Intermediate- and high-risk melanoma

Opinion statement Intermediate and high risk for recurrence melanoma comprise a unique subset of patients with surgically treatable melanoma for whom cure is possible but relapse and distant metastases likely. Strategies to improve the prognosis for such patients with effective adjuvant therapies are critical. In recent randomized trials conducted by the cooperative groups in the United States of patients at high risk for recurrence (patients with thick primary melanomas and those with regional lymph node metastases) administered adjuvant therapy with high-dose interferon alfa-2b (HDI), relapse-free survival and overall survival rates improved significantly. Research efforts in this area continue to assess the role of intermediate-dose interferon, but there is no convincing evidence of success of the lower-dose regimens, despite the reduction in toxicity. For a subset of patients at highest risk (two or more involved lymph nodes), a regimen of therapy for metastatic stage IV melanoma (interleukin-2 based biochemotherapy) is being compared with HDI in an ongoing phase III trial. For intermediate-risk melanoma, no effective adjuvant therapy is available. For such patients, enrollment in ongoing clinical trials assessing the role of shorter courses of HDI or vaccines should be encouraged.     

Antithrombotic therapy in high-risk pregnancy

Venous thromboembolism remains a major cause of morbidity and mortality associated with pregnancy and puerperium. Specific risk factors for this disorder can be identified before or during pregnancy and delivery. The heritable defects believed to be associated with venous thrombosis are factor V Leiden mutation; elevated antiphospholipid antibodies; and deficiencies of antithrombin, protein C, and protein S. Women with a history of thromboembolism and thrombophilia should receive antenatal and postpartum thrombosis prophylaxis.     

Treatment of high-risk smoldering myeloma

Multiple myeloma (MM) is a hematologic malignancy of the plasma cell that causes symptoms of bone pain, renal failure, and anemia. It is usually preceded by a precursor disease state, such as smoldering multiple myeloma (SMM) or monoclonal gammopathy of undetermined significance (MGUS), and traditional dogma dictates that treatment should be initiated on frank MM symptom development. Emerging evidence suggests that a defined group of "high-risk SMM" may benefit from early treatment, before organ damage and symptoms actually occur. The following article frames the evidence for treatment of high-risk SMM by defining risk categories, reviewing existing therapeutic trial data, and exploring the long-term biologic implications of early treatment.     

Chemotherapy of high-risk trophoblastic neoplasia

With recent progress in chemotherapy, the prognosis of patients with trophoblastic neoplasia has greatly improved, but the remission rate of patients with choriocarcinoma remains unfavorable. The Committee for Trophoblastic Disease of the Japan Society of Obstetrics and Gynecology reported the results of hospital registration at 77 institutions throughout Japan in 1987. In this report, the survival rates of patients treated during the 7 years from 1974 to 1980 were described as follows. The 5-year survival rate has approached 100% for patients with invasive mole, while the rate for patients with choriocarcinoma is now approaching 80%. As far as choriocarcinoma is concerned, the survival rate depends on the presence of metastases. The 5-years survival rate for patients without metastases has approached 100%, while that for patients with metastases is barely 60%. Patients with poor-prognosis choriocarcinoma present difficult and challenging problems for the clinician. These patients are best treated on the basis of the prognostic scoring system proposed by Bagshawe. The higher the score, the greater the risk of drug resistance developing during traditional therapy. To date, our experience with the MECA regimen would indicate that it is most effective for patients with high-risk trophoblastic neoplasia. We now also recommend that all high-risk patients should receive at least four additional courses of the regimen after a negative hCG titer has been obtained. After complete remission has been achieved, further follow up should be repeated every month for at least three years.     

Retinoid therapy of high-risk neuroblastoma

Retinoids are derivatives of vitamin A that include all trans-retinoic acid (ATRA), 13-cis-retinoic acid, (13-cis-RA), and fenretinide (4-HPR). High levels of either ATRA or 13-cis-RA can cause arrest of cell growth and morphological differentiation of human neuroblastoma cell lines, and phase I trials showed that higher and more sustained drug levels were obtained with 13-cis-RA relative to ATRA. A phase III randomized trial showed that high-dose, pulse therapy with 13-cis-RA given after completion of intensive chemoradiotherapy (with or without autologous bone marrow transplantation) significantly improved event-free survival in high-risk neuroblastoma. The cytotoxic retinoid 4-HPR achieved multi-log cell kills in neuroblastoma cell lines resistant to ATRA and 13-cis-RA, and a pediatric phase I trial has shown it to be well tolerated. Cytotoxicity of 4-HPR is mediated at least in part by increasing tumor cell ceramide levels and combining 4-HPR with ceramide modulators increased anti-tumor activity in pre-clinical models. Thus, further clinical trials of 4-HPR in neuroblastoma, and of 4-HPR in combination with ceramide modulators, are warranted.     

Adjuvant chemotherapy in high-risk malignant melanoma

Fifty-nine patients with regional or hematogenous recurrence of malignant melanoma following resection of all the gross tumor were randomized to observation or chemotherapy. The chemotherapy consisted of BCNU 80 mg/M2 I.V. every 4 weeks, actinomycin-D 0.01 mg/kg and vincristine 1.0 mg/M2 I.V. every 2 weeks, for a total of 6 months. The chemotherapy protocol was tolerated well without appreciable objective side effects. At a median follow-up period of 11.5 months, the disease-free survival time for the chemotherapy treated group is significantly longer than for the control group (P = 0.01). The estimated median disease-free survival time is 4 months in the surgical control group and 9 months in the chemotherapy group. At present, the proportion of patients remaining disease-free is 43% for the surgical control and 55% for the chemotherapy treated group. More patients and follow-up are needed, but this preliminary report suggests that nitrosourea-based protocols need to be evaluated further as adjuvant treatment of malignant melanoma.     

高风险垂体腺瘤的临床病理特征

  目的  探讨高风险垂体腺瘤的临床病理特征及诊断要点。  方法  选取2017年6月至2020年9月北京大学国际医院收治的24例高风险垂体腺瘤患者,进行形态学观察、免疫组织化学染色及基因检测,同时收集患者的临床资料并进行随访,综合分析病理特点与临床特征的相互关系。  结果  24例高风险垂体腺瘤中男性14例,女性10例,发病年龄28～68岁,平均年龄45.4岁,临床表现为鞍区占位或激素分泌异常的症状。肿瘤最大径0.7～4.8 cm,影像学提示侵袭性腺瘤12例。根据固有激素、转录因子和低分子量角蛋白的免疫组织化学染色特点,结合临床症状及血清激素水平进行诊断,其中稀疏颗粒型生长激素细胞腺瘤4例,沉默性促肾上腺皮质激素细胞腺瘤12例,男性泌乳激素细胞大腺瘤6例,多激素PIT-1阳性腺瘤2例。基因检测1例存在GNAS基因突变。14例获得随访资料,2例复发（其中1例因肿瘤复发死亡）。  结论  高风险垂体腺瘤的诊断应该结合免疫组织化学、血清激素水平及临床症状综合分析,并且需要提示临床复发和进展的风险。      

Concurrent chemoradiation for high-risk prostate cancer

There are estimated to be 220800 cases of prostate cancer diagnosed in 2015, making up 26% of all cancer diagnoses. Fortunately, adenocarcinoma of the prostate is often a highly treatable malignancy. Even though the majority of prostate cancer patients present with localized disease, prostate cancer still accounts for over 27000 deaths a year. There is a subset of patients that are likely to recur after locoregional treatment that is thought of as a “high-risk” population. This more aggressive subset includes patients with clinical stage greater than T2b, Gleason score greater than 7, and prostate specific antigen greater than 20 ng/dL. The rate of biochemical relapse in this high risk group is 32%-70% within five years of definitive focal therapy. Given these discouraging outcomes, attempts have been made to improve cure rates by radiation dose escalation, addition of androgen depravation therapy, and addition of chemotherapy either sequentially or concurrently with radiation. One method that has been shown to improve clinical outcomes is the addition of chemotherapy to radiotherapy for definitive treatment. Concurrent chemoradiation with 5-fluorouracil, estramustine phosphate, vincristine, docetaxel, and paclitaxel has been studied in the phase I and/or II setting. These trials have identified the maximum tolerated dose of chemotherapy and radiation that can be safely delivered concurrently and established the safety and feasibility of this technique. This review will focus on the addition of concurrent chemotherapy to radiotherapy in the definitive management of high-risk prostate cancer.     

Multimodal approaches to high-risk prostate cancer

Widespread use of testing for prostate-specific antigen (PSA) has led to a migration in the stage and grade of prostate cancer (PCa), with most men presenting with localized disease. However, 20%-35% of patients still present with high-risk disease (PSA > 20 ng/mL, biopsy Gleason score 8-10, or clinical stage T3). Despite advances in various treatment modalities, patients with high-risk disease have a significant chance of recurrence and death after surgery, often because of the presence of early occult metastasis at time of diagnosis. The optimal management of high-risk pca remains controversial. The present article aims to discuss the traditional approaches and the more recent evolution toward multimodal therapies.     

多学科综合治疗——改善高危前列腺癌患者的预后

手术和放疗是局限性前列腺癌主要的治疗方法,但对于高危前列腺癌单用局部治疗预后不佳,超过50％的患者会复发。手术、放疗、内分泌治疗和化疗的联合应用目前被认为是提高高危前列腺癌疗效的重要途径。本文总结了目前高危前列腺癌综合治疗的相关文献,期望能为我国高危前列腺癌综合治疗方案的选择提供借鉴和参考。     

Noninterferon-based adjuvant therapy for high-risk melanoma

High-dose interferon is the only treatment approved by the FDA for adjuvant therapy of melanoma. However, its efficacy in this setting is questionable and its administration is associated with considerable toxicity. Many new agents are being tested clinically that hold the promise of greater efficacy and less toxicity but none of these have yet shown efficacy in controlled trials. These include biologics such as vaccines, cytokines, monoclonal antibodies, gene transfer, cellular therapies and angiogenesis inhibitors as well as chemotherapy combinations.     

Synchronous high-risk melanoma and lymphoid neoplasia

Large population-based studies have shown a significant association between melanoma and lymphoid neoplasia, particularly non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukaemia (CLL), that is independent of any treatment received for the initial tumour. This study examines the presentation, diagnosis, treatment and progress of three patients who developed advanced melanoma concurrently with a lymphoid neoplasm (one NHL, two CLLs), in order to illustrate their association, discuss common aetiological factors and examine possible therapeutic options. As it is the melanoma rather than the lymphoid neoplasm that represents the bigger threat to overall survival, initial treatment should be targeted towards this cancer. However, because of the interplay between the diseases and the possible side-effects of the various treatments, the choice of adjuvant therapy requires careful consideration. Immunosuppression associated with chemotherapy may permit a more aggressive course for the melanoma, while locoregional radiotherapy is contraindicated following lymph node dissections. As immunotherapy is of benefit in the treatment of melanoma and has also been recently shown to be effective in the management of lymphoid neoplasia, we instituted interferon-alpha as adjuvant therapy for these patients, thereby utilizing a single agent to treat the dual pathologies. The three patients have now been followed-up for 6 months without evidence of disease recurrence or progression.     

Lung cancer screening in high-risk populations

Although the number of smokers per capita has declined appreciably in the United States in the past 30 years, smokers still make up about one quarter of the adult population. It does not appear that the number of US smokers will decrease further in the next century, and the number may even increase due to the popularity of smoking among teenagers. Epidemiological data indicate that women are more susceptible, dose-for-dose, to the adverse effects of tobacco smoke. Since women make up a large percentage of today s smokers, lung cancer rates may increase in the future. Current guidelines recommend against lung cancer screening based on chest x-ray and sputum morphology; however, new highly sensitive detection methods are available that may make screening more effective, especially if combined with analysis of risk factors for lung cancer and biomarkers of damage to the airways that may identify individuals at highest risk for lung malignancies. Lung cancer will continue to be a major public health problem in the next century. Advances in the field of early detection may make lung cancer screening practical and effective in the near future.     

Management of the high-risk patient.

While breast cancer is affecting American women at an epidemic rate, certain patients are identified as being at particularly high risk because of environmental, endocrine, genetic, and pathologic risk factors. Risk assessment, dietary, and psychological counseling, as well as breast cancer screening, are the function of a high-risk breast cancer program. Our own program is discussed.     

Radical prostatectomy for high-risk prostate cancer

Treatment for high-risk prostate cancer(PCa)(cT3 PCa, Gleason score 8-10 or PSA>20 ng/mL)remains controversial. Radiotherapy with androgen deprivation therapy(ADT)is widely used for high-risk prostate cancer. However, there is a considerable overlap of outcomes among risk groups, suggesting that the so-called high-risk prostate cancer group consists of a heterogeneous population in terms of tumor biology. Actually, the over-staging of cT3a PCa is relatively frequent and occurs in 13-27%of cases. Thus, radical prostatectomy(RP)alone is a reasonable treatment option for selected patients with high-risk prostate cancer. RP can provide an excellent biochemical and clinical progression-free survival for these patients if they have a pathologically organ-confined disease, or their tumors are extirpated completely with a negative surgical margin. A thorough preoperative evaluation, including imaging study and the use of a nomogram, is mandatory for selecting candidates appropriate for RP. Our recent study indicates that a positive biopsy core percentage is a strong independent predictor of organ-confined disease in these high-risk patients. In cases of adverse tumor characteristics, such as positive surgical margin, extraprostatic extension and seminal vesicle invasion, the patient must be informed of the likelihood of a multimodal approach. The use of adjuvant radiotherapy may be reasonable after recuperation from surgery. Immediate ADT may be indicated for those with positive pelvic lymph node.     

Prognostication of the high-risk WM patient

Waldenström's macroglobulinemia is characterized by a protracted course in most patients and the median survival may be long. However, a subset of patients may present with more aggressive disease that is associated with short survival. In order to better characterize these “poor-risk” patients, we identified patients who died within 2 years from the initiation of front-line treatment. These patients were older and had more often features of aggressive disease, such as elevated LDH and low serum albumin than the standard-risk population. Furthermore, only a minority of poor-risk patient had a response to initial therapy. However, conventional clinical factors or even the lack on response could not adequately identify poor-risk patients, indicating the need for novel molecular or other markers that would be able to effectively recognize patients at greatest need for aggressive therapies.     

Adjuvant chemotherapy for high-risk endometrial cancer

Identification of histopathologic factors that predict the risk of tumor recurrence allows for selection of women with endometrial cancer who might benefit from adjuvant therapy. Most studies of adjuvant treatment have focused on external-beam irradiation or oral progestational agents and have failed to document a survival advantage for treated patients. Although recurrent or metastatic endometrial tumors often respond to salvage treatment with cytotoxic agents, there is relatively little experience with postoperative systemic chemotherapy used in an adjuvant setting. A few nonrandomized trials-using doxorubicin/platinum-based regimens-have suggested that adjuvant chemotherapy may be beneficial in some patient subsets. Data from larger-scale, randomized trials do not exist. Additional clinical experience is needed before a definite role for adjuvant chemotherapy can be established.