Detection and induction of CTLs specific for SYT-SSX-derived peptides in HLA-A24(+) patients with synovial sarcoma

To investigate the immunogenic property of peptides derived from the synovial sarcoma-specific SYT-SSX fusion gene, we synthesized four peptides according to the binding motif for HLA-A24. The peptides, SS391 (PYGYDQIMPK) and SS393 (GYDQIMPKK), were derived from the breakpoint of SYT-SSX, and SS449a (AWTHRLRER) and SS449b (AWTHRLRERK) were from the SSX region. These peptides were tested for their reactivity with CTL precursors (CTLps) in 16 synovial sarcoma patients using HLA-A24/SYT-SSX peptide tetramers and also for induction of specific CTLs from four HLA-A24(+) synovial sarcoma patients. Tetramer analysis indicated that the increased CTLp frequency to the SYT-SSX was associated with pulmonary metastasis in synovial sarcoma patients (p < 0.03). CTLs were induced from PBLs of two synovial sarcoma patients using the peptide mixture of SS391 and SS393, which lysed HLA-A24(+) synovial sarcoma cells expressing SYT-SSX as well as the peptide-pulsed target cells in an HLA class I-restricted manner. These findings suggest that aberrantly expressed SYT-SSX gene products have primed SYT-SSX-specific CTLps in vivo and increased their frequency in synovial sarcoma patients. The identification of SYT-SSX peptides may offer an opportunity to design peptide-based immunotherapeutic approaches for HLA-A24(+) patients with synovial sarcoma.     

CANCER OF THE LUNG IN WOMEN

Cancer of the lung in women has the same signs and symptoms as in men, but the disease seems to advance more rapidly. Of 35 female patients, half were under radiation therapy (for inoperable tumor) within four months after the first manifestation. In three of the five who had no symptoms, the cancer when diagnosed was inoperable.Scalene node biopsy confirmed metastasis in nine of the eleven cases in which it was used, and this procedure should be used after diagnosis whenever metastasis is not evident.Of the 35 women, two received only chemotherapy, 32 radiotherapy. Only four were alive at the time of report—one without evidence of disease at 20 months, one with symptoms of disease at 11 months, two under chemotherapy at two months, For 29 who received palliative or radical irradiation to the primary tumor site, the median survival time was 26 weeks.     

慢性淋巴细胞性甲状腺炎合并甲状腺结节的临床分析

目的:研究分析中国东北地区慢性淋巴细胞性甲状腺炎(CLT)合并甲状腺结节的诊断和治疗方式.方法:回顾性分析2009年9月--2010年12月收治经病理证实的CLT合并甲状腺结节的共151病例,依据不同的病理类型分组,就临床特点、诊断和治疗进行比较.结果:CLT合并甲状腺乳头状癌组共58例,女性51例,男性7例,平均年龄37.5±4岁,平均病程18个月,28例为腺体内单发结节,病灶平均直径为0.9± 0.56 cm,36例病灶直径小于1.0 cm,42例见结节内伴钙化.CLT合并良性结节组98例,女性患者93例,男性患者5例,平均年龄48.1±9岁,平均病程72个月,34例为腺体内单发结节,病灶平均直径1.8± 0.42 cm,35例病灶直径小于1.0 cm,10例见结节内伴钙化.两组在发病年龄、病程、结节个数及钙化方面的差异均有统计学意义.结论:CLT合并甲状腺癌微小癌多见,淋巴结转移率低,彩超提示单发结节或者结节合并钙化的病例,应行手术治疗.     

SYT-SSX1 (synovial sarcoma translocated) regulates PIASy ligase activity to cause overexpression of NCOA3 protein

Chromosomal translocations are a major source of genetic abnormalities causally linked to certain malignancies. Synovial sarcoma is an aggressive soft tissue tumor characterized by a chromosomal translocation between chromosome 18 and X, generating oncoproteins such as SYT-SSX1 and SYT-SSX2. The molecular mechanism underlying the oncogenic potential of SYT-SSX1/2 is not clear. Here we show that SYT-SSX1 leads to up-regulation of NCOA3, a protein critical for the formation of various cancers. The increase of NCOA3 is essential for SYT-SSX1-mediated synovial sarcoma formation. SYT-SSX1 does so by increasing the sumoylation of NCOA3 through interaction with a SUMO E3 ligase, PIASy, as well as the sumoylation of NEMO. NEMO has also been shown to physically interact with NCOA3. Increased sumoylation of NCOA3 leads to its increased steady state level and nuclear localization. Our findings represent the first example that an oncoprotein directly regulates substrate modification by a SUMO E3 ligase, and leads to overexpression of a protein essential for tumor formation. Such a mechanistic finding provides an opportunity to design specific therapeutic interventions to treat synovial sarcoma.     

Primary pleural synovial sarcoma with diffuse pleural involvement: A case report

Synovial sarcoma (SS) is a mesenchymal tumor which generally affects the soft tissues of the extremities. Primary pleural synovial sarcoma (PPSS) is a very rare and aggressive subtype of SS. A 73-year-old male patient presented with chest-back pain and dyspnea. Hypermetabolic diffuse pleural lesions were detected in ¹⁸F-FDG PET/CT performed after pleural nodular thickenings were observed on CT. As the result of the molecular analysis performed in the excisional biopsy, SYT-SSX mutation was detected and the patient was diagnosed as SS. Pazopanib treatment was commenced. We are reporting a very rare case of PPSS with diffuse pleural involvement.     

原发性骨恶性纤维组织细胞瘤24例临床特征及预后分析

摘要 目的：总结原发性骨恶性纤维组织细胞瘤（PBMFH）的临床特征和预后。方法：回顾性分析我院2000年10月至2011年1月收治的24例PBMFH患者的术前影像学资料、诊断依据、治疗方案和随访资料。结果：24例患者全部通过术后病理确诊,穿刺准确率为75.00%.胸部X线检查结果显示：2例发现肺部转移灶,22例未发现肺部转移灶。肿瘤局部X线检查结果显示：3例出现骨质溶解性破坏,1例出现肿块影,20例表现为骨膜反应。MRI检查结果显示：4例MRI检查肿瘤局部情况时发现3例T1WI等信号、T2WI稍高信号,1例T1WI低信号、T2WI低信号。本研究中行放化疗18例,有6例（33.33%）发生转移,转移时间为6~45个月,中位转移时间为（25.30±6.24）个月,单纯手术治疗6例中有5例发生转移（83.33%）,转移发生时间为3~6月,中位转移时间为（5.00±0.24）个月。结论：PBMFH患者单纯手术出现转移多发生于术后5月,根治性手术辅以放化疗出现转移多发生于术后25月。由此可见,术前穿刺活检病理有助于疾病诊断,术后辅助化疗有助于降低PBMFH的复发率和转移率。     

Less Aggressive Surgical Procedure for Treatment of Solid Pseudopapillary Tumor: Limited Experience from a Single Institute

Objectives

To evaluate the clinical characteristics and radiological features of solid pseudopapillary tumor (SPT) and assess surgical therapy strategy.

Methods

A retrospective review was performed in 62 patients pathologically confirmed of SPT treated between 2003 and 2014. The clinical features, radiological examinations and surgical strategies were analyzed.

Results

56 females and 6 males were included in this study, mean age was 26 years old (range: 8–66 years old) with mean size of the tumor was 7.2 cm (range: 3–15 cm), and most tumor were commonly located in the head of pancreas (n = 29). Among all the cases, 3 patients had liver metastasis and underwent resection of SPT and liver metastasis. Furthermore, we performed 29 cases of local tumor excision; other patients underwent pancreaticoduodenectomy, middle pancreatectomy, middle pancreatectomy with splenectomy, distal pancreatectomy with spleen preservation, distal pancreatectomy with splenectomy and duodenum-preserving pancreatic head resection. No patient suffered from lymph node metastases. After median follow-up of 46 months (range: 2–135 months), no mortality or local recurrence or distant metastasis was found.

Conclusions

Solid pseudopapillary tumor is a latent malignant tumor with excellent prognosis. If feasible, less aggressive resection without regular lymphadenectomy is recommended for treatment of patients with SPT.     

Secernin-1 as a novel prognostic biomarker candidate of synovial sarcoma revealed by proteomics

We aimed to develop prognostic biomarkers for synovial sarcoma employing a proteomic approach. We examined the proteomic profile of synovial sarcoma using two-dimensional difference gel electrophoresis (2D-DIGE). We identified 20 protein spots whose intensity was statistically different (p<0.01) between a group of eight patients who were alive and continuously disease-free for over five years and a group of five patients who died of the disease within two years post diagnosis. Mass spectrometric protein identification demonstrated that these 20 spots corresponded to 17 distinct gene products. Three of the 20 spots corresponded to secernin-1 and had higher intensity in the good prognosis group. The prognostic performance of secernin-1 was further examined immunohistochemically in 45 synovial sarcoma cases. The 5-year survival rate was 77.6% and 21.8% for patients with secernin-1 positive and negative primary tumors respectively (p=0.0015). The metastasis-free survival was significantly higher in the patient group with high secernin-1 expression compared to that with low expression (p=0.0012). Uni- and multivariate analyses revealed that secernin-1 expression was a powerful prognostic factor compared to other clinico-pathological parameters examined. These results indicate that secernin-1 may be used as a biomarker to predict the overall and metastasis-free survival in synovial sarcoma patients.     

Analysis of Lymph Node Metastasis Correlation with Prognosis in Patients with T2 Gastric Cancer

Purpose

To investigate the correlated factors for lymph node metastasis and prognosis for patients with T2 gastric cancer.

Methods

A total of 442 patients with T2 gastric cancer who underwent gastrectomy from January 1996 to December 2009 were evaluated. The clinicopathological parameters were analyzed for lymph node metastasis and prognosis, including gender, age, tumor size, tumor location, histological type, depth of invasion, vascular tumor emboli, nervous invasion, resection type, and pathological stage.

Results

The rate of lymph node metastasis was 45.9%. Univariate analysis showed that depth of invasion, tumor size, and vascular tumor emboli were associated with lymph node metastasis. Logistic regression demonstrated that depth of invasion, tumor size, and vascular tumor emboli were independently predictive factors for lymph node metastasis. The 5-year survival rate was 64.0%. Multivariate analysis showed that tumor size, tumor location, resection type, and pathological stage were independent prognostic factors. Based on tumor size, there were significant differences of 5-year survival between small size tumor (<6 cm) and large size tumor (≥6 cm) according to stage IIA (P = 0.006). Based on tumor location, there were significant differences of 5-year survival among different tumor location according to stage IB. Based on resection type, there were significant differences of overall 5-year survival between curative surgery and palliative surgery according to stage IIB (P = 0.015) and IIIA (P = 0.001).

Conclusion

Depth of invasion, tumor size, and vascular tumor emboli were independently predictive factors for lymph node metastasis. Tumor size, tumor location, resection type, and pathological stage were independent prognostic factors.     

淋巴结转移阴性的胃癌患者临床病理特征及生存探讨

目的:探讨淋巴结转移阴性胃癌患者的临床病理特征以及预后影响因素。方法:收集2000年1月至2009年1月我院收治的胃癌患者325例,其中经病理检查显示淋巴结转移阴性的105例患者作为阴性组(LN-组),另229例阳性患者作为阳性组(LN+组),比较两组的临床病理特征及临床预后。结果:LN-组的肿瘤直径、浸润深度及术后化疗与LN+组比较差异显著(P0.05);LN-组的5年生存率为76.2%,显著高于LN+组的43.2%(P0.05)。未透浆膜的LN-患者3年、5年生存率显著高于浸透浆膜者,术后化疗的LN-患者5年生存率显著高于未化疗者(P0.05),肿瘤直径5 cm的LN-患者3、5年生存率显著高于≥5 cm者(P0.05)。单因素分析显示浸润深度、肿瘤大小及术后化疗与LN-胃癌患者的预后具有密切关系(P0.05)。COX多因素分析显示浸润深度是影响LN-胃癌患者临床预后的独立因素(P0.05)。结论:淋巴结转移阴性胃癌患者的病灶多位于中下部,男性多于女性,发病年龄多在60岁以内,肿瘤直径多不超过5 cm,浸润深度多未浸透浆膜,临床预后优于淋巴结转移阳性胃癌患者,浸润深度是影响淋巴结转移阴性胃癌患者临床预后的独立因素。     

Crisscross CTL induction by SYT-SSX junction peptide and its HLA-A*2402 anchor substitute

To investigate the effects of anchor substitutions in SYT-SSX junction peptide, an HLA-A24 anchor residue (position 9) of the SYT-SSX B peptide (GYDQIMPKK) was substituted to more favorable residues according to the HLA-A24-binding motif. Among four substitutes constructed, a substitute with isoleucine (termed K9I peptide) most apparently enhanced the affinity for HLA-A24 molecule. Subsequent in vitro CTL induction analysis using PBMCs of 15 HLA-A24(+) synovial sarcoma patients revealed that the original B peptide allowed to induce synovial sarcoma-specific CTLs from 7 patients (47%), whereas such CTLs were inducible from 12 patients (80%) with K9I peptide. Moreover, the extent of cytotoxicity against HLA-A24(+) synovial sarcoma cell lines was higher in K9I peptide-induced CTLs than B peptide-induced CTLs. Influence of anchor substitution on peptide/TCR interaction was evaluated by cytotoxicity assays against autologous cells and tetramer analysis. CTLs induced from a synovial sarcoma patient using K9I peptide did not lyse autologous PHA blasts or EBV-infected B cells. In vitro stimulations of PBMCs from 5 HLA-A24(+) synovial sarcoma patients with K9I peptide increased the frequency of T cells reacting with both HLA-A24/K9I peptide tetramer and HLA-A24/B peptide tetramer. In contrast, the frequency of T cells reacting with HLA/HIV-derived peptide tetramer remained low. These findings support the validity in design of anchor residue substitution in SYT-SSX fusion gene-derived peptide, and provide a potential clue to the current stagnation in vaccination trials of fusion gene-derived natural junction peptides.     

嫌色性肾细胞癌17例临床病理学分析

目的探讨嫌色性肾细胞癌的临床病理特征、诊断与鉴别诊断要点。方法对17例嫌色性肾细胞癌进行组织形态学、免疫组化染色及Hale’s胶样铁染色观察,结合文献对其临床表现、病理形态特点及鉴别诊断进行探讨。结果嫌色性肾细胞癌17例,大体肿瘤直径3-10.5cm。镜下肿瘤由嫌色细胞和嗜酸细胞构成,呈片状、梁状和腺泡状分布。嫌色细胞体积较大,多角形,胞膜清晰,胞质半透明细网状,胞核皱缩,可见核沟及核异型,核仁不明显;而嗜酸细胞胞质嗜酸,可见明显的核周空晕。免疫组化:EMA 100%阳性,CD10 52.9%阳性,Vimentin阴性,CK7 88.2%阳性,P504S29.4%阳性,CD11794.1%阳性。Hale’s胶样铁染色100%阳性。17例中12例随访6个月到3年,仅1例在术后15个月发现肝脏转移,其余均未发现复发及转移。结论嫌色性肾细胞癌是一种少见的肾肿瘤,恶性程度相对较低,预后良好。掌握该肿瘤独特的病理学特征,对鉴别其他肾上皮性肿瘤有重要帮助。     

Long-term survival results after treatment for oligometastatic brain disease

AimThe aim of this study was to characterize the survival results of patients with up to four brain metastases after intense local therapy (primary surgery or stereotactic radiotherapy) if extracranial metastases were absent or limited to one site, e.g. the lungs.BackgroundOligometastatic disease has repeatedly been reported to convey a favorable prognosis.Material and methodsThis retrospective study included 198 German and Norwegian patients treated with individualized approaches, always including brain radiotherapy. Information about age, extracranial spread, number of brain metastases, performance status and other variables was collected. Uni- and multivariate tests were performed.ResultsMedian survival was 16.5 months (single brain metastasis) and 9.8 months (2–4, comparable survival for 2, 3 and 4), respectively (p = 0.001). After 5 years, 15 and 2% of the patients were still alive. In patients alive after 2 years, added median survival was 23 months and the probability of being alive 5 years after treatment was 26%. In multivariate analysis, extracranial metastases were not significantly associated with survival, while primary tumor control was.ConclusionLong-term survival beyond 5 years is possible in a minority of patients with oligometastatic brain disease, in particular those with a single brain metastasis. The presence of extracranial metastases to one site should not be regarded a barrier towards maximum brain-directed therapy.     

18F-fluoro-deoxy-glucose focal uptake in very small pulmonary nodules: fact or artifact? Case reports

ABSTRACT: BACKGROUND: F-fluoro-deoxy-glucose (18F-FDG) positron emission tomography integrated/combined with computed tomography (PET-CT) provides the best diagnostic results in the metabolic characterization of undetermined solid pulmonary nodules. The diagnostic performance of 18F-FDG is similar for nodules measuring at least 1 cm and for larger masses, but few data exist for nodules smaller than 1 cm. CASE PRESENTATION: We report five cases of oncologic patients showing focal lung 18F-FDG uptake on PET-CT in nodules smaller than 1 cm. We also discuss the most common causes of 18F-FDG false-positive and false-negative results in the pulmonary parenchyma. In patient 1, contrast-enhanced CT performed 10 days before PET-CT did not show any abnormality in the site of uptake; in patient 2, high-resolution CT performed 1 month after PET showed a bronchiole filled with dense material interpreted as a mucoid impaction; in patient 3, contrast-enhanced CT performed 15 days before PET-CT did not identify any nodules; in patients 4 and 5, contrast-enhanced CT revealed a nodule smaller than 1 cm which could not be characterized. The 18F-FDG uptake at follow-up confirmed the malignant nature of pulmonary nodules smaller than 1 cm which were undetectable, misinterpreted, not recognized or undetermined at contrast-enhanced CT. CONCLUSION: In all five oncologic patients, 18F-FDG was able to metabolically characterize as malignant those nodules smaller than 1 cm, underlining that: 18F-FDG uptake is not only a function of tumor size but it is strongly related to the tumor biology; functional alterations may precede morphologic abnormalities. In the oncologic population, especially in higher-risk patients, PET can be performed even when the nodules are smaller than 1 cm, because it might give an earlier characterization and, sometimes, could guide in the identification of alterations missed on CT.     

Long-term outcomes in patients with metastatic melanoma vaccinated with melanoma peptide-pulsed CD34+ progenitor-derived dendritic cells

Between March 1999 and May 2000, 18 HLA-A*0201⁺ patients with metastatic melanoma were enrolled in a phase I trial using a dendritic cell (DC) vaccine generated by culturing CD34⁺ hematopoietic progenitors. This vaccine includes Langerhans cells. The DC vaccine was loaded with four melanoma peptides (MART-1/MelanA, tyrosinase, MAGE-3, and gp100), Influenza matrix peptide (Flu-MP), and keyhole limpet hemocyanin (KLH). Ten patients received eight vaccinations, one patient received six vaccinations, one patient received five vaccinations, and six patients received four vaccinations. Peptide-specific immunity was measured by IFN-γ production and tetramer staining in blood mononuclear cells. The estimated median overall survival was 20 months (range: 2–83), and the median event-free survival was 7 months (range: 2–83). As of August 2005, four patients are alive (three patients had M1a disease and one patient had M1c disease). Three of them have had no additional therapy since trial completion; two of them had solitary lymph node metastasis, and one patient had liver metastasis. Patients who survived longer were those who mounted melanoma peptide-specific immunity to at least two melanoma peptides. The present results therefore justify the design of larger follow-up studies to assess the immunological and clinical outcomes in patients with metastatic melanoma vaccinated with peptide-pulsed CD34-derived DCs.Joseph W. Fay and A. Karolina Palucka have equally contributed to this work     

Managing soft tissue sarcomas in a developing country: are prognostic factors similar to those of developed world?

ABSTRACT: BACKGROUND: Managing soft tissue sarcomas (STS) in a developing country with limited financial resources and a poor health referral system is a challenge. Presenting late, these extremity STS are prone to recurrence despite apparently complete resection. This study aimed to explore and compare the impact of clinico-pathological factors on recurrence and survival in Pakistan with the corresponding figures quoted from the developed world. METHODS: An institutional review was performed on all patients with primary STS of the extremities operated on between 1994 and 2008. The prognostic influence of clinical, pathologic, and treatment variables on local recurrence free survival (LRFS), metastasis free survival (MFS) and overall survival (OS) were analyzed by univariate and multivariate Cox regression analysis and Kaplan Meier survival curves. RESULTS: A total of 84 patients with a mean age of 41.8 +/- 21.9 years were included in the study. The local recurrence rate was 14.3% after a median of 6 (mean 7.4) months. Metastases occurred in 7 patients (8.3%) and 65 patients were alive without evidence of disease after a mean follow-up of 52.6 +/- 39.8 months. Tumor size > 5 cm, grade 3 tumors and margin < 10 mm significantly increased local recurrence rates. A margin >= 10 mm and age < 45 years significantly enhanced cumulative survival. Significant multivariate risk factors for metastases were margin < 10 mm and tumor grade G3. CONCLUSIONS: Despite a poor health referral system in our country, our results are no different from those reported from the developed world. Surgical margins and tumor grade prognostically influenced LRFS, MFS and OS.     

HPV+/-宫颈癌患者临床特点与预后的对比分析

目的:探讨HPV阴性与HPV阳性宫颈癌的临床特点及其和预后的关系。方法:选取住院手术的HPV呈阴性与阳性的宫颈癌患者各86例,且两组患者在年龄、FIGO临床分期相近。分析两组患者的年龄、肿瘤临床分期、病理分型、原发肿瘤大小、分化程度、基层浸润深度、淋巴结转移、治疗方案情况及其5年RFS和总生存时间。结果:两组间宫颈癌患者肿瘤分化程度、肌层浸润深度、淋巴结转移间差异有统计学意义(P0.05)。HPV阳性组和HPV阴性组随访时间分别为63(13~87)个月、61(9~90)个月,5年总生存率分别为70.4%和61.3%,平均总生存时间分别为(73.15±2.74)月和(62.72±3.03)月,差异有统计学意义(p0.05)。HPV阴性组和HPV阳性组5年RFS分别为52.3%和66.4%,平均RFS为(51.57±4.62)月和(58.83±3.46)月,差异有统计学意义(p0.05)。结论:HPV阴性宫颈癌瘤体倾向于低分化,易发生局部侵犯和淋巴结转移,其临床预后较差。     

Predictive Factors of Superior Mediastinal Nodal Metastasis from Papillary Thyroid Carcinoma—A Prospective Observational Study

Objectives

The purpose of this study was to demonstrate the incidence rates and predictive factors of superior mediastinal lymph node (SMLN) metastasis in PTC (papillary thyroid carcinoma) patients.

Methods

A prospective observational study was performed between January 2009 and January 2011. PTC patients who had tumors with a maximal diameter greater than 1 cm and clinically negative SMLNs were included in this study. Finally, a total of 217 patients who underwent total thyroidectomy with central compartment neck dissection (CND) and elective superior mediastinal lymph node dissection (SMLND), with or without modified radical neck dissection (MRND) and revisional CND, were included.

Results

Occult SMLN metastasis was present in 15.7% (34/217). Cytological classifications of tumor, BRAFV600E mutation, Tumor size, T-stage, perithyroidal extension, lymphovascular invasion, multifocality, and paratracheal pN(+) were not predictive of SMLN metastasis (P > .05), while revision surgery, pretracheal pN(+), and multiple lateral pN(+) were associated with SMLN metastasis. There were no major complications related to SMLND. Transient and permanent hypoparathyroidism was observed in 69 cases (31.8%) and 8 cases (3.6%), respectively.

Conclusions

Despite clinically negative SMLN in preoperative evaluation, SMLN metastasis can be predicted for patients with a PTC tumor size larger than 1 cm, pretracheal LN metastasis, multiple lateral metastasis, and revisional surgery.