自体造血干细胞移植联合利妥昔单抗治疗CD+20B细胞淋巴瘤

 采用自体造血干细胞移植（AHSCT）治疗中,高危侵袭性淋巴瘤已获得了较好疗效,但仍有部分移植患者因复发而死亡。复发的根源主要为微小残留病变,包括体内残留的肿瘤细胞和移植物中的肿瘤细胞污染。利妥昔单抗可靶向性清除CD+20 B细胞,因此,对CD+20 B细胞淋巴瘤患者,移植前后应用利妥昔单抗可起到体内净化和清除残留病灶作用,AHSCT联合利妥昔单抗有望进一步提高CD+20 B细胞淋巴瘤的疗效。     

6D image guidance for spinal non-invasive stereotactic body radiation therapy: Comparison between ExacTrac X-ray 6D with kilo-voltage cone-beam CT

Purpose

To investigate setup discrepancies measured with ExacTrac X-ray 6 degree-of-freedom (6D) and cone-beam computed tomography (CBCT) for patients under treatments of stereotactic body radiation therapy (SBRT).

Materials and methods

In this work, phantom and patient studies were performed. In the phantom studies, an anthropomorphic phantom was placed with pre-defined positions, and imaged with ExacTrac X-ray 6D and CBCT to test the accuracy of the imaging systems. In the patient studies, 16 spinal SBRT patient cases were retrospectively analyzed. The patients were initially positioned in customized immobilization cradles and then aligned with ExacTrac X-ray 6D and CBCT. The setup discrepancies were computed and quantitatively analyzed.

Results

This study indicates modest discrepancies between ExacTrac X-ray 6D and CBCT with spinal SBRT. The phantom experiments showed that translational and rotational discrepancies in root-mean-square (RMS) between ExacTrac X-ray 6D and CBCT were, respectively, <1.0 mm and <1°. In the retrospective patient studies, translational and rotational discrepancies in RMS between ExacTrac X-ray 6D and CBCT were <2.0 mm and <1.5°.

Conclusions

ExacTrac X-ray 6D represents a potential alternative to CBCT; however, pre-caution should be taken when only ExacTrac X-ray 6D is used to guide SBRT with small setup margins.     

Sacral chordomas: Impact of high-dose proton/photon-beam radiation therapy combined with or without surgery for primary versus recurrent tumor

PURPOSE: To assess the efficacy of definitive treatment of sacral chordoma by high-dose proton/photon-beam radiation therapy alone or combined with surgery. METHODS AND MATERIALS: The records of 16 primary and 11 recurrent sacral chordoma patients treated from November 1982 to November 2002 by proton/photon radiation therapy alone (6 patients) or combined with surgery (21 patients) have been analyzed for local control, survival, and treatment-related morbidity. The outcome analysis is based on follow-up information as of 2005. RESULTS: Outcome results show a large difference in local failure rate between patients treated for primary and recurrent chordomas. Local control results by surgery and radiation were 12/14 vs. 1/7 for primary and recurrent lesions. For margin-positive patients, local control results were 10 of 11 and 0 of 5 in the primary and recurrent groups, respectively; the mean follow-up on these locally controlled patients was 8.8 years (4 at 10.3, 12.8, 17, and 21 years). Radiation alone was used in 6 patients, 4 of whom received > or =73.0 Gy (E); local control was observed in 3 of these 4 patients for 2.9, 4.9, and 7.6 years. CONCLUSION: These data indicate a high local control rate for surgical and radiation treatment of primary (12 of 14) as distinct from recurrent (1 of 7) sacral chordomas. Three of 4 chordomas treated by > or =73.0 Gy (E) of radiation alone had local control; 1 is at 91 months. This indicates that high-dose proton/photon therapy offers an effective treatment option.     

Value of routine follow-up procedures for patients with stage I/II cervical cancer treated with combined surgery-radiation therapy.

BACKGROUND: The aim of this study was to determine the value of routine follow-up for the detection of recurrence in patients treated for cervical cancer. PATIENTS AND METHODS: From 1986 to 1998, 583 women with stage I and II cervical carcinoma were treated with combined surgery-radiation therapy. After treatment, follow-up was based on clinical examination, a systematic Pap smear and radiography (chest X-ray and abdomino-pelvic ultrasonography). RESULTS: Forty-five patients had recurrence observed with a delay > or = 6 months following the end of treatment. Thirty-eight patients had symptoms and seven were asymptomatic at the time of their recurrence. Among asymptomatic patients only two recurrences were diagnosed following routine examinations. Survival is similar in asymptomatic and symptomatic recurrent patients. CONCLUSIONS: In conclusion, follow-up of patients treated for cervical cancer based on routine Pap smears and systematic radiography does not permit earlier detection of recurrence and does not increase survival.     

Primary hepatocellular cancer in the explanted liver: outcome of transplantation and risk factors for HCC recurrence.

AIM: To evaluate the risk of recurrence of hepatocellular cancer (HCC) after liver transplantation (LT). METHODS: The clinical records of 104 patients with HCC in the explanted liver were examined. RESULTS: HCC recurrence occurred in 12 patients. Recurrence was observed in all patients with a single nodule greater than 5 cm. Among the 5 patients with more than 3 tumours with a maximum diameter of 4.5 cm, no recurrence occurred. The survival rates were 81% and 64% at 1 and 5 years, respectively; the recurrence-free survival at 1 and 5 years was, respectively, 93% and 82%. Pre-LT alpha-fetoprotein (AFP) increased at a greater magnitude in patients who experienced recurrence, compared to those who did not. Tumour diameter, differentiation, satellitosis, AFP and the magnitude of AFP increase were predictive of recurrence. The 1- and 5-year recurrence-free survival for the 68 patients who had a single nodule up to 5 cm, or up to 3 nodules all less than 4.5 cm and with a maximum cumulative diameter of 8 cm, or more than 3 nodules all less than 2.5 cm, were 95% and 92%, respectively. For the 13 patients not meeting these criteria, the 1- and 5-year recurrence-free survival was, respectively, 75% and 54% (log Rank test p=0.019). CONCLUSIONS: Patients with more than 3 small HCC nodules before LT could still have a good outcome without recurrence. A rapid increase in AFP could be useful in identifying patients with a greater risk of post-LT HCC recurrence.     

Results of radiation therapy combined with neoadjuvant hormonal therapy for stage III prostate cancer: comparison of two different definitions of PSA failure

Background We herein report the clinical outcome of radical radiation therapy combined with neoadjuvant hormonal therapy (NHT) for stage III (International Union Against Cancer [UICC] 1997: UICC 97) prostate cancer. Prostate-specific antigen (PSA) failure-free survival was assessed according to two different definitions, and the appropriateness of each definition is discussed. Methods Between October 1997 and December 2000, 27 patients with stage III prostate cancer were enrolled in this study. The median pretreatment PSA level was 29 ng/ml (range, 7.4–430 ng/ml). The Gleason score (GS) was 7 or more in 22 patients (81%). All patients received 3 months of NHT with a luteinizing hormone-releasing hormone (LH-RH) analogue, in combination with an antiandrogen (flutamide), given during the first 2 weeks, followed by 70-Gy external-beam radiation therapy (EBRT) in 35 fractions. The initial 46 Gy was given with a four-field technique, while the remainder was given with a dynamic conformal technique. No adjuvant hormonal therapy (AHT) was given. Results The median follow-up time was 63 months. PSA levels decreased to the normal range (<4 ng/ml) after irradiation in all but one patient. The 5-year PSA failure-free survival was 34.8% according to the American Society for Therapeutic Radiology and Oncology (ASTRO) definition and it was 43.0% according to the “nadir plus 2” definition. Discordance of the results between the two definitions was seen in two patients. The 5-year overall and cause-specific survivals were 83.0% and 93.3%, respectively. No severe acute or late adverse effects were observed. Conclusion Seventy Gy of EBRT following 3 months of NHT produced therapeutic results comparable to those reported in other studies which used long-term AHT. The value of long-term AHT for Japanese men should be tested in a clinical trial.     

Non-human to human organ transplantation: its biologic basis and a potential role for radiation therapy

There is an inadequate supply of human donor organs for transplantation. Xenotransplantation, the transplantation of organs from non-human animals to humans, is one of the potential solutions to this problem. The pig appears to be the preferred donor. For xenotransplantation to be successful, researchers must deal with three fundamental problems: (1) Hyperacute rejection of porcine organs, related to binding of xenoreactive natural antibodies of the recipient to antigens on the graft's endothelial cells, must be overcome. (2) Transmission of animal pathogens to humans must be prevented. Concern about zoonosis is not only directed to the transplant recipient but also concerns the risk that an infectious agent will be transferred from the recipient to the general population. (3) The xenografted organ must be physiologically compatible with the recipient. The physiological function of a pig organ in a human and its ability to sustain a human are problematic. Total lymphoid irradiation (TLI) and thoraco-abdominal irradiation (TAI) as immunosuppressive modalities have been investigated in rodent-to-rodent, large mammals and non-human primates-to-primates, and pig-to-primate models. In certain clinical situations, TLI and TAI may prove to be important components for the preparation of the xenotransplant recipient. Progress in genetic engineering and cloning may soon lead to clinical trials in xenotransplantation.     

Feasibility of combined modality therapy for localized high-grade soft tissue sarcomas in adults.

Seventeen consecutive patients with localized, high grade soft tissue sarcomas had resection of their primary tumor, radiation therapy and chemotherapy. The soft tissue sarcoma was primary in 14 patients and regionally recurrent in 3 patients. Chemotherapy consisted of cyclophosphamide 500 Mg/M² day 1, Adriamycin (ADR) 60 mg/M² day 2, and DTIC 400 Mg/M² days 1 and 2, given every 21 days to a maximum ADR dose of 450 mg/M². Cyclophosphamide and DTIC were then given to a total duration of 1 year. Radiation therapy consisted of 4000–5000 rad by megavoltage photons in 5 weeks, and in selected cases, an additional 1500–2000 rad by electron beam boost in the tumor bed delivered over 2 additional weeks. Following surgery, 12 patients were treated sequentially with an interval of chemotherapy, radiation therapy and then the completion of chemotherapy.The added morbidity of this sequential approach is minimal: one patient of 12 had delayed primary healing of her wound, 1 of 10 patients required a break in radiation therapy because of skin erythema. Four patients were treated with intensive pre-chemotherapy radiation therapy because of inadequate surgical margins. The median time on study was 18 months from onset of treatment (range, 8–41 months). Although there have been no local, regional or distant recurrences, the follow-up time is inadequate to assess the therapeutic benefit of this combined modality treatment.     

CDK4/6抑制剂联合内分泌治疗晚期乳腺癌

内分泌治疗因疗效显著并具有安全性,是激素受体阳性(HR+)晚期乳腺癌患者的主要治疗方法。近年来内分泌领域发展迅速,如何延迟或逆转内分泌耐药及内分泌治疗新药物成为临床研究关注的焦点。研究发现,内分泌治疗耐药可能与CDK-RB-E2F通路有关,针对该通路的细胞周期蛋白依赖性激酶(CDK)4/6抑制剂可显著延缓HR+晚期乳腺癌患者内分泌耐药。CDK4/6抑制剂与内分泌药物联合使用,可提高HR+晚期乳腺癌患者的治疗客观缓解率,并可显著改善无进展生存期(PFS)。现就CDK4/6抑制剂的作用机制、药物有效性和安全性及相关临床试验做一综述。     

Proton beam therapy for invasive bladder cancer: a prospective study of bladder-preserving therapy with combined radiotherapy and intra-arterial chemotherapy

PURPOSE: To present outcomes of bladder-preserving therapy with proton beam irradiation in patients with invasive bladder cancer. METHODS AND MATERIALS: Twenty-five patients with transitional cell carcinoma of the urinary bladder, cT2-3N0M0, underwent transurethral resection of bladder tumor(s), followed by pelvic X-ray irradiation combined with intra-arterial chemotherapy with methotrexate and cisplatin. Upon completion of these treatments, patients were evaluated by transurethral resection biopsy. Patients with no residual tumor received proton irradiation boost to the primary sites, whereas patients demonstrating residual tumors underwent radical cystectomy. RESULTS: Of 25 patients, 23 (92%) were free of residual tumor at the time of re-evaluation; consequently, proton beam therapy was applied. The remaining 2 patients presenting with residual tumors underwent radical cystectomy. Of the 23 patients treated with proton beam therapy, 9 experienced recurrence at the median follow-up time of 4.8 years: local recurrences and distant metastases in 6 and 2 patients, respectively, and both situations in 1. The 5-year overall, disease-free, and cause-specific survival rates were 60%, 50%, and 80%, respectively. The 5-year local control and bladder-preservation rates were 73% and 96%, respectively, in the patients treated with proton beam therapy. Therapy-related toxicities of Grade 3-4 were observed in 9 patients: hematologic toxicities in 6, pulmonary thrombosis in 1, and hemorrhagic cystitis in 2. CONCLUSIONS: The present bladder-preserving regimen for invasive bladder cancer was feasible and effective. Proton beam therapy might improve local control and facilitate bladder preservation.     

High-dose therapy and autologous stem cell transplantation for chemoresistant Hodgkin lymphoma: the Seattle experience

BACKGROUND.: High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the standard treatment for patients with chemosensitive relapsed/refractory Hodgkin lymphoma (HL), but this therapy is commonly denied to patients with resistant disease. We explored the utility of HDT and ASCT for chemoresistant HL because there are few established therapies for these patients. METHODS.: Sixty-four chemoresistant HL patients underwent HDT followed by ASCT at our center. Baseline characteristics included median age = 35 years (range, 14-59 years), stage III/IV = 49 (77%), nodular sclerosis histology = 51 (80%), and prior radiation = 32 (50%). Twenty-six patients (41%) received total body irradiation (TBI)-based regimens, and 38 (59%) underwent non-TBI conditioning. RESULTS.: The estimated 5-year overall survival (OS) and progression-free survival (PFS) were 31% and 17%, respectively (median follow-up = 4.2 years). Multivariate analysis only identified year of transplant as independently associated with improved OS (P = .008) and PFS (P = .04), with patients receiving transplants in later years having better outcome. The probabilities of 3-year PFS for patients receiving transplants during 1986 to 1989, 1990 to July 1993, August 1993 to 1999, and 2000 to 2005 were 9%, 21%, 33%, and 31%, respectively. CONCLUSIONS.: These data suggest that HDT and ASCT may result in prolonged remissions and survival for a subset of chemoresistant HL patients, with improved outcomes in patients receiving transplants more recently. Cancer 2008. (c) 2008 American Cancer Society.     

Pomalidomide,Cyclophosphamide, and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma: Real-World Analysis of the Pethema-GEM Experience

IntroductionTreatment of relapsed/refractory multiple myeloma (RRMM) is highly challenging, especially for patients with disease refractory to initial therapy, and in particular for disease developing refractoriness to lenalidomide. Indeed, with currently approved treatments, median progression-free survival (PFS) in the lenalidomide-refractory setting is less than 10 months, reflecting the difficulty in treating this patient population. Pomalidomide is a second-generation immunomodulatory drug that has shown activity in lenalidomide-refractory disease in the setting of different combinations.Patients and MethodsA real-world study was conducted by the Spanish Myeloma group in a cohort of patients with RRMM treated with pomalidomide, cyclophosphamide, and dexamethasone (PomCiDex). One hundred patients were treated with a median of 3 prior lines of therapy.ResultsOverall response rate was 39%, with a clinical benefit rate of 93%. Median PFS was 7.6 months; median overall survival (OS) was 12.6 months. Median PFS and OS survival were consistent across the different subgroups analyzed. Prolonged PFS and OS were found in patients with responsive disease.ConclusionOur results compared favorably with those obtained with different pomalidomide-based combinations in a similar patient population. PomCiDex remains a manageable, cost-effective, and all-oral triplet combination for RRMM patients.     

Unexpected toxicity of combined modality therapy for small cell carcinoma of the lung. A Southwest Oncology Group study.

Combination chemotherapy with cyclophosphamide, vincristine, methotrexate and Adriamycin was delivered to 35 patients with small-cell carcinoma of the lung (28 with extenstive and 7 with limited disease), including elective administration of intrathecal methotrexate. Whole-brain irradiation (3000 rad in 10 fractions) was then administered, with concomitant systemic cyclophosphamide and methotrexate for patients with extensive disease. Those with limited disease received concomitant chest irradiation without chemotherapy. Maintenance therapy then involved cyclophosphamide 750 mg/m² day 1, and methotrexate 30 mg/m²days 1 and 8, every 3 weeks. In only 2 patients reinduction was carried out at 24 weeks with the original chemotherapy.Myelosuppression was severe; there were at least 2 drug-related deaths from this cause in the induction period, and 15 febrile episodes with leukopenia. Stomatitis was more frequent and more severe in “maintenance” than in “induction” courses, especially the first maintenance course which was given with concomitant whole-brain irradiation. In addition, 13 episodes of unusual toxicity occurred in close temporal relation to systemic methotrexate administration, usually associated with stomatitis, in patients who were on maintenance therapy. These included 3 episodes of loss of consciousness, 4 of generalized erythroderma, 2 of “flu”-like syndrome, and I each of the following: fatal, bilateral interstitial pneumonia; reversible, eosinophilic pleural effusion; acute myocardial infarction; and renal compromise with hematuria. As a result of this unexpected and protean toxicity, the pilot study was discontinued. However, at this time seven patients (4 with extensive and 3 with limited disease) remain in complete remission.     

内皮分化基因受体介导溶血磷脂酸：肿瘤靶向治疗的新靶点

溶血磷脂酸(lysophosphatidic acid,LPA)是一种对多种细胞具有不同生物学活性的磷脂介质,在组织中广泛存在.从细胞形态学改变到细胞功能的影响,LPA可产生如促进细胞增殖、迁移和耐药等生物学效应.如其他生物递质一样,LPA与细胞表面特定的G蛋白偶合受体(Gprotein-coupled receptor,GPCR)发生交联作用,这些受体主要有Edg-2/LPA1、Edg-4/LPA2和Edg-7/LPA3等,它们被命名为内皮分化基因或溶血磷脂受体亚家族(endothelial differentiation gene or lysophospholipid receptor subfamily,Edg/LPAR subfamily).LPA在体内外参与细胞增殖以及血管生成等病理生理过程,LPA代谢和Edg/LPA受体功能的异常与肿瘤的发生、发展相关,可能是肿瘤临床诊治的潜在靶点.本文阐述了LPA通过Edg/LPA受体介导在肿瘤发生和发展中的作用及其机制,并就其在胰腺癌临床诊治中的意义进行了评价.     

Nanoliposome-mediated FL/TRAIL double-gene therapy for colon cancer: in vitro and in vivo evaluation

Objective

To investigate the therapeutic effects of cationic nanoliposome-mediated gene therapy combined with immunotherapy for colon cancer treatment.

Methods

Recombinant plasmids containing green and red fluorescent protein reporter genes were constructed using gene cloning methods. Gene-carrying cationic nanoliposomes were prepared based on the electrostatic adherence principle and then transfected into dendritic cells (DC), which were transplanted into colon cancer cells.

Results

Recombinant plasmids containing green or red fluorescent protein reporter genes were successfully constructed by gene cloning and confirmed by restriction enzyme digestion and sequencing. Gene-carrying cationic nanoliposomes were transfected into colon cancer cells, and good gene expression was detected. A better level of apoptosis was observed in the combined group of tyrosine kinase receptor 3 ligand (FL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), while the lowest level was detected in the control group. The parameters in the FL and TRAIL groups were between the above-mentioned combined group.

Conclusion

Cationic nanoliposomes have the advantage of being gene carriers. The joint therapeutic effects of the two genes are superior to those of a single gene. Gene therapy combined with immunotherapy has significant implications for cancer treatment.