Comprehensive analysis of gene mutations and mismatch repair in Chinese colorectal cancer patients.

BACKGROUND: RAS, BRAF, and mismatch repair (MMR)/microsatellite instability (MSI) are crucial biomarkers recommended by clinical practice guidelines for colorectal cancer (CRC). However, their characteristics and influencing factors in Chinese patients have not been thoroughly described. AIM: To analyze the clinicopathological features of KRAS, NRAS, BRAF, and PIK3CA mutations and the DNA MMR status in CRC. METHODS: We enrolled 2271 Chinese CRC patients at the China-Japan Friendship Hospital. MMR proteins were tested using immunohistochemical analysis, and the KRAS/NRAS/BRAF/PIK3CA mutations were determined using quantitative polymerase chain reaction. Microsatellite status was determined using an MSI detection kit. Statistical analyses were conducted using SPSS software and logistic regression. RESULTS: The KRAS, NRAS, BRAF, and PIK3CA mutations were detected in 44.6%, 3.4%, 3.7%, and 3.9% of CRC patients, respectively. KRAS mutations were more likely to occur in patients with moderate-to-high differentiation. BRAF mutations were more likely to occur in patients with right-sided CRC, poorly differentiated, or no perineural invasion. Deficient MMR (dMMR) was detected in 7.9% of all patients and 16.8% of those with mucinous adenocarcinomas. KRAS, NRAS, BRAF, and PIK3CA mutations were detected in 29.6%, 1.1%, 8.1%, and 22.3% of patients with dMMR, respectively. The dMMR was more likely to occur in patients with a family history of CRC, aged < 50 years, right-sided CRC, poorly differentiated histology, no perineural invasion, and with carcinoma in situ, stage I, or stage II tumors. CONCLUSION: This study analyzed the molecular profiles of KRAS, NRAS, BRAF, PIK3CA, and MMR/MSI in CRC, identifying key influencing factors, with implications for clinical management of CRC.

Comparative clinicopathological and immunohistochemical study of micronodular thymoma and micronodular thymic carcinoma with lymphoid stroma.

AIM: To elucidate the clinicopathological and immunohistochemical characteristics of micronodular thymomas (MNTs) and micronodular thymic carcinomas (MNCs) with lymphoid stroma. METHODS: We examined four cases of MNTs and three cases of MNCs pathologically and immunohistochemically. RESULTS: There were prominent cystic changes infive of the seven cases. The neoplasms contained epithelial tumour cells arranged in a micronodular growth pattern lined by cystic walls and separated by abundant lymphoid stroma. Only the tumour cell component of MNCs showed signs of malignancy characterised by cytological atypia and increased mitotic activity. Neoplastic MNC epithelial cells showed strong positivity for CD5 and CD117. However, no immature lymphocytes (TdT-positive and CD99-positive) were present in and around the tumour nodules. None of the patients died or suffered from disease due to MNTs or MNCs. CONCLUSION: MNTs and MNCs are rare and less aggressive forms of thymic tumours and can be differentially diagnosed by immunohistochemistry.

Micronodular thymic tumor with lymphoid stroma: A case report and review of the literature.

BACKGROUND: Micronodular thymic tumors with lymphoid stroma include micronodular thymoma with lymphoid stroma (MNT) and micronodular thymic carcinoma with lymphoid hyperplasia (MNC), whose micromorphological features are lymphoid stromal hyperplasia and nodular arrangement of tumor epithelial cells. This type of tumor is rare; therefore, the corresponding clinical guidelines, histopathological diagnostic criteria, prognostic factors, and therapeutic regimens have not been established. CASE SUMMARY: This study covers a novel presentation of MNC in a patient and summarizes the clinicopathological characteristics of this type of tumor by using pooled-analysis methods. Morphologically, this tumor type is a series of benign to malignant pedigrees. We establish the following criteria for the classification of micronodular thymic tumors with lymphoid stroma: (1) Tumor cells with moderate-to-severe dysplasia; (2) Tumor cell mitotic figures > 2/10 high-power fields; (3) Appearance of neoplastic necrosis; (4) No terminal deoxynucleotidyl transferase-positive immature T lymphocytes within the tumor; (5) Tumor cells with a Ki-67 index ≥ 10%; and (6) Tumor cells express CD5. Cases that fall into the borders of two categories in terms of morphology are attributed to atypical MNT. It is proposed that the diagnosis of MNT should be established on the diagnostic criteria mentioned above. CONCLUSION: Our diagnostic algorithm can effectively distinguish malignant tumors from benign tumors and provides a potent basis for predicting a prognosis, which offers a practical reference for oncologists and pathologists.

Phase 2 study using oral thalidomide-cyclophosphamide-prednisone for idiopathic multicentric Castleman disease.

Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder. The anti-interleukin 6 (IL-6) therapy siltuximab is not available everywhere, and is not effective for over one-half of patients. Alternative treatment approaches are urgently needed. In the first iMCD clinical trial directed against a target other than IL-6 signaling, we investigated a thalidomide-cyclophosphamide-prednisone (TCP) regimen in newly diagnosed iMCD patients. This single-center, single-arm, phase 2 study enrolled 25 newly diagnosed iMCD patients between June 2015 and June 2018. The TCP regimen (thalidomide 100 mg daily for 2 years; oral cyclophosphamide 300 mg/m2 weekly for 1 year; prednisone 1 mg/kg twice a week for 1 year) was administered for 2 years or until treatment failure. The primary end point was durable tumor and symptomatic response for at least 24 weeks. Twelve patients (48%) achieved the primary end point with no relapse, 3 patients (12%) demonstrated stable disease, and 10 patients (40%) were evaluated as treatment failure. Even when considering all patients, there were significant (P < .05) improvements in median symptom score, IL-6 level, hemoglobin, erythrocyte sedimentation rate, albumin, and immunoglobulin G. Among responders, the median levels of all evaluated parameters significantly improved, to the normal range, after treatment. The regimen was well tolerated. One patient died of pulmonary infection and 1 patient had a grade 3 adverse event (rash); 2 patients died following disease progression. Estimated 1-year progression-free survival and overall survival were 60% and 88%, respectively. The TCP regimen is an effective and safe treatment of newly diagnosed iMCD patients, particularly when siltuximab is unavailable. This trial was registered at www.clinicaltrials.gov as #NCT03043105.

Pathological evaluation of neoadjuvant chemotherapy in advanced gastric cancer.

BACKGROUND: Although pathological evaluation has been considered an effective evaluation method, some problems still exist in practice. Therefore, we explored whether there are more reasonable and practical pathological evaluation criteria for neoadjuvant chemotherapy in patients with advanced gastric cancer. Here, we aim to determine pathological judgment criteria for neoadjuvant chemotherapy in patients with advanced gastric cancer. METHODS: Eighty-seven patients with cT2-4 or cN+ were enrolled in this study. Pathological factors for overall survival (OS) were investigated using univariate and multivariate analyses, and the pathological criteria for neoadjuvant chemotherapy were then determined. RESULTS: A total of 87 patients underwent 3-4 cycles of neoadjuvant chemotherapy, with 67 (77.0%), 15 (17.2%), and 5 (5.8%) receiving Folfox6, Xelox, and SOX regimens, respectively. All patients showed different levels of graded histological regression (GHR) of the primary tumor, with a ≥ 50% regression rate of 50.6%. The univariate analysis showed that GHR ≥ 50% (p = 0.022), 66.7% (p = 0.013), and 90% (p = 0.028) were significantly correlated with OS. The multivariate analysis demonstrated that ypTNM (II/III) stage was significantly associated with OS compared with ypTNM (0+I) stage [HR = 3.553, 95% CI 1.886-6.617; HR = 3.576, 95% CI 1.908-6.703, respectively] and that the Lauren classification of diffuse type was also an independent risk factor for OS compared with the intestinal type (HR = 3.843, 95% CI 1.443-10.237). CONCLUSIONS: The Lauren classification and ypTNM stage after neoadjuvant chemotherapy are independent prognostic factors in advanced gastric cancer. A GHR ≥ 50%/< 50% can be used as the primary criterion for advanced gastric cancer after neoadjuvant chemotherapy to determine postoperative adjuvant chemotherapy regimens.

Prognostic relevance of UCH-L1 and α-internexin in pancreatic neuroendocrine tumors.

Prognostic biomarkers for the pancreatic neuroendocrine tumors are needed. Proteomic study on insulinoma has been rarely reported. We identified the differential expression of proteins between insulinoma and their paired tissues by proteomic analysis, and evaluated the prognostic significance of specific proteins in pancreatic neuroendocrine tumors including insulinoma. The differential expression of select proteins was validated in more than 300 tumors using immunohistochemical staining and western blot. Methylation of UCH-L1 promoter in tumors was examined by methylation specific PCR and validated by sequencing. The concurrent expression of UCH-L1 and α-internexin was correlated with the prognosis in 2 independent collectives of patients with tumors. Sixty-two and 219 proteins were significantly down-regulated and up-regulated in insulinomas, respectively. Demethylation of UCH-L1 promoter was associated with UCH-L1 expression in tumors (p = 0.002). The concurrent expression of UCH-L1 and α-internexin in pancreatic neuroendocrine tumors was significantly associated with better overall survival and disease-free survival in the combination of both cohorts (log rank p = 3.90 × 10-4 and p = 3.75 × 10-5, respectively) and in each of cohorts. The prognostic value of both proteins was also validated in patients with stage II and III tumors (p = 0.017 and p = 0.006, respectively). The proteins UCH-L1 and α-internexin could be independent prognostic biomarkers of pancreatic neuroendocrine tumors.

The diagnostic dilemma of tumor induced osteomalacia: a retrospective analysis of 144 cases.

Diagnostic delay of tumor induced osteomalacia (TIO) is common in clinic practice. To investigate the diagnostic condition of TIO in China and raise clinicians' awareness of TIO, we retrospectively analyzed clinical manifestations, biochemical features, and specially evaluated missed diagnoses and misdiagnoses among 144 TIO patients from Peking Union Medical College Hospital during December 1982 to December 2014. Clinical presentations of TIO mainly included bone pain, difficulty in walking, pathological fractures, muscle weakness, and height loss. TIO patients demonstrated hypophosphatemia (0.48±0.13 mmol/L), elevated serum alkaline phosphatase (277.9±152.6 U/L), reduced tubular maximum for phosphorus/glomerular filtration rate (0.39±0.14) and markedly elevated serum fibroblast growth factor 23 (FGF23) (median level 302.9 pg/mL). The average time from onset to a correct diagnosis was 2.9±2.3 years while the mean duration from onset to tumor resection was 5.4±4.2 years. The initial misdiagnosis rate was 95.1% (137/144) and 240 case-times of misdiagnoses occurred among the 144 cases. The most frequent misdiagnoses were intervertebral disc herniation, spondyloarthritis (including ankylosing spondylitis) and osteoporosis. A total of 43.1% (62/144) cases with hypophosphatemia presented on their laboratory sheets were neglected and missed diagnosed. Our study showed that TIO was frequently misdiagnosed and missed diagnosed due to its rarity, insidious onset, nonspecific clinical manifestations and clinicians' poor recognition. It is necessary to test serum phosphorus in patients with musculoskeletal symptoms and difficulty in walking. The measurement of serum FGF23 is rather valuable. Once hypophosphatemia is discovered, TIO should be suspected and it is highly recommended to search for tumors and perform curative surgery.

Fatal pulmonary Kaposi sarcoma in an HIV seronegative AIDS patient.

INTRODUCTION: Although HIV antibody tests have been widely accepted in clinical diagnosis of HIV infection, they may not be sufficient to diagnose all subjects with HIV infection. Except negative result of antibody test in the well-known" acute window phase", in rare cases, patients do not develop HIV antibodies despite demonstrable infection. Primary pulmonary Kaposi sarcoma (KS) without mucocutaneous involvement accounts for only 0-15% of all AIDS-related KS. KS is rare among Chinese subjects, especially in persons of Han descent. METHODS: A case of seronegative AIDS with primary pulmonary Kaposi sarcoma (KS) was reported. It's a 46-year-old Chinese man presented with sore throat, hemoptysis, fever, dyspnea and multiple lung nodules. The lung lesions grew over a 5-month period so as the symptoms worsened. The possibility of AIDS was discounted by his physicians because of the repeatedly negative HIV antibodies tests despite the ELISA tests or Western blot tests. Histopathologic diagnosis of fine needle lung biopsy in local hospital was undetermined. After admission, HIV infection was eventually confirmed by plasma HIV RNA testing. Histopathologic diagnosis of Lung Kaposi sarcoma was made through repeated fine needle aspiration biopsy as well as the review of former one. Multiple antibiotics and chemotherapy were administrated with no clinical effect due to advanced stage and the patient passed away soon after diagnosis. RESULTS: This is the first case of seronegative HIV-1 infection with presentation of primary pulmonary KS. CONCLUSION: This case underscores the importance of plasma RNA test in conjunction with HIV antibody test for some rare patients with HIV infection who present with severe immunodeficiency and opportunistic infections or malignancy.

PD-1 expression on the surface of peripheral blood CD4+ T cell and its association with the prognosis of patients with diffuse large B-cell lymphoma.

The aim of the study was to investigate the relationship between PD-1 expression on the surface of CD4+ T cells and prognosis of patients with diffuse large B-cell lymphoma (DLBCL). Sixty patients who were newly diagnosed with DLBCL and 39 healthy controls were enrolled. In CD4+ T cells of DLBCL patients, the median MFI of PD-1 were 541.5 (range: 348.25-758.75), significantly higher than 250 (range: 211-326) in healthy controls (P < 0.001). The ZAP70, PI3K, and NFAT mRNA expression levels of patients were 0.47, 0.47, and 0.62 times, respectively, of those of the healthy controls (P < 0.05). In patients with the percentage of PD-1 on CD4+ T cells ≥30.25%, their EFS and OS were significantly lower than patients with PD-1+ CD4+ T cells <30.25% (P < 0.05). The possible explanation is that high PD-1 expression on CD4+ cells of DLBCL patients may impair T-cell function and thus contribute to poor prognosis. There was no relationship between PD-1 surface expression on CD4+ T cells and PD-1 expression within the biopsy of tumor microenvironments from DLBCL patients.

Cranial and lumbosacral hypertrophic pachymeningitis associated with systemic lupus erythematosus: A case report.

BACKGROUND: Hypertrophic pachymeningitis (HP) is a chronic disease characterized by inflammatory hypertrophy and fibrosis of dura mater. It can be divided into cranial and spinal forms depending on the location of the lesion. HP involving 2 separate sites simultaneously is quite uncommon. CASE SUMMARY: This study presents a case of a 49-year-old woman with pathologically confirmed cranial and lumbosacral hypertrophic pachymeningitis associated with systemic lupus erythematosus (SLE), which is a rare etiology of HP. She experienced persistent numbness and pain of the left lower limb, followed by headache and seizures. In laboratory tests, levels of erythrocyte sedimentation rate and C-reactive protein were elevated, and antinuclear antibodies and anti-double-strand deoxyribonucleic acid (DNA) antibodies were detected. Magnetic resonance imaging revealed dural thickening with homogenous gadolinium enhancement both at lumbosacral level and over cerebral convexities. Histology suggested chronic inflammation in spinal dura mater with extensive fibrosis, dense lymphoplasmacytic infiltrate, and focal vasculitis. Treatment with corticosteroids and cyclophosphamide was started with significant clinical and radiological improvement. CONCLUSION: HP is etiologically heterogeneous. Despite its rarity, SLE should be considered in the differential diagnosis of HP. Early recognition and therapy may provide an optimal outcome.

Evaluation of clinicopathologic characteristics and the BRAF V600E mutation in Erdheim-Chester disease among Chinese adults.

Erdheim-Chester disease (ECD) is a rare form of histiocytosis with a broad, non-specific clinical spectrum. Here, we retrospectively evaluated the clinical and pathologic characteristics, presence of the BRAF V600E mutation, treatment options, and outcomes of Chinese patients diagnosed with ECD at our center. Patients diagnosed with ECD between January 2010 and April 2015 at Peking Union Medical College Hospital were included for study. We evaluated baseline characteristics, reviewed histological material, and tested for the presence of the BRAF V600E mutation using immunohistochemistry and polymerase chain reaction (PCR). Sixteen patients were diagnosed with ECD. Median disease duration (from the first symptom to diagnosis) was 22.5 months (range, 3-100 months). The main sites of involvement included bone (93.8 %), cardiovascular region (43.8 %), skin (31.3 %), central nervous system (25 %), and "hairy kidney" (25 %). The BRAF V600E mutation was detected in 68.8 % patients using PCR and 50 % patients with immunohistochemistry. Three patients could not be diagnosed using histological analysis owing to similarities with Rosai-Dorfman disease, and diagnosis in these cases was confirmed based on the BRAF V600E mutation status. Ten patients (62.5 %) received IFN-α as first-line treatment. Thirteen patients (81.3 %) were still alive at median follow-up of 14.5 months. ECD remains a largely overlooked disease, and increased recognition by clinicians and pathologists is necessary for effective diagnosis and treatment. The presence of the BRAF V600E mutation may facilitate discrimination of ECD from other non-Langerhans cell histiocytoses.

Comparison of Clinical and Ultrasonographic Features of Poorly Differentiated Thyroid Carcinoma and Papillary Thyroid Carcinoma.

BACKGROUND: The clinical behavior and management of poorly differentiated thyroid carcinoma (PDTC) are very different from papillary thyroid carcinoma (PTC). By comparing the clinical and ultrasonographic features between the two tumors, we proposed to provide more possibilities for recognizing PDTC before treatment. METHODS: The data of 13 PDTCs and 39 age- and gender-matched PTCs in Peking Union Medical College Hospital between December 2003 and September 2013 were retrospectively reviewed. The clinical and ultrasonic features between the two groups were compared. RESULTS: The frequencies of family history of carcinoma, complication with other thyroid lesions, lymph node metastases, recurrent laryngeal nerve injuries, and distant metastases were higher in PDTCs (30.8%, 61.6%, 69.2%, 23.1%, and 46.2%, respectively) than those in PTCs (2.6%, 23.1%, 25.6%, 2.6%, and 2.6%, respectively) (P < 0.05). The mortality rate of PDTCs was greatly higher than PTCs (P < 0.01). Conventional ultrasound showed that the size of PDTCs was larger than that of PTCs (3.1 ± 1.9 cm vs. 1.7 ± 1.0 cm). Clear margins and rich and/or irregular blood flow were found in 92.3% of PDTCs, which differed substantially from PTCs (51.7% and 53.8%, respectively) (P < 0.05). CONCLUSIONS: PDTC is more aggressive and its mortality rate is higher than PTCs. Accordingly, more attention should be given to suspicious thyroid cancer nodules that show large size, regular shape, and rich blood flow signals on ultrasound to exclude the possibility of PDTCs.

Gorham-Stout disease: radiological, histological, and clinical features of 12 cases and review of literature.

Gorham-Stout disease (GSD) is an exceedingly rare disease characterized by progressive osteolysis and angiomatosis. We investigate the features of this disease and evaluate the effects of bisphosphonates (BPs) on it. The clinical, radiological, and pathological characteristics of 12 patients diagnosed with GSD were summarized. Immunohistochemical staining with specific lymphatic endothelial markers (D2-40), vascular markers (CD 31, CD 34), and vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 3 (VEGFR-3) was performed in specimens of bone biopsy. Patients were treated with either BPs or conjunction therapy of radiation and BPs. The effects of BPs were evaluated by the change of radiological progression, bone mineral density (BMD) and bone turnover biomarkers. To further evaluate the prognosis, a literature review was done. Idiopathic massive osteolysis was found in all patients, including 11 polyostotic and one mono-ostotic osteolysis. Soft tissue lymphangioma was presented in four patents. Four patients were complicated with chylothorax. Endothelial cells lining the proliferative vessels were positive for CD31 and CD34 and D2-40. Mild expression of VEGF and VEGFR-3 was also revealed. Stabilization in osteolysis and improvement in BMD were observed after single therapy with BPs or combined with radiotherapy. High mortality rate was found in patients with chylothorax. Spontaneous, progressive osteolysis is the most typical sign of GSD. BPs and radiotherapy can contribute to the clinical stabilization in bone lesion of GSD. The complicated chylothorax possibly indicates poor prognosis.

Adipositas cordis sudden death: a series of 79 patients.

BACKGROUND: The principal aim of this study was to investigate the clinical, epidemiological and pathologic features for a series of 79 cases of adipositas cordis sudden death. METHODS: We analyzed clinical and autopsy pathological features of 79 patients (43 females and 36 males) with adipositas cordis who died suddenly between 1975 and 2010. Data were extracted from China National Knowledge Infrastructure and Wan Fang Database. RESULTS: The average age of the 79 cases was 36.6 ± 1.4 years old ranging from 13 to 68, and 82.3% of them were between 20 to 50 years old. Sudden death was the first symptom in 62 (78.5%) of the cases, only 17 (21.5%) had a history of chest distress or dyspnea. More than 4/5 (87.3%) of the cases had no any past medical history. At autopsy, the subjects' heart weight was mild or moderately increased, and a large amount of fatty tissues but not fibrous or fibro fatty was accumulated underneath the epicardium and infiltrated toward the right ventricle walls, and even infiltrated to all layers of the cardiac walls. Regional epidemiological data showed that about 80% of cases were living north and only 20% were living south of the Yangzi River, but not any familial heredity. CONCLUSION: Adipositas cordis sudden death is a very severe disease, it occurs mostly in youth and middle-aged and sudden death is often the first symptom. There is a significant regional difference, but not any genetic correlation. The pathogenesis of adipositas cordis sudden death should to be further explored.

Endoscopic ultrasound in restaging and predicting pathological response for advanced gastric cancer patients after neoadjuvant chemotherapy.

AIM: To evaluate the role of endoscopic ultrasound (EUS) in restaging and predicting response after neoadjuvant chemotherapy in patients with advanced gastric cancer. METHODS: In all, 48 advanced gastric cancer patients were recruited from June 2007 to December 2010 after providing their written, informed consent. All patients underwent an EUS before and after three cycles of neoadjuvant chemotherapy (FOLFOX 6), and then a radical resection was performed 3-4 weeks after chemotherapy. The results of EUS were compared to the pathological results of the resected specimens. RESULTS: After chemotherapy, the overall sensitivity of EUS for T classification was 63 percent (T2: 44%, T3: 68%, T4: 90%), and overstaging (31%) was more frequent than understaging (6%). The sensitivity and specificity of EUS for N classification were 56 and 50 percent, respectively (N0: without lymph node metastasis, N1: with lymph node metastasis), with 15 percent overstaged and 32% understaged. EUS revealed that T and/or N downstaging occurred in 46 percent (22/48) of patients after chemotherapy, most of whom had a favorable pathological response to the chemotherapy compared with other patients without T and/or N downstaging. No T or N upstaging was observed after neoadjuvant chemotherapy. CONCLUSIONS: The accuracy of restaging by EUS for T and N classification was not as good as pathological data for locally advanced gastric cancer patients after neoadjuvant chemotherapy. However, T and/or N downstaging confirmed by EUS correlated well with the degree of pathological response to chemotherapy.