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It is usually delivered according to the original empirical six-weekly schedule introduced by Morales in 1976 [212] anxiety symptoms go away buy cheap venlor on line. Several randomized controlled trials and meta-analyses reported an absolute benefit of 5­8% for neoadjuvant chemotherapy [219­221]. However, to date, there is no accurate marker to predict response to chemotherapy and thus, non-responders might lose chance of survival due to postponed surgery. Cisplatin-based combination chemotherapy is the recommended first-line strategy [192]. During the three last decades, stage and grade migration have exhibit a trend towards more aggressive disease. It is associated with chronic exposure to aristolochic acid contained in Aristolochia fangchi and clematis, plants present abundantly in the Balkans or in Chinese herbs [234, 235]. The surgical procedure includes the dissection of regional lymph nodes as part of the treatment but also to stage the cancer extension and thus, to select properly the candidates for adjuvant chemotherapy. An extended lymph node dissection is preferable and survival has been shown to increase with the number of lymph nodes dissected [214]. The procedure can be performed through a classical open approach, laparoscopically, or robot-assisted laparoscopy. After bladder removal, urinary diversion options are: abdominal diversion (urethrocutaneostomy, ileal, or colonic conduit and some forms of continent pouches), urethral diversion (orthotopic urinary diversion through intestinal neobladder pouches), or rectosigmoid diversion (uretero-rectostomy). The choice depends on predicted post-operative continence, comorbidities, cognitive functions, and life expectancy. Overall, radical cystectomy is a morbid procedure with estimated perioperative mortality of 3% and early complications (within three months of surgery) in up to 50­60% of cases [215]. Bladder-sparing multimodal therapy Bladder-sparing multimodal therapy integrating radiotherapy and cisplatin-based chemotherapy can be offered as an alternative to surgical cystectomy for well-selected patients or when surgical extirpation cannot be performed [192]. In this setting, long-term oncologic outcomes are comparable to radical cystectomy [218]. Imaging Imaging of the upper urinary tract is usually performed after a negative cystoscopy. Any recurrence should shift back the therapeutic strategy to the gold standard nephroureterectomy when possible. The different conservative approaches include resection or laser vaporization under flexible ureteroscopic approach, a percutaneous access (pyelocaliceal location) or a segmental ureteral resection with wide margins (ureteral location) [226]. The sensitivity and specificity are, respectively, 96% and 99%, and accuracy ranges from 59­88% [236]. Accuracy decreases notably when the lesions are smaller than 1 cm with described sensitivities of 89% for lesions <5 mm and 40% for lesions <3 mm [236]. It can be increased by gathering urine in situ (renal cavities with ureteral catheterization) [237]. Diagnostic ureteroscopy Diagnostic ureteroscopy with a flexible device allows visualization and biopsies of the tumour all along the upper urinary tract. However, undergrading occurs frequently, imposing a thorough follow-up after conservative strategies [239]. Molecular markers Several studies assessed the diagnostic value of markers related to molecular pathways involved in urothelial carcinoma pathogenesis (tumour cell adhesion, angiogenesis, proliferation, epithelial-mesenchymal transition, mitosis, and apoptosis among others) [240­243]. However, due to the low incidence of this disease, internal and external validation of such markers on large cohorts is challenging and none of these markers are currently approved in routine clinical practice [226]. Nephroureterectomy is no more relevant in this setting except for palliative indications. Although randomized control trials is still lacking, platinum-based chemotherapy seems to have similar effect as for bladder carcinoma [247]. The commonest is clear cell histology which accounts for over 70% of renal malignancies. Approximately 25­30% of people have metastatic spread by the time they are diagnosed with renal cell carcinoma [248]. Less common (and less malignant histological types) include oncocytoma and chromophore tumours. Laparoscopic or open approach appeared to be equivalent based on a prospective study [244]. According to fundamental onco-surgery principles, the specimen has to be removed en bloc in order to prevent tumour seeding from the urinary tract [225]. There is a high level of evidence (1b) that immediate postoperative single dose instillation of mitomycin C after nephroureterectomy prevents bladder recurrence [246] (European guidelines recommendation grade B). As these subtypes differ in clinical course and response to therapy knowledge of the subtype may be of importance prior to planning therapy in certain clinical settings [252]. Approximately 30% of small renal masses are benign and a pretreatment biopsy may aid in selecting the best approach in patients with comorbidity or renal function impairment. The role of active surveillance of small renal tumours is controversial and currently under investigation. It is of concern that even tumours smaller than 4 cm carry a risk of developing metastatic disease and the growth rate does not follow a linear pattern but instead may unpredictably increase in 20­25% of patients in active surveillance protocols. As a consequence, nephron-sparing surgery-or partial nephrectomy-is regarded the standard of care for renal tumours of 4 cm diameter. The surgical approach can be open, laparoscopic, or robot-assisted and will largely depend on the local surgical expertise and facilities.

The goal of surgery should be to achieve negative margins anxiety fatigue cheap venlor online american express, often necessitating reconstruction by plastic surgery [74­76]. When cosmetic/function preservation is an issue, limited positive margins may be accepted, and a wider resection postponed when a recurrence occurs. Malignant peripheral nerve sheath tumours these tumours often arise from a major peripheral nerve, which can be identified macroscopically. They can occur sporadically or in the context of neurofibromatosis type 1 syndrome. The high-grade variant is marked by an early propensity for distant metastases [91­93]. When originating from a peripheral nerve, they also may spread along the nerve fibres proximally or distally. Wider margins at this level should be obtained (if possible at least 4 cm of macroscopic healthy nerve) to limit this loco-regional failure, which eventually may reach the spinal cord. Leiomyosarcoma this sarcoma may arise from skin, soft tissues, visceral organs, or vessels and it is one of the commonest histological subtypes [77]. The approach to skin leiomyosarcoma is easy, since the invasion of surrounding tissues is limited and the metastatic potential almost nil. On the contrary, soft tissues leiomyosarcoma often presents as large masses and has a systemic risk as high as 50% [77, 78]. Adjuvant treatments are often discussed with the patient, although their impact on local and distant outcome is limited. They typically have a high metastatic risk and spread to liver before other organs. Vascular leiomyosarcomas predominantly arise from veins and often abut outside the vessel extending in the soft tissues [80, 81]. The affected vascular tract should be resected en bloc with adjacent soft tissues. Intravascular tumour thrombi may be present and should be removed en bloc with the disease. The metastatic risk is significant, although a fraction of them may have a long natural history. Angiosarcoma Management of primary and radiation-associated (secondary) angiosarcoma is challenging because of the multifocality of this disease [94­97]. Since surgery is rarely curative, it should not be considered as the only treatment choice, especially for scalp angiosarcoma. Surgery may be reserved for patients who are experiencing problems with local control (bleeding from a fungating tumour) or who only appear to have a solitary site of disease by both clinical examination and imaging while undergoing systemic therapy. Epithelioid and clear cell sarcomas Both of these tumours tend to affect young adults and to occur in distal extremities. At variance with all other histological subtypes, they may give rise to in-transit metastasis along the affected limb and to loco-regional lymph node metastases [98­100]. Accurate staging of the whole limb is mandatory and sentinel lymph node biopsy should be considered as part of the routine approach to primary disease. A more aggressive variant of epithelioid sarcoma tends to occur to the limb roots and the trunk and is called proximal-type epithelioid sarcoma [101]. This variant behaves as a very aggressive unclassified sarcoma, having a high risk of hematogenous distant spread. Its sensitivity to conventional chemotherapy is higher, but fast progression after response is often observed. If a preoperative treatment is planned, the status of the disease has to be carefully monitored. Pleomorphic liposarcoma, unclassified pleomorphic sarcoma, synovial sarcoma these tumours, although different from a histological and biological standpoint, are usually approached the same way [82­86]. They predominantly affect the extremities and present as large and deeply located masses. They have a significant metastatic risk and are often treated by combined modalities. Myxofibrosarcoma this malignant tumour, when located superficially, infiltrates through soft tissue (subcutaneous fat and investing fascia) some centimetres beyond the ostensible margins of the visible or palpable mass. When located intramuscularly, the extension of the infiltration is usually limited by anatomical barriers, although it has a higher propensity to invade them as compared to other histological subtypes. It demonstrates a 30% rate of local recurrence and a 16% rate of distant recurrence [87­90]. Wide surgical margins (2 cm beyond the clinical boundaries of the palpable mass in general and up to 4 cm for the superficial ones) should be the goal of surgery, which often requires complex wound closure or flap reconstruction by a plastic and reconstructive surgeon, as well as Radiation-induced sarcomas Radiation-induced sarcomas are rare and include a variety of histological subtypes, the most common of which are pleomorphic undifferentiated sarcoma, angiosarcoma, malignant peripheral nerve sheath tumours, and leiomyosarcoma [103, 104]. Beside the inherent characteristics of each histological subtype, they are all marked by a high propensity to locally recur, given the difficulty in obtaining clear margins. In fact, it is very difficult to distinguish tumour infiltration of healthy tissues from radiation-induced changes around the tumour site. Systemic chemotherapy and re-irradiation are often considered, given the overall dismal prognosis. Bone sarcomas Surgery of bone sarcomas primarily consists of resection of the affected bone, surrounded by healthy tissue whenever needed and feasible [105, 106]. Adequate staging by bone scan and cross-sectional imaging should be performed to understand the extent of the disease in the affected bone and the presence of satellite or skip lesions. Resected peripheral bones are usually replaced by prostheses of variable lengths and complexity [107, 108]. Bone pure allografts can also be used, especially when tendon and joints need to be replaced. In the last years, composed allografts (bone grafts + prostheses) have been successfully used in several conditions [109, 110].

In all studies anxiety 6 months postpartum buy 75 mg venlor visa, c-Kit protein expression failed to demonstrate prognostic utility for response to therapy or survival. The expression of p53 protein by itself had no prognostic value for treatment benefit or survival. Metastasis-suppressor genes have been recently recognized as genes that modulate the capability of the malignant clone for systemic dissemination without affecting the primary tumour malignant transformation process. Despite reliance on neoplastic vessels, tumours are relatively hypoxic compared to normal tissues. In those patients, the tumoural hypoxic phenotype was significantly associated with worse survival. Although these features are not different from those seen in several advanced malignancies of known primary site, they provide a sound basis for implementation of therapies modulating angiogenesis. The most common type is adenocarcinoma of well- to moderate-differentiation (50%), followed by poorly or undifferentiated adenocarcinomas (30%), squamous cell carcinoma (15%), and undifferentiated neoplasms (5%). With modern immunohistochemistry undifferentiated neoplasms can be better characterized as non-specified carcinomas, neuroendocrine tumours, lymphomas, germ-cell tumours, melanomas, and sarcomas, or embryonal malignancies (Table 59. The tools for this investigation include diagnostic pathology with specific immunohistochemistry, molecular technology, imaging technology, endoscopic workup, and occasional serum tumour markers. Well to moderately differentiated Poorly differentiated or undifferentiated 50% 30% 15% 5% Squamous cell carcinoma (M8070/3) Undifferentiated neoplasms Non-specified carcinoma Neuroendocrine tumours (M8246/3) Lymphomas (M9590/3) Germ cell tumours (M 9064/3O) Melanomas (M 8720/3) Sarcomas (M 8800/3) Embryonal malignancies (M 9070/3) Light microscopy Light microscopic examination, using routine staining with haematoxylin and eosin or other staining, i. Mammography Mammography is used to detect breast primary sites in women with isolated axillary lymph node involvement by an adenocarcinoma. Extensive endoscopic evaluation in the absence of clinical or laboratory findings should be avoided, since sensitivity is extremely low [1, 2]. However, some serum markers could be helpful in certain clinicopathological subsets, i. This classification is based on age, sex, histopathology, clinical presentation, and organ or tissue involvement. This classification offers great help to the practising oncologist for both diagnostic and therapeutic management and provides at the same time prognostic and predictive value (Table 59. They present with axillary lymphadenopathy of either N1 (48%) or N2-3 disease (52%). Ductal carcinomas are the most common histology (83%) with a good to moderate differentiation in the majority of the patients. Poorly-differentiated carcinoma with midline distribution this is a predominantly male disease occurring at a median age of 56 years. It presents with nodal involvement of midline distribution affecting mainly mediastinal, retroperitoneal, or supraclavicular lymph nodes. In some cases, peripheral nodes, lung, or pleural metastatic lesions can also be observed. Elevated alpha-fetoprotein and -chorionic gonadotropin levels are found in less than 20% of the patients. Histologically, these tumours are characterized as poorly differentiated or undifferentiated carcinomas without the expression of any specific immunoperoxidase staining, apart from the presence of an i(12p) chromosomal abnormality-favouring germ cell tumour in some patients [50]. Squamous cell carcinoma involving cervical lymph nodes this subset represents 5% of patients and affects middle-aged or elderly mainly male patients with a strong history of tobacco and alcohol abuse. Clinical presentation is characterized by unilateral enlargement of upper or middle cervical lymph nodes. Occasionally, the detection of Epstein­Barr or human papilloma virus, with the support of molecular techniques, could be helpful in distinguishing nasopharyngeal from oropharyngeal primary tumours [51, 52]. Classification of clinicopathological subsets Women with serous papillary adenocarcinoma of the peritoneal cavity this subset is also called primary peritoneal adenocarcinoma and accounts for 7­20% of all pelvic or peritoneal serous papillary cancers. It seems to affect women three to seven years older than ovarian carcinoma patients, with a median age of 55­65 years. The main symptoms and signs are abdominal pain and distention, ascites, and palpable masses. Signs of constipation with intestinal obstruction are more commonly seen in late stages. The disease is predominantly located in the peritoneal, mesenteric, omental, and ovarian surfaces as well as in pelvic and retroperitoneal nodes. Histopathologically, these are serous papillary adenocarcinomas, with or without psammoma bodies. High-grade neuroendocrine tumours are the most common, representing almost 80% of all cases. These are poorly-differentiated tumours with disseminated disease and a rapidly-growing behaviour. Low-grade tumours are mainly located in the liver and manifest with symptoms associated with secretion of vasoactive peptides. Two important prognostic factors were: (a) the number of involved axillary nodes and (b) the absence of residual gross disease. Loco-regional failure in locally irradiated patients is around 15­25% and mean five-year overall survival is 72% with a median follow-up of 62 months. The impact of adjuvant systemic treatment at three-year overall survival is estimated to be approximately 22%. One should keep in mind that all therapeutic data in these patients are based on type 3 level of evidence [49].