ALS pathogenesis: Recent insights from genetics and mouse models

For the vast majority of cases of amyotrophic lateral sclerosis (ALS) the etiology remains unknown. After the discovery of missense mutations in the gene coding for the Cu/Zn superoxide dismutase 1 (SOD1) in subsets of familial ALS, several transgenic mouse lines have been generated with various forms of SOD1 mutants overexpressed at different levels. Studies with these mice yielded complex results with multiple targets of damage in disease including mitochondria, proteasomes, and secretory pathways. Many unexpected discoveries were made. For instance, the toxicity of mutant SOD1 seems unrelated to copper-mediated catalysis but rather to formation of misfolded SOD1 species and aggregates. Transgenic studies revealed a potential role of wtSOD1 in exacerbating mutant SOD1-mediated disease. Another key finding came from chimeric mouse studies and from Cre-lox mediated gene deletion experiments which have highlighted the importance of non-neuronal cells in the disease progression. Involvement of cytoskeletal components in ALS pathogenesis is supported by several mouse models of motor neuron disease with neurofilament abnormalities and with genetic defects in microtubule-based transport. Recently, the generation of new animal models of ALS has been made possible with the discovery of ALS-linked mutations in other genes encoding for alsin, dynactin, senataxin, VAPB, TDP-43 and FUS. Following the discovery of mutations in the TARDBP gene linked to ALS, there have been some reports of transgenic mice with high level overexpression of WT or mutant forms of TDP-43 under strong gene promoters. However, these TDP-43 transgenic mice do not exhibit all pathological features the human ALS disease. Here, we will describe these new TDP-43 transgenic mice and discuss their validity as animal models of human ALS.     

Review of large deep lipomatous tumours

BACKGROUND: Lipomatous tumours comprise a range of diagnoses. There are controversies regarding the histopathological diagnosis, nomenclature, diagnostic method, surgical management, roles of radiotherapy and the risk of metastasis, local recurrence and dedifferentiation. This study describes our experience with such tumours. METHODS: Retrospective review of 224 soft tissue tumours from the Senior Author's (J. W. S.) database identified 28 patients with deep lipomatous tumours. Clinical features and outcomes were studied with median follow up of 1.5 years. RESULTS: Eleven deep lipomas, six deep atypical lipomas, four well-differentiated (lipoma-like) liposarcomas, three well-differentiated liposarcomas and four liposarcomas were studied. Preoperative diagnosis was established by image-guided core biopsy in 20 patients, excisional biopsy in 6, incisional biopsy in 1 and fine-needle aspiration in 1. All patients diagnosed with deep lipoma and deep atypical lipoma underwent marginal excision. The median size of the excised tumour was 11 cm. Recurrence occurred in three deep atypical lipomas and one liposarcoma. Dedifferentiation occurred in one deep atypical lipoma, which transformed into a liposarcoma. None had metastasis or died of metastatic malignancy. CONCLUSION: Large deep lipomatous tumours are uncommon and although they do not tend to metastasize, they not infrequently recur locally. Hence their local treatment to prevent local recurrence is important. Key aspects in achieving a complete, but marginal resection of the deep atypical lipoma and the well-differentiated lipoma-like liposarcoma is accurate preoperative diagnosis with core biopsy and accurate imaging to assess deep unsuspected extensions of the tumour.     

精索黏液性脂肪肉瘤1例报告并文献复习

目的:探讨精索黏液性脂肪肉瘤诊断与治疗方法。方法:回顾性分析1例右侧精索较大黏液性脂肪肉瘤患者临床资料。术前检查未发现局部及远处转移后,经腹股沟切口,在内环口处切断精索并将带包膜的肿瘤连同睾丸和附睾一起切除。未行放疗或化疗。结果:切除一18.0 cm ×10.0 cm ×7.5 cm肿块,精索2 cm,睾丸3 cm×3 cm×2 cm,随访15个月,肿瘤未复发。结论:精索黏液性脂肪肉瘤罕见,多高分化的恶性肿瘤。很少发生转移。高位结扎精索并彻底切除肿瘤组织则预后良好。复发也是局部的,可行再切除加局部放疗或化疗。     

An unusual case of primary colonic dedifferentiated liposarcoma

INTRODUCTION

İn this paper, we present a rare case of primary dedifferantiated liposarcoma (DDLS) of the colon, management of which is unclear and difficult to cope with.

PRESENTATION OF CASE

71 year old female patient with complaints of abdominal pain and swelling was referred to our clinic with the diagnosis of intraabdominal mass. 23 cm × 19 cm × 18 cm tumor starting from the neighborhood of left liver lobe and extending toward pelvic floor was detected on computed tomography. At laparotomy, a multilobulated, soft and yellowish mass was arising from transvers colon and invading greater curvature of stomach. En-bloc removal of the tumor including segmental colon and gastric wedge resection was performed. Postoperative histopathological diagnosis was consistent with dedifferentiated liposarcoma.

DISCUSSION

Liposarcomas are rarely encountered in the gastrointestinal tract. Previously, only ten cases of primary liposarcoma of the colon have been reported worldwide and to our knowledge DDLS of transverse colon is the first case reported in the literature. DDLS is a high-grade aggressive tumor carrying the ability to metastasize. Despite complete removal of tumor recurrence is common in DDLS.

CONCLUSION

The constellation of findings in our patient demonstrates that liposarcomas which histologically exhibit dedifferentiation are associated with a poor clinical prognosis and advocating surgery alone is not recommended.     

A moderate dose of preoperative radiotherapy may improve resectability in myxoid liposarcoma

BackgroundHistotype specific neoadjuvant therapy response data is scarce in soft tissue sarcomas. This study aimed to assess the impact of a moderate radiotherapy (RT) dose on resectability and to correlate MRI parameters to pathological treatment response in Myxoid Liposarcoma (MLS).MethodsThis prospective, multicenter, single-arm, phase 2 trial assessed the radiological effects of 36 Gy of preoperative radiotherapy in primary non-metastatic MLS (n=34). Distance of the tumor to the neurovascular bundle, tumor dimensions, fat fraction, enhancing fraction were determined on MRI scans at baseline, after 8 and 16 fractions, and preoperatively. Pathological response was established by central pathology review.ResultsPreoperative radiotherapy resulted in a median increase of 2 mm (IQR 0 to 6) of the distance of the tumor to the neurovascular bundle. As compared to baseline, the median change of the tumor volume, craniocaudal diameter and axial diameter at preoperative MRI were −60% (IQR -74 to -41), −19% (IQR -23 to -7) and −20% (IQR -29 to -12), respectively. The median fat fraction of 0.1 (IQR 0.0–0.1) and enhancing fraction of 0.8 (IQR 0.6 to 0.9) at baseline, changed to 0.2 (IQR 0.1 to 0.5) and to 0.5(IQR 0.4 to 0.9) preoperatively, respectively. Radiological signs of response in terms of volume, enhancing fraction and fat fraction were correlated with specific pathological signs of response like hyalinization, necrosis and fatty maturation.ConclusionsA moderate dose of preoperative radiotherapy may improve resectability in MLS and could facilitate achievement of clear margins and function preservation. MRI features which were predictive for expressions of pathological response, can play a role in further personalization of neoadjuvant treatment strategies in order to improve outcome in MLS.     

Dedifferentiated liposarcoma with an inflammatory malignant fibrous histiocytoma-like component presenting a leukemoid reaction

A rare case of dedifferentiated llposarcoma (well-differentiated llposarcoma with an inflammatory mallgnant fibrous histiocytoma (MFH)-like anaplastlc component) occurrtng in a 69-year-old male is presented. The patient had noticed a dull pain in his left loin and thigh for about 1 month. Computed tomography examination revealed a low-density mass lesion, measuring about 6 cm In diameter, in the left lliopsoas muscie, and It was surgically removed. Grossly, the lesion was composed of an encapsulated, soft, whitish mass and an adjacent, well-demarcated, yellowish hard nodule, measuring about 2.5 cm In diameter. Microscopically, both lesions showed features of an inflammatory variant of MFH and a sclerosing type of well-differentiated liposarcoma, respectively. To our knowledge, only two cases of dedifferentiated liposarcoma combined with inflammatory MFH as a dedifferentiated component have been recorded in the literature. The salient feature of the present case is a systemic inflammatory reaction, as shown by prominent leukocytosis (up to 73 900/mm³) and the elevated serum value of C reactive protein (up to 26.0 mg/dL), which were transiently reduced after surgery. The Inflammatory reaction was suggested to be induced by cytokines, such as granulocyte colony-stimulating factor and interleukin-6, which were probably produced by the tumor cells in the present case, because the elevated serum values of those cytokines were decreased after surgery.     

外生性肾血管平滑肌脂肪瘤与腹膜后脂肪肉瘤的CT征象分析

目的 探讨CT征象能否准确诊断与鉴别外生性肾血管平滑肌脂肪瘤与腹膜后脂肪肉瘤.方法 回顾性分析17例外生性肾血管平滑肌脂肪瘤和7例腹膜后脂肪肉瘤的MDCT图像,使用Fisher确切概率法对CT征象与两种肿瘤之间的关系进行比较.结果 肿块与肾脏交界面的肾皮质缺损、肿块内粗大血管、肾动脉分支供血及肿块内血管穿过肾实质走行仅或主要见于外生性肾血管平滑肌脂肪瘤(P均<0.01);肾脏向前移位和肿块内非脂肪成分强化结节灶仅或主要见于腹膜后脂肪肉瘤(P均<0.01).钙化、肿块内和(或)周围出血及合并的其他血管平滑肌脂肪瘤在外生性肾血管平滑肌脂肪瘤和腹膜后脂肪肉瘤中的差异并无统计学意义(P均>0.05).结论 CT征象能有效鉴别外生性肾血管平滑肌脂肪瘤与腹膜后脂肪肉瘤.     

1例右侧睾丸旁混合型脂肪肉瘤超声表现

<正>患者男，64岁，阴囊右侧坠胀不适3月余；既往无特殊病史。查体：阴囊右侧肿大，无触痛，表面皮肤无明显异常。超声：右侧睾丸中下极25 mm×35 mm实性低回声结节，内部回声不均，边界不清(图1A),CDFI于其周边及内部见点状血流信号，阻力指数(resistance index, RI)呈低阻型；超声造影呈“快进快退”等增强模式(图1B、1C);右侧睾丸向右移位约2 cm, 另于其左外侧见29 mm×37 mm实性较均匀低回声结节，     

1例肝脏原发性去分化脂肪肉瘤超声造影表现

<正>患者女，51岁，体检发现右上腹占位2个月；既往无特殊病史。查体：腹膨隆，右上腹扪及直径约15cm质硬包块，活动度差。实验室检查未见明显异常。超声：肝右叶15cm×12cm杂乱回声肿块，形态较规则，边界不清，内部及周边见数个斑片状强回声（图1A）；超声造影见动脉期肿块呈不均匀高增强（图1B），门脉期及延迟期相强化程度逐渐减低，下份见片状无增强区（图1C）；考虑肿瘤性病变，     

Follow-up of patients with retroperitoneal sarcoma

Retroperitoneal sarcomas (RPS) are rare malignancies that are potentially curable by complete surgical resection. A regular surveillance program is normally commenced following surgery due to the risk of local recurrence (LR), especially in low-intermediate grade disease, and distant metastases (DM), especially in high-grade RPS. Consensus guidelines usually advocate for more frequent imaging during the first 2–3 years and less intensive imaging over a prolonged period thereafter, reflecting the incidence pattern of LR and DM. Definitive evidence for the most effective imaging schedule has never been provided, and retrospective studies have not shown an association between follow-up intensity and survival. Improvement in the prediction of recurrence patterns has been sustained by prognostic dynamic nomograms, which are now capable of forecasting disease behaviour in each patient according to specific features. Incorporation of such tools in clinical practice may help to stratify patients and tailor ongoing surveillance to the risk of recurrence. This may help to relieve patients’ anxiety while awaiting results of surveillance investigations, and also reduce the economic and environmental burden of repeated imaging. A randomized controlled study (SARveillance Trial) is proposed to shed light on this controversial topic, allowing clinicians to harmonize the follow-up protocol of patients undergoing surgery for RPS.