicular nuclei with prominent nucleoli. They had an abundant amount of cytoplasm, which was slightly eosinophilic or amphophilic. Multinucleated cells with atypical nuclear features were observed to be scattered in some areas. Multifocal necrosis and hemorrhage were also noted. Distinct squamous features and obvious glandular features were absent. Immunohistochemically, the most tumor cells were coexpressed positive for both TTF-1 and p40. In our study, NSCLC with TTF-1 and p40 coexpression is rare; therefore, it is necessary to obtain further data and examine similar cases to establish more precise definitions and clinicopathological features.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Fator Nuclear 1 de Tireoide , Fatores de Transcrição , Proteínas Supressoras de Tumor , Humanos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Masculino , Idoso , Fator Nuclear 1 de Tireoide/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Fatores de Transcrição/metabolismo , Biomarcadores Tumorais/metabolismoRESUMO
A 58-year-old man with anti-melanoma differentiation-associated gene 5-positive dermatomyositis (MDA5-DM) developed Epstein-Barr virus (EBV)-associated malignant lymphoma as other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD) during the combined immunosuppressive therapy of high-dose prednisolone, tacrolimus, and intravenous cyclophosphamide for MDA5-DM. Serum EBV DNA was detected, and EBV-encoded small RNA was positive in the tissue sample of LPD, indicating that EBV reactivation contributed to the pathogenesis of LPD in our case. The patient underwent chemotherapy, including rituximab, promptly after discontinuation of tacrolimus and cyclophosphamide, resulting in complete remission of the malignant lymphoma, and MDA5-DM has not recurred with 3.5 mg/d of prednisolone monotherapy. We reviewed 19 cases of OIIA-LPD in patients with idiopathic inflammatory myopathies and herein report the first case of MDA5-DM complicated with OIIA-LPD. Among the 19 patients, 7 showed regression of LPD only following withdrawal of immunosuppressants, 9 took chemotherapy for LPD, and 5 died. It should be noted that patients with MDA5-DM-associated rapidly progressive interstitial lung disease could develop OIIA-LPD because they receive aggressive immunosuppressive therapy.
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Dermatomiosite , Infecções por Vírus Epstein-Barr , Transtornos Linfoproliferativos , Masculino , Humanos , Pessoa de Meia-Idade , Infecções por Vírus Epstein-Barr/complicações , Dermatomiosite/tratamento farmacológico , Tacrolimo/uso terapêutico , Herpesvirus Humano 4 , Imunossupressores/uso terapêutico , Ciclofosfamida/uso terapêutico , Transtornos Linfoproliferativos/tratamento farmacológico , Transtornos Linfoproliferativos/patologia , Prednisolona/uso terapêutico , Doença IatrogênicaRESUMO
Pulmonary and extrapulmonary complications after coronavirus disease 2019 (COVID-19) have been major public health concerns during the COVID-19 pandemic. Although post-COVID-19 pulmonary manifestations cover a wide spectrum, eosinophilic pneumonia (EP) has rarely been reported. To date, only four cases of EP potentially triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been reported, all of which required systemic corticosteroid therapy. We herein report the first case of post-COVID-19 EP resolution without systemic corticosteroid therapy. We also review the literature regarding EP associated with SARS-CoV-2 infection and vaccination.
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COVID-19 , Eosinofilia Pulmonar , Humanos , SARS-CoV-2 , Eosinofilia Pulmonar/tratamento farmacológico , Eosinofilia Pulmonar/etiologia , Pandemias , Corticosteroides/uso terapêuticoRESUMO
The incidence of needle breakage is estimated to be 0.000007%, and most needle breaks occur during inferior alveolar nerve block (IANB) administration and are localized to the pterygomandibular space. Although immediate surgical intervention is recommended for the removal of the fracture needles, intraoperative localization of a broken injection needle fragment can be challenging. Here, we present the case of a 36-year-old woman who underwent dental extraction of the left lower wisdom tooth under local anesthesia at a private office. At that time, a disposable 33G needle was broken and accidentally inserted into the pterygomandibular space during IANB. A broken injection needle was presented at the base of the left coronoid process of the mandible on computed tomography (CT). We successfully removed the broken injection needle using fluoroscopy and assisted endoscopy under general anesthesia.
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Epstein-Barr virus (EBV) -positive mucocutaneous ulcer (EBVMCU) was first described as a lymphoproliferative disorder in 2010. In recent years, EBVMCU has been reported in the field of oral surgery. On the other hand, medication-related osteonecrosis of the jaw (MRONJ) is an osteomyelitis that occurs in patients receiving antiresorptive agents including bisphosphonates (BP) and/or denosumab developing with bacterial infections such as dental diseases and mucositis. MRONJ caused by EBVMCU in the elderly has not been reported. Here, we report a rare case of MRONJ caused by EBVMCU in the elderly. The patient, an 82-year-old woman, had received BP for more than 2 years. An ulcerative lesion was found in the palatal mucosa; biopsy performed from the site confirmed the diagnosis of EBVMCU. At follow-up, the lesion disappeared spontaneously. At the 6-month follow-up, bone formation was observed at the site of the lesion, and the sequestrum was removed. At the 12-month follow-up healing of the EBVMCU region was seen indicating a good prognosis.
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Ameloblastic fibrosarcoma (AFS) is the most common odontogenic sarcoma, but the incidence is relatively low, and its molecular biology is poorly understood. We experienced a young female patient with a rapidly growing soft tissue tumor of the left maxilla, which eventually occupied the left side of the oral cavity. Histologically, the tumor mainly consisted of a proliferation of atypical spindle to polygonal cells without any specific differentiation, but a small number of benign odontogenic epithelial foci mainly in the tumor periphery were also noted; thus, a diagnosis of AFS was made. We performed whole-exome sequencing (WES) on the tumor to investigate its molecular features and identify therapeutic options. We found that the tumor harbored EGFR exon 20 insertions and MDM2 amplification; the former may be a target for newly developed tyrosine kinase inhibitors in case of recurrence. To the best of our knowledge, this is the first case of AFS for which WES was performed and with EGFR mutation. Our case provides new genetic information on AFS and suggests that comprehensive genetic analysis can clarify the molecular biology in rare cancers, potentially leading to the proposal of therapeutic strategies.
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Fibrossarcoma , Neoplasias Bucais , Tumores Odontogênicos , Receptores ErbB/genética , Éxons/genética , Feminino , Fibrossarcoma/diagnóstico por imagem , Fibrossarcoma/genética , Humanos , Maxila , Tumores Odontogênicos/patologia , Sequenciamento do ExomaRESUMO
Malnutrition is associated with the prognosis of malignant disease. The geriatric nutritional risk index (GNRI), based on serum albumin (ALB) levels and the present and ideal body weight, is a simple screening tool with which to predict the risk of malnutrition and mortality in patients. We hypothesised that nutritional markers could predict the prognosis of patients with oral squamous cell carcinoma (OSCC). The primary predictor variable was the GNRI score and the primary outcome variable was overall survival (OS). Univariate and multivariate analyses were performed using a Cox proportional hazard model to identify independent prognostic factors. The sample comprised 155 patients, of whom 17 presented with a low GNRI score (≤98) and 138 with a high GNRI score (≥ 98). There was a significant difference in OS when patients were stratified according to GNRI scores, with OS rates of 29.2% and 76.4% for scores of 98 and under and scores of over 98, respectively (p < 0.001). Univariate analyses showed that OS was significantly associated with GNRI score, age, T classification, N classification, stage, body mass index (BMI), prognostic nutrition index, and ALB levels. Analysis identified three independent predictive factors for OS: age (hazard ratio (HR) 2.184; 95% confidence interval (CI) 1.119 to 4.261; p = 0.022), stage (HR 2.684; 95% CI 1.457 to 5.367; p = 0.011), and GNRI score (HR 4.559; 95% CI 2.172 to 9.570; p <0.001). The results suggest that the GNRI score (>98 vs ≤98) is a good prognostic marker in patients with OSCC, along with age and stage.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Desnutrição , Neoplasias Bucais , Idoso , Avaliação Geriátrica/métodos , Humanos , Desnutrição/diagnóstico , Neoplasias Bucais/diagnóstico , Estado Nutricional , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
Pathological diagnosis is used for examining cancer in detail, and its automation is in demand. To automatically segment each cancer area, a patch-based approach is usually used since a Whole Slide Image (WSI) is huge. However, this approach loses the global information needed to distinguish between classes. In this paper, we utilized the Distance from the Boundary of tissue (DfB), which is global information that can be extracted from the original image. We experimentally applied our method to the three-class classification of cervical cancer, and found that it improved the total performance compared with the conventional method.
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Neoplasias do Colo do Útero , Automação , Feminino , HumanosRESUMO
Various treatments for oral vascular malformation (VM) have been reported. Polidocanol and absolute ethanol have also been reported for sclerotherapy. However, there are still few reports on the therapeutic effect and dosage of polidocanol sclerotherapy. Therefore, we examined its therapeutic effects on oral VM. There were 17 sites of VMs, with nine patients diagnosed with oral VM at the Department of Dental and Oral Surgery, Tsukuba University Hospital. The medical records were retrospectively investigated to determine the site, hemangioma volume, polidocanol injection volume, and therapeutic effect. The volume of hemangiomas was calculated using magnetic resonance images. Based on the site, oral VMs were observed in the tongue, buccal mucosa, lips, and oral floor in eight, three, five, and one patients, respectively. The average size of the site was 3071 mm3. The average injection dose of polidocanol at one site was 2.86 mL, the average number of administrations was 1.6, and the response rate was 88.2%. No adverse events were observed. The median numerical rating scale scores were 2/10 (0-6/10) and 0/10 (0-1/10) the day after surgery and 1 week after surgery, respectively. Univariate regression analysis of the total dose in successful cases provided the following formula: 1.3 + 0.00025 × volume (mm3) (mg). Polidocanol sclerotherapy is an effective treatment method for oral VM.
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The prevalence of medication-related osteonecrosis of the jaw (MRONJ) associated with molecular-targeted therapies such as bevacizumab and sunitinib has been constantly increasing in recent years. MRONJ frequently occurs after invasive dental procedures such as tooth extraction in patients currently or with a previous history of receiving antiresorptive agents including bisphosphonates and/or denosumab. Here, we report a rare case of spontaneously occurring MRONJ of the mandible in a 52-year-old Japanese woman with chronic myelogenous leukemia (CML) who was administered imatinib for 9 years. She had never been treated with antiresorptive agents, and her MRONJ developed spontaneously. Although there have been few reports of MRONJ related to imatinib, our case reported here indicates that imatinib may be capable of causing spontaneous MRONJ.
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INTRODUCTION: A histologic grading system for invasive lung adenocarcinoma (ADC) has been proposed by the International Association for the Study of Lung Cancer (IASLC) Pathology Committee in June 2020. This study evaluated the prognostic value of the IASLC histologic grading system (the IASLC system) in a large Japanese cohort. METHODS: We performed comprehensive histologic subtyping using the semiquantitative estimation of five major patterns and complex glandular patterns in patients with a completely resected lung ADC and determined the histologic grade using the IASLC system. Concordance index and receiver-operating characteristic curves were used to evaluate the clinical utility of the IASLC system for recurrence and death; the comparison was performed with the architectural-pattern system (the Arch system) and the grading system on the basis of the two most predominant patterns (the Sica's system). RESULTS: Of 1002 patients with invasive ADC, 235 had recurrent disease and 166 died of lung cancer. The concordance index and area under the curve of the IASLC system were 0.777 and 0.807 for recurrence and 0.767 and 0.776 for death, respectively. These were similar to those of the Arch system (0.763 and 0.796 for recurrence, 0.743 and 0.755 for death) and the Sica's system (0.786 and 0.814 for recurrence, 0.762 and 0.773 for death). CONCLUSIONS: We reported that the IASLC system for invasive lung ADC has prognostic significance by evaluating a large Japanese cohort. We believe that the IASLC grading system will provide physicians with better information for postsurgery treatment.
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Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Recidiva Local de Neoplasia/patologia , Estadiamento de NeoplasiasRESUMO
Chemotherapeutic nucleoside analogs, such as Ara-C, 5-Fluorouracil (5-FU) and Trifluridine (FTD), are frequently incorporated into DNA by the replicative DNA polymerases. However, it remains unclear how this incorporation kills cycling cells. There are two possibilities: Nucleoside analog triphosphates inhibit the replicative DNA polymerases, and/or nucleotide analogs mis-incorporated into genomic DNA interfere with the next round of DNA synthesis as replicative DNA polymerases recognize them as template DNA lesions, arresting synthesis. To address the first possibility, we selectively disrupted the proofreading exonuclease activity of DNA polymerase ε (Polε), the leading-strand replicative polymerase in avian DT40 and human TK6 cell lines. To address the second, we disrupted RAD18, a gene involved in translesion DNA synthesis, a mechanism that relieves stalled replication. Strikingly, POLE1exo-/- cells, but not RAD18-/- cells, were hypersensitive to Ara-C, while RAD18-/- cells were hypersensitive to FTD. gH2AX focus formation following a pulse of Ara-C was immediate and did not progress into the next round of replication, while gH2AX focus formation following a pulse of 5-FU and FTD was delayed to the next round of replication. Biochemical studies indicate that human proofreading-deficient Polε-exo- holoenzyme incorporates Ara-CTP, but subsequently extend from this base several times less efficiently than from intact nucleotides. Together our results suggest that Ara-C acts by blocking extension of the nascent DNA strand and is counteracted by the proofreading activity of Polε, while 5-FU and FTD are efficiently incorporated but act as replication fork blocks in the subsequent S phase, which is counteracted by translesion synthesis.
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Antimetabólitos Antineoplásicos/farmacologia , Citarabina/farmacologia , DNA Polimerase II/genética , DNA Polimerase II/metabolismo , Replicação do DNA , Tolerância a Medicamentos/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Dano ao DNA , Proteínas de Ligação a DNA/genética , Técnicas de Inativação de Genes , Genótipo , Humanos , Mutação , Ubiquitina-Proteína Ligases/genéticaRESUMO
INTRODUCTION: Undifferentiated carcinomas with osteoclast-like giant cells (UC-OGCs) of the ampullary region are very rare, with only a few cases reported to date. The clinicopathological features, treatment options, and prognosis of UC-OGCs are unclear. This report describes a patient with UC-OGCs of the ampullary region. PRESENTATION OF CASE: A 78-year-old male patient was admitted for epigastric pain and fever. Contrast-enhanced computed tomography revealed a 2.6-cm mass at the duodenal papilla. Duodenoscopy revealed a smooth red protruding mass compressing the orifice of the papilla of Vater. Biopsy of the mass showed proliferation of osteoclast-like giant cells. A subtotal stomach-preserving pancreaticoduodenectomy was performed, and the tumor was histologically diagnosed as an UC-OGCs of the ampullary region. Carcinoma in situ was also observed, spreading from the tumor at the terminal segment of the common bile duct to the common hepatic duct, with carcinoma cells at the surgical margin of the common hepatic duct. One year after surgery, the patient is alive and without tumor recurrence. DISCUSSION: UC-OGCs of the ampullary region is very rare neoplasm containing osteoclast-like giant cells and mononuclear cells. Osteoclast-like giant cells may originate from reactive mesenchymal cells and carcinoma in situ may spread to the common hepatic duct. Surgery including pancreaticoduodenectomy may be a treatment option for resectable tumors, whereas gemcitabine may be a treatment option for unresectable tumors. CONCLUSION: Carcinoma in situ may spread quite far (5cm) to the common hepatic duct, making it desirable to intraoperatively confirm negative bile duct margins by rapid pathologic diagnosis.