Circulating Tumor DNA Analysis Guiding Adjuvant Therapy in Stage II Colon Cancer
The role of adjuvant chemotherapy in stage II colon cancer continues to be debated. The presence of circulating tumor DNA (ctDNA) after surgery predicts very poor recurrence-free survival, whereas its absence predicts a low risk of recurrence. The benefit of adjuvant chemotherapy for ctDNA-positive patients is not well understood.
We conducted a trial to assess whether a ctDNA-guided approach could reduce the use of adjuvant chemotherapy without compromising recurrence risk. Patients with stage II colon cancer were randomly assigned in a 2:1 ratio to have treatment decisions guided by either ctDNA results or standard clinicopathological features. For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery prompted oxaliplatin-based or fluoropyrimidine chemotherapy. Patients who were ctDNA-negative were not treated. The primary efficacy end point was recurrence-free survival at 2 years. A key secondary end point was adjuvant chemotherapy use.
在接受随机分组的455例患者中，302例被分配至ctDNA指导的治疗组，153例被分配至标准治疗组。中位随访期为37个月。ctDNA指导组接受辅助化疗的患者比例低于标准治疗组（15% vs. 28%；相对危险度，1.82；95%置信区间[CI]，1.25~2.65）。在2年无复发生存率的评估中，ctDNA指导的治疗不劣于标准治疗（分别为93.5%和92.4%；绝对差，1.1个百分点；95% CI，-4.1~6.2[非劣效性界值，-8.5个百分点]）。3年无复发生存率如下：接受辅助化疗的ctDNA阳性患者为86.4%，而未接受辅助化疗的ctDNA阴性患者为92.5%。
Of the 455 patients who underwent randomization, 302 were assigned to ctDNA-guided management and 153 to standard management. The median follow-up was 37 months. A lower percentage of patients in the ctDNA-guided group than in the standard-management group received adjuvant chemotherapy (15% vs. 28%; relative risk, 1.82; 95% confidence interval [CI], 1.25 to 2.65). In the evaluation of 2-year recurrence-free survival, ctDNA-guided management was noninferior to standard management (93.5% and 92.4%, respectively; absolute difference, 1.1 percentage points; 95% CI, −4.1 to 6.2 [noninferiority margin, −8.5 percentage points]). Three-year recurrence-free survival was 86.4% among ctDNA-positive patients who received adjuvant chemotherapy and 92.5% among ctDNA-negative patients who did not.
ctDNA指导的Ⅱ期结肠癌治疗减少了辅助化疗的使用，同时未降低无复发生存率。（由澳大利亚国家健康和医学研究委员会[Australian National Health and Medical Research Council]等资助；DYNAMIC在澳大利亚和新西兰临床试验注册系统[Australian New Zealand Clinical Trials Registry]注册号为ACTRN12615000381583。）
A ctDNA-guided approach to the treatment of stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival. (Supported by the Australian National Health and Medical Research Council and others; DYNAMIC Australian New Zealand Clinical Trials Registry number, ACTRN12615000381583.)
Jeanne Tie, Joshua D. Cohen, Kamel Lahouel, Circulating Tumor DNA Analysis Guiding Adjuvant Therapy in Stage II Colon Cancer. DOI: 10.1056/NEJMoa2200075
Treatment of Anal High-Grade Squamous Intraepithelial Lesions to Prevent Anal Cancer
The incidence of anal cancer is substantially higher among persons living with the human immunodeficiency virus (HIV) than in the general population. Similar to cervical cancer, anal cancer is preceded by high-grade squamous intraepithelial lesions (HSILs). Treatment for cervical HSIL reduces progression to cervical cancer; however, data from prospective studies of treatment for anal HSIL to prevent anal cancer are lacking.
We conducted a phase 3 trial at 25 U.S. sites. Persons living with HIV who were 35 years of age or older and who had biopsy-proven anal HSIL were randomly assigned, in a 1:1 ratio, to receive either HSIL treatment or active monitoring without treatment. Treatment included office-based ablative procedures, ablation or excision under anesthesia, or the administration of topical fluorouracil or imiquimod. The primary outcome was progression to anal cancer in a time-to-event analysis. Participants in the treatment group were treated until HSIL was completely resolved. All the participants underwent high-resolution anoscopy at least every 6 months; biopsy was also performed for suspected ongoing HSIL in the treatment group, annually in the active-monitoring group, or any time there was concern for cancer.
在接受随机分组的4459名参与者中，4446名（99.7%）被纳入至进展为癌症的时间分析。中位随访时间为25.8个月，治疗组诊断出9例病例（每100，000人-年173例；95%置信区间[CI]，90~332），主动监测组诊断出21例（每100，000人-年402例；95% CI，262~616）。治疗组进展为肛门癌的发生率比主动监测组低57%（95% CI，6~80；时序检验P=0.03）。
Of 4459 participants who underwent randomization, 4446 (99.7%) were included in the analysis of the time to progression to cancer. With a median follow-up of 25.8 months, 9 cases were diagnosed in the treatment group (173 per 100,000 person-years; 95% confidence interval [CI], 90 to 332) and 21 cases in the active-monitoring group (402 per 100,000 person-years; 95% CI, 262 to 616). The rate of progression to anal cancer was lower in the treatment group than in the active-monitoring group by 57% (95% CI, 6 to 80; P=0.03 by log-rank test).
在活检证实肛门HSIL的参与者中，与主动监测相比，治疗肛门HSIL显著降低了肛门癌风险。（由美国国立癌症研究所[National Cancer Institute]资助；在ClinicalTrials.gov注册号为NCT02135419。）
Among participants with biopsy-proven anal HSIL, the risk of anal cancer was significantly lower with treatment for anal HSIL than with active monitoring. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT02135419.)
Joel M. Palefsky, Jeannette Y. Lee, Naomi Jay, Treatment of Anal High-Grade Squamous Intraepithelial Lesions to Prevent Anal Cancer. DOI: 10.1056/NEJMoa2201048
Chapare Hemorrhagic Fever and Virus Detection in Rodents in Bolivia in 2019
2019年6月，玻利维亚卫生部（Bolivian Ministry of Health）报道了一组出血热病例，这些病例始于卡拉纳维市（Caranavi），扩散至拉巴斯市（La Paz）。病例的病因不明。
In June 2019, the Bolivian Ministry of Health reported a cluster of cases of hemorrhagic fever that started in the municipality of Caranavi and expanded to La Paz. The cause of these cases was unknown.
We obtained samples for next-generation sequencing and virus isolation. Human and rodent specimens were tested by means of virus-specific real-time quantitative reverse-transcriptase–polymerase-chain-reaction assays, next-generation sequencing, and virus isolation.
我们发现了9例出血热，其中4例死亡。鉴定出病原体属于哺乳类沙粒病毒属（Mammarenavirus），具体为引起查帕雷出血热（CHHF）的查帕雷哺乳类沙粒病毒或称查帕雷病毒（CHAPV）。我们发现医护人员间可能发生了院内传播。一些CHHF患者有神经系统表现，存活患者的恢复期漫长。我们在人体多种体液（包括血液；尿液；鼻咽、口咽和支气管肺泡灌洗液；结膜；以及精液），以及在从捕获的小耳侏儒稻大鼠（small-eared pygmy rice rat）（小耳小啸鼠[Oligoryzomys microtis]）采集的样本中检出CHAPV RNA。在存活的CHHF患者中，截至症状出现后170天仍可检出病毒RNA；在症状出现后86天采集的一份精液样本中分离出了CHAPV。
Nine cases of hemorrhagic fever were identified; four of the patients with this illness died. The etiologic agent was identified as Mammarenavirus Chapare mammarenavirus, or Chapare virus (CHAPV), which causes Chapare hemorrhagic fever (CHHF). Probable nosocomial transmission among health care workers was identified. Some patients with CHHF had neurologic manifestations, and those who survived had a prolonged recovery period. CHAPV RNA was detected in a variety of human body fluids (including blood; urine; nasopharyngeal, oropharyngeal, and bronchoalveolar-lavage fluid; conjunctiva; and semen) and in specimens obtained from captured small-eared pygmy rice rats (Oligoryzomys microtis). In survivors of CHHF, viral RNA was detected up to 170 days after symptom onset; CHAPV was isolated from a semen sample obtained 86 days after symptom onset.
我们鉴定出查帕雷哺乳类沙粒病毒是CHHF的病原体。研究发现该疾病发生了动物传人事件，并且可能发生了人际传播。我们在啮齿类动物小耳小啸鼠中检出该病毒。（由玻利维亚卫生部[Bolivian Ministry of Health]等资助。）
M. Chapare mammarenavirus was identified as the etiologic agent of CHHF. Both spillover from a zoonotic reservoir and possible person-to-person transmission were identified. This virus was detected in a rodent species, O. microtis. (Funded by the Bolivian Ministry of Health and others.)
Roxana Loayza Mafayle, Maria E. Morales-Betoulle, Carla Romero, Chapare Hemorrhagic Fever and Virus Detection in Rodents in Bolivia in 2019. DOI: 10.1056/NEJMoa2110339
Sequential Stem Cell–Kidney Transplantation in Schimke Immuno-osseous Dysplasia
肾移植后的移植肾存活需要终生免疫抑制，但不能最终防止慢性排斥反应导致的移植肾丢失。我们开发了一种方法，试图消除三例同时患有T细胞免疫缺陷和肾衰竭的Schimke免疫-骨发育不良患者的免疫排斥和移植后免疫抑制的需要。每名患者都接受了来自相同供者的αβ T细胞耗竭和CD19 B细胞耗竭的单倍体造血干细胞移植和肾脏的序贯移植。在肾移植后22~34个月，患者实现了全供者造血嵌合和功能性的体外T细胞耐受，在没有接受免疫抑制治疗的情况下，肾功能持续正常。（由Kruzn for a Kure基金会资助。）
Lifelong immunosuppression is required for allograft survival after kidney transplantation but may not ultimately prevent allograft loss resulting from chronic rejection. We developed an approach that attempts to abrogate immune rejection and the need for post-transplantation immunosuppression in three patients with Schimke immuno-osseous dysplasia who had both T-cell immunodeficiency and renal failure. Each patient received sequential transplants of αβ T-cell–depleted and CD19 B-cell–depleted haploidentical hematopoietic stem cells and a kidney from the same donor. Full donor hematopoietic chimerism and functional ex vivo T-cell tolerance was achieved, and the patients continued to have normal renal function without immunosuppression at 22 to 34 months after kidney transplantation. (Funded by the Kruzn for a Kure Foundation.)
Alice Bertaina, Paul C. Grimm, Kenneth Weinberg, Sequential Stem Cell–Kidney Transplantation in Schimke Immuno-osseous Dysplasia. DOI: 10.1056/NEJMoa21170