多西紫杉醇联合氟尿嘧啶及顺铂治疗晚期胃癌

 目的 观察国产多西紫杉醇（TAT）联合亚叶酸钙／5-氟尿嘧啶（CF／5Fu）及顺铂（DDP）治疗晚期胃癌的临床疗效与不良反应。方法 41例晚期胃癌患者接受TAT与CF／5-Fu及DDP联合化疗：TAT75mg／m2，静滴1h，d1；CF100mg，静滴2h，d1-5；5-Fu500mg／m2，22h微泵持续静滴，d1-5；DDP25mg／m2，静滴，d，1-3。28天为一个周期。治疗2个周期后评价疗效和不良反应。结果 41例患者均可评价疗效。完全缓解2例，部分缓解23例，有效率61．0％。中位疾病进展时间7．5个月，中位生存期10．6个月，1年生存率41．5％。主要不良反应为骨髓抑制，脱发和周围神经炎。结论 国产多西紫杉醇联合亚叶酸钙／5-氟尿嘧啶及顺铂治疗晚期胃癌缓解率高，毒副反应可以耐受。     

低剂量5-氟尿嘧啶持续静注联合顺铂治疗晚期胃癌的临床研究

目的 :评价低剂量 5 氟尿嘧啶 (5 FU)持续滴注联合顺铂 (DDP)治疗晚期胃癌的疗效及其毒副作用。方法 :4 3例晚期胃癌 ,应用 5 FU 2 5 0mg m2 ·d ,经静脉微量泵持续 2 4小时注射 (civ) ,DDP 6mg m2 ·d ,1小时 ,每周 5天 ,均连用 3周 ;间隔1周后重复。化疗 2周期为 1疗程 ,按WHO标准评价疗效和毒性。结果 :4 3例中有 32例可以进行评价 ,其中CR 2例 (6 3% ) ,PR 11例 (34 4 % ) ,NC 7例 (2 1 9% )和PD 12例 (37 5 % ) ,总有效率 4 0 7% ;毒副反应主要为消化道反应 ,骨髓抑制较轻。结论 :低剂量 5 FU持续静注加顺铂方案是一个有效而低毒的方案 ,适用于晚期胃癌患者     

The Influence of Systemic Inflammation on Treatment Response and Survival in Anal Squamous Cell Cancer

AimsThe incidence of anal squamous cell cancer (SCCA) is rising. Although chemoradiotherapy (CRT) provides a chance of cure, a proportion of patients have an incomplete response or develop recurrence. This study assessed the value of inflammation-based prognostic indicators, including the modified Glasgow Prognostic Score (mGPS) and neutrophil:lymphocyte ratio (NLR), in patients with SCCA treated by CRT with curative intent.Material and methodsPatients with histologically confirmed SCCA were identified from pathology records. Medical records were retrospectively reviewed and clinical, pathological and treatment characteristics were abstracted. The mGPS (0 = normal C-reactive protein [CRP] and albumin, 1 = CRP >10 mg/l and 2 = CRP >10 mg/l and albumin <35 mg/l) and NLR were calculated from routine blood tests obtained prior to CRT.ResultsIn total, 118 patients underwent CRT for SCCA between December 2007 and February 2018. Of these, 99 patients had appropriate pretreatment blood results available. Systemic inflammation as indicated by NLR >3 and mGPS >0 was present in 41% and 39% of patients, respectively. Most patients had T2 or larger tumours (n = 85, 86%) without nodal involvement (n = 64, 65%). An elevated mGPS was associated with more advanced T-stage (56% versus 35%, P = 0.036). NLR >5 was associated with nodal positivity (56% versus 31%, P = 0.047). On multivariate analysis, more advanced T-stage (odds ratio 7.49, 95% confidence interval 1.51–37.20, P = 0.014) and a raised mGPS (odds ratio 5.13, 95% confidence interval 1.25–21.14, P = 0.024) were independently related to incomplete CRT response. An elevated mGPS was prognostic of inferior survival (hazard ratio 3.09, 95% confidence interval 1.47–6.50, P = 0.003) and cancer-specific survival (hazard ratio 4.32, 95% confidence interval 1.54–12.15, P = 0.006), independent of TNM stage.ConclusionSystemic inflammation, as measured by the mGPS, is associated with an incomplete CRT response and is independently prognostic of inferior survival in patients with SCCA. The mGPS may offer a simple marker of inferior outcome that could be used to identify high-risk patients.     

晚期肺鳞癌的治疗

肺癌是全世界肿瘤死亡的首要原因,肺鳞癌（squamous cell lung cancer, SQCLC）作为肺癌的一种常见的病理类型,全世界每年约40余万人因其致死。其常规治疗方法主要包括手术治疗、化学治疗和分子靶向治疗。但是大多数患者确诊的时候已经是晚期,失去了手术的机会。尽管分子靶向治疗在肺腺癌的治疗中具有里程碑式的作用,但是对肺鳞癌而言,尚无特异性的分子靶标药物,因此,对于晚期肺鳞癌的标准治疗仍是含铂双药方案。而大多数患者经历了一线、二线治疗失败后都面临无药可用的状态。本文旨在对晚期肺鳞癌的常规治疗进行系统性的综述,探讨晚期肺鳞癌的治疗方案以及发展方向。     

PFC方案治疗晚期食管贲门癌的临床观察

目的：观察PFC方案（紫杉醇联合氟尿嘧啶和顺铂）治疗晚期不能手术或手术未能完全切除及术后复发的食管癌和贲门癌患者的疗效和毒性。方法：41例患者分别接受PFC方案化疗2～6周期,按WHO标准评价疗效及毒副反应。结果：41例均可评价,其中完全缓解（CR）3例7．3％,部分缓解（PR）18例43．9％,稳定（SD）15例36．6％,进展（PD）5例12.2％。中位疾病进展时间为7．9个月,中位生存时间为11．3个月。结论：PFC方案治疗晚期食管贲门癌患者安全有效,毒副反应较轻。     

小剂量5-FU持续滴注与小剂量PDD联合治疗晚期胃肠道癌35例临床观察

目的　观察和分析小剂量氟脲嘧啶 (5 -FU)与小剂量顺铂 (PDD)联合治疗晚期胃肠道癌的临床疗效和毒副反应。方法　 35例中胃癌 2 2例 ,肠癌 13例。 5 -FU 2 0 0mg/m2 每天 ,持续静滴 3～ 4周 ;PDD 6mg/m2 每天 ,静滴 2小时 ,每周 5天 ,连用 3～ 4周。结果　无CR病例 ,PR17例 ,总有效率为 48 6 %。胃癌有效率为 5 4 6 % ,肠癌有效率为 38 5 % ,用过含 5 -FU方案治疗的患者有效率为43 8%。主要毒性反应为口腔炎、腹泻、恶心、呕吐。骨髓抑制轻 ,多为Ⅰ°～Ⅱ°。绝大多数患者能耐受该方案治疗。结论　作者认为该方案疗效好 ,毒副反应轻 ,治疗费用少 ,便于开展 ,值得临床推广、研究     

草酸铂或顺铂联合氟脲嘧啶及醛氢叶酸治疗晚期胃癌的对比研究

目的：比较L-OHP＋CF＋5-FU方案与DDP＋CF＋5-FU方案对初次化疗的Ⅲ期胃癌患者的疗效、不良反应及生活质量的改善情况。方法：A组（34例）接受L-OHP＋CF＋5-FU方案治疗；B组（36例）接受DDP＋CF＋5-FU方案治疗。两组均以3周为1周期．重复3个周期。客观疗效与不良反应按WHO标准进行评价，生活质量根据临床受益疗效评价。结果：A、B两组客观疗效（CR＋PR）分别为52．9％及50．0％，P〉0．05；白细胞减少及恶心呕吐反应B组均较A组明显（P〈0．01）；外周神经炎A组比B组明显（P〈0．05），但较轻微，均在Ⅰ～Ⅱ度范围内。两组均未发现其他严重的不良反应。临床受益疗效A组高于B组（P〈0．05）。结论：L-OHP＋CF＋5-FU方案与DDP＋CF＋5-FU方案治疗晚期胃癌的客观疗效无明显差异性．但前者耐受性好，患者生活质量改善明显。     

足叶乙甙,顺氯氨铂联合胸部放疗治疗局限性晚期肺鳞癌疗效观察

应用前瞻性研究方法，对５３例（Ⅲａ２０例，Ⅲｂ期３３例）局限性晚期未行手术治疗的肺鳞癌患者采用足叶乙甙及顺氯氨铂化疗，并加用胸部６０Ｃｏ照射。平均接受化疗２．４疗程，放疗总量６０Ｇｙ。结果：２例完全缓解（ＣＲ），２３例部分缓解（ＰＲ），总有效率４７．２％（ＣＲ＋ＰＲ），中位生存期１５．８个月，平均缓解期７．５个月。化疗中出现恶心、呕吐Ⅰ度者９例，Ⅱ度者４例，粒细胞减少Ⅰ度者７例，Ⅱ度者６例，Ⅲ度者１例。连续放疗组中发生放射性肺炎者占２８．２％（１１／３９），放射性心肌心包炎１例，分段放疗组中无此类副作用，认为该方案治疗肺鳞癌效果显著，分段放疗可减少副作用且疗效不受影响。     

Impact of Time to Treatment Initiation in Patients with Human Papillomavirus-positive and -negative Oropharyngeal Squamous Cell Carcinoma

Aims

The distinct difference in disease phenotype of human papillomavirus-positive (HPV+) and -negative (HPV–) oropharyngeal squamous cell cancer (OPSCC) patients might also be apparent when assessing the effect of time to treatment initiation (TTI). We assessed the overall survival and progression-free survival (PFS) effect from increasing TTI for HPV+ and HPV– OPSCC patients.

奥沙利铂联合氟脲嘧啶与甲酰四氢叶酸治疗晚期大肠癌临床观察

目的：观察奥沙利铂联合化疗治疗晚期大肠癌的临床疗效。方法：33例晚期大肠癌患者，用奥沙早铂（Oxaliplatin,L-OHP由法国赛诺菲公司生产，商品名为乐沙定Eloxatin)130mg/m^2，静脉滴注2小时；甲酰四氢叶酸（CF）200mg/m^2，静脉滴注2小时；5－氟脲嘧啶（5－FU）0.5g在CF滴完后静推，然后5－FU3.0g/m^2用一次性便携式静脉输液器持续静脉滴注48小时，每3周1重复1次，治疗2周期后评定疗效，有效病例在4周后确认疗效。结果：33例中CR3例，PR13例，SD13例，PD4例，总有效率（CR＋PR）48．5％。毒副作用主要是Ⅰ-Ⅱ度恶心呕吐，腹泻，感觉神经毒性，粘膜炎，骨髓抑制，静脉炎等。结论：奥沙利铂联合5－FU＋CF治疗晚期大肠癌效果良好，不良反应能耐受，值得临床推广使用。     

丝裂霉素、5-氟脲嘧啶、顺铂联合治疗晚期胃癌的临床观察

目的探讨性研究晚期胃癌的姑息性联合化疗方案。方法自1992年3月至1996年12月,我们采用丝裂霉素（MMC）、5-氟脲嘧啶（5－Fu）和顺铂（DDP）联合化疗方案治疗晚期胃癌35例。结果近期总有效率（CR＋PR）为68．57％,其中CR8．57％,PR60％;中位生存时间（MST）13．5月;1、2、3、5年生存率分别为82．75％、22．85％、7．62％和7．62％。消化道反应和骨髓抑制轻微,但有一定的心脏毒性反应和相关感染发生。结论本MFP方案疗效较满意,毒副反应轻,建议在晚期胃癌患者中应用,尤以低分化腺癌者较为适用。     

肺鳞癌与人乳头瘤病毒相关性研究

目的:了解肺鳞癌组织中人乳头瘤病毒存在情况,并分析人乳头瘤病毒与肺癌发生部位、性别因素、角化程度、吸烟因素的关系.方法:采用地高辛标记的DNA探针对肺癌组织进行原位杂交检测,同时结合临床资料分析多种因素的相关性.结果:肺鳞癌组织,鳞状上皮生化组织、粘膜慢性炎组织HPV检出率分别为48.4%,27.4%,5.6%,各组比较差异显著(P＜0.01),中心型肺癌与周围型肺癌组织HPV检出率分别为50.6%和4.4%,两组比较差异显著(P＜0.01).男女两组HPV检出率分别为46.1%和54.3%,差异无显著性(P＞0.05).吸烟组HPV检出率为50.6%,非吸烟组为43.9%,差异不显著(P＞0.05).结论:肺癌组织中存在一定比例HPV感染,HPV感染与肺鳞癌关系密切,中心型肺癌与HPV感染密切相关,HPV感染与性别及吸烟因素未发现明显相关性.人乳头瘤病毒感染可能与肺癌发生发展有关.     

Positron Emission Tomography-Computed Tomography Surveillance after (Chemo)Radiotherapy in Advanced Head and Neck Squamous Cell Cancer: Beyond the PET-NECK Protocol

AimsTo evaluate the implementation of 18-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) surveillance after (chemo)radiotherapy, to compare outcomes for those who achieved a complete (CR), equivocal (EQR) and incomplete (ICR) nodal response on 12-week PET-CT according to their human papillomavirus (HPV) status, and to assess the safety of ongoing surveillance beyond 12 weeks in the HPV-positive EQR group.Materials and methodsAll patients with node-positive head and neck squamous cell carcinoma (HNSCC) treated with (chemo)radiotherapy between January 2013 and September 2017 were identified. PET-CT responses were classified as CR, ICR or EQR. Patient outcomes were obtained from electronic records.ResultsIn total, 236 patients with a minimum of 2 years of follow-up were identified. The mean age was 59 years; 79.3% had N2 disease; 77.1% of patients had oropharyngeal cancer and 10.1% had squamous cell carcinoma of unknown primary, of whom 82.0% (169) were HPV positive; 78.0% received chemoradiotherapy. The median time from the end of radiotherapy to PET-CT was 91 days. Of the HPV-related HNSCC, 60.4% achieved CR, 29.0% EQR and 10.6% ICR. With a median follow-up of 41.7 months, there was no difference in survival between patients with HPV-related HNSCC achieving CR and EQR (median overall survival not reached for both, P = 0.67) despite the omission of immediate neck dissection in 98.0% of the EQR group.ConclusionPatients with HPV-positive HNSCC who have achieved EQR have comparable survival outcomes to those who achieved a CR despite the omission of immediate neck dissections; this shows the safety of ongoing surveillance beyond 12 weeks in this group of patients.     

Comprehensive Genomic Profiling of Advanced Esophageal Squamous Cell Carcinomas and Esophageal Adenocarcinomas Reveals Similarities and Differences

Background.

Esophageal squamous cell carcinomas (ESCCs) and esophageal adenocarcinomas (EACs) account for >95% of esophageal malignancies and represent a major global health burden. ESCC is the dominant histology globally but represents a minority of U.S. cases, with EAC accounting for the majority of U.S. cases. The patient outcomes for advanced ESCC and EAC are poor, and new therapeutic options are needed. Using a sensitive sequencing assay, we compared the genomic profiles of ESCC and EAC with attention to identification of therapeutically relevant genomic alterations.

Methods.

Next-generation sequencing-based comprehensive genomic profiling was performed on hybridization-captured, adaptor ligation-based libraries to a median coverage depth of >650× for all coding exons of 315 cancer-related genes plus selected introns from 28 genes frequently rearranged in cancer. Results from a single sample were evaluated for all classes of genomic alterations (GAs) including point mutations, short insertions and deletions, gene amplifications, homozygous deletions, and fusions/rearrangements. Clinically relevant genomic alterations (CRGAs) were defined as alterations linked to approved drugs and those under evaluation in mechanism-driven clinical trials.

Results.

There were no significant differences by sex for either tumor type, and the median age for all patients was 63 years. All ESCCs and EACs were at an advanced stage at the time of sequencing. All 71 ESCCs and 231 EACs featured GAs on profiling, with 522 GAs in ESCC (7.4 per sample) and 1,303 GAs in EAC (5.6 per sample). The frequency of clinically relevant GAs in ESCC was 94% (2.6 per sample) and 93% in EAC (2.7 per sample). CRGAs occurring more frequently in EAC included KRAS (23% EAC vs. 6% ESCC) and ERBB2 (23% EAC vs. 3% ESCC). ESCC samples were enriched for CRGA in PIK3CA (24% ESCC vs. 10% EAC), PTEN (11% ESCC vs. 4% EAC), and NOTCH1 (17% ESCC vs. 3% EAC). Other GAs that differed significantly between histologic tumor types included SMAD4 (14% EAC vs. 1% ESCC), RB1 (14% ESCC vs. 2% EAC), SOX2 (18% ESCC vs. 1% EAC), and NFE2L2 (24% ESCC vs. 1% EAC).

Conclusion.

ESCC and EAC share similarly high frequencies of overall and clinically relevant genomic alterations; however, the profiles of genomic alterations in the two diseases differ widely, with KRAS and ERBB2 far more frequently altered in EAC compared with ESCC and with mammalian target of rapamycin (MTOR) pathway genes (PIK3CA and PTEN) and NOTCH1 more frequently altered in ESCC compared with EAC. Comprehensive genomic profiling highlights the promise of identifying clinically relevant genomic alterations in both ESCC and EAC and suggests new avenues for molecularly directed therapies in esophageal cancer.

Implications for Practice:

Both esophageal squamous cell carcinoma and esophageal adenocarcinoma are aggressive cancers with poor patient response to conventional chemotherapy and radiation treatment. In this study, comprehensive genomic profiling was performed for 302 advanced esophageal cancers, and it was found that the frequently altered genes and biological pathways differed between the two subtypes. Also, a high frequency of clinically relevant genomic alterations was noted for both types of esophageal cancer as a means of finding a potential targeted therapy to be used in addition to or as an alternative to conventional treatment.     

紫杉醇联合顺铂每周方案治疗老年晚期非小细胞肺癌临床观察

背景与目的 肺癌是最常见的恶性肿瘤之一,随着人口老龄化,老年晚期非小细胞肺癌(non-small cell lung cancer,NSCLC)患者的比例逐渐增大,如何给予这些病人最佳的治疗是目前研究的热点.本研究的目的在于观察紫杉醇联合顺铂每周方案一线治疗年龄≥70岁晚期NSCLC患者的疗效和毒副反应.方法 年龄≥70岁初治的晚期NSCLC患者(IIIB和IV期)50例,接受紫杉醇联合顺铂每周方案化疗:紫杉醇(PTX)80 mg/m2加入5%葡萄糖溶液250 mL中静脉滴注1 h,第1,8天,用紫杉醇前常规给予抗过敏预处理;顺铂(DDP)20 mg/m2加入3%氯化钠溶液250 mL中静脉滴注,第1,8天,21天为1周期.结果 共入组50例患者,在可评价疗效的48例患者中,CR 1例,PR 18例,SD 26例,PD 3例,有效率为39.6%,中位生存期为14.8(95%CI:3.2-32.2)个月,1年生存率58.3%,中位疾病进展时间4.5(1.7-7.8)月.主要不良反应是白细胞下降(60%)、贫血(62%)、恶心呕吐(30%)、脱发(100%),未出现与化疗相关的死亡.结论 年龄≥70岁老年晚期非小细胞肺癌(NSCLC)患者可以耐受紫杉醇联合顺铂每周方案化疗,并可以从中获益.     

MVP方案治疗晚期非小细胞肺癌

目的：观察丝裂霉素（ＭＭＣ）、长春花碱酰胺（ＶＤＳ）和顺铂（ＰＤＤ）组成的ＭＶＰ方案治疗非小细胞肺癌的疗效及副作用。方法：４２例晚期非小细胞肺癌患者接受ＭＶＰ方案治疗,每例至少２个周期,按ＷＨＯ疗效及毒性标准进行评价。结果：ＭＶＰ方案对非小细胞肺癌的有效率为４２．９％,主要毒性反应为骨髓抑制,其次为发及周围神经炎,其他系统毒性均较轻。结论ＭＶＰ方案对非小细胞肺癌疗效较高,毒性反应较轻,可以作为治疗     

异环磷酰胺加长春酰胺和顺铂联合治疗晚期非小细胞肺癌

目的:评价异环磷酰胺(IFO)、长春酰胺(VDS)和顺铂(DDP)联合方案(IVP)治疗晚期非小细胞肺癌的疗效和毒副反应.方法:78例非小细胞肺癌均以IVP方案化疗,IFO1.2g/m~2静脉滴注,第1～5天,VDS 2.5mg/m~2静脉滴注,第1、8天,DDP 60～80mg/m~2静脉滴注,第1天.每4周为—周期,2～3个周期后评价疗效.结果:CR3例,PR37例,SD31例和PD7例,总有效率为51.3%,毒副反应主要为骨髓抑制.结论:IVP方案是治疗晚期非小细胞肺癌疗效较好的方案之一,其毒副作用经对症处理后可以克服.     

紫杉醇联合顺铂每周方案治疗老年晚期非小细胞肺癌临床观察

背景与目的肺癌是最常见的恶性肿瘤之一,非小细胞肺癌(Non-small-cell lung cancer,NSCLC)占肺癌总例数的80%.随着人口老龄,晚期老年NSCLC患者的比例逐渐增     

Perfusion Computed Tomography in Predicting Treatment Response of Advanced Esophageal Squamous Cell Carcinomas

Background: The purpose of this study was to prospectively evaluate the predictive value of perfusioncomputed tomography (CT) for response of local advanced esophageal carcinoma to radiotherapy andchemotherapy. Materials and Methods: Before any treatment, forty-three local advanced esophageal squamouscell carcinomas were prospectively evaluated by perfusion scan with 16-row CT from June 2009 to January 2012.Perfusion parameters, including perfusion (BF), peak enhanced density (PED), blood volume (BV), and time topeak (TTP) were measured using Philips perfusion software. Seventeen cases received definitive radiotherapyand 26 received concurrent chemo-radiotherapy. The response was evaluated by CT scan and esophagography.Differences in perfusion parameters between responders and non-responders were analyzed, and ROCs were usedto assess predictive value of the baseline parameters for treatment response. Results: There were 25 responders(R) and 18 non-responders (NR). Responders showed significantly higher BF (R:34.1 ml/100g/min vs NR: 25.0ml/100g/min, p=0.001), BV (23.2 ml/100g vs 18.3 ml/100g, p=0.009) and PED (32.5 HU vs 28.32HU, P=0.003) thannon-responders. But the baseline TTP (R: 38.2s vs NR: 44.10s, p=0.172) had no difference in the two groups.For baseline BF, a threshold of 36.1 ml/100g/min achieved a sensitivity of 56%, and a specificity of 94.4% fordetection of clinical responders from non-responders. Conclusions: The results suggest that the perfusion CTcan provide some helpful information for identifying tumors that may respond to radio-chemotherapy.     

Clinicopathologic Features Associated With Human Papillomavirus/p16 in Patients With Metastatic Squamous Cell Carcinoma of the Anal Canal

Background.

The incidence of anal carcinoma in the U.S. continues to increase steadily, and infection with the human papillomavirus (HPV) is an established risk factor for the development of anal carcinoma. However, the clinicopathologic characteristics of patients with metastatic squamous cell carcinoma of the anal canal according to HPV status have not yet been defined.

Materials and Methods.

The records of patients treated for metastatic squamous cell carcinoma of the anal canal at the MD Anderson Cancer Center from June 2005 to August 2013 were reviewed. The patients were tested for the presence of HPV DNA by in situ hybridization and/or the p16 oncoprotein by immunohistochemistry. Associations between the presence of HPV and clinicopathologic attributes were measured.

Results.

Of the 72 patients reviewed, 68 tumors (94%) had detectable HPV. Patients with HPV-negative tumors were more likely to be of nonwhite ethnicity (odds ratio, 8.7) and have a strong (>30 pack-year) tobacco history (odds ratio, 8.7). A trend toward improved survival from the time of diagnosis of metastatic disease was noted among patients with HPV-positive tumors.

Conclusion.

Most patients with metastatic anal cancer had detectable HPV, with differences in tobacco history and ethnicity detected according to HPV status. The high frequency of HPV positivity for patients with metastatic anal cancer has important implications for novel immunotherapy treatment approaches, including ongoing clinical trials with immune checkpoint blockade agents using antibodies targeting the programmed death-1 receptor.

Implications for Practice:

Previous studies investigating the clinical features of patients with anal cancer focused on those with early-stage disease. The present study characterizes, for the first time, clinical and pathological features according to human papillomavirus (HPV) status for patients with metastatic anal cancer. A high frequency of HPV-positive tumors and correlations between HPV status and both ethnicity and tobacco history was found. No standard-of-care therapy is available for patients with metastatic anal cancer, and most receive cytotoxic chemotherapy. The high prevalence of HPV in the current population generates optimism for ongoing clinical trials investigating the role of immune checkpoint blockade agents as a novel treatment approach for this disease.