抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

BACKGROUND Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown. METHODS We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells. RESULTS Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib. CONCLUSIONS A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib.

/pdf/activating-mutations-in-the-epidermal-growth-factor-receptor-4a7r2t8eq0.pdf

Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib

METHODS In this phase 3, open-label study, we randomly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival. RESULTS The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with carboplatin–paclitaxel. The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority, as compared with carboplatin– paclitaxel, with respect to progression-free survival in the intention-to-treat population (hazard ratio for progression or death, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene (EGFR) mutation, progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin–paclitaxel (hazard ratio for progression or death, 0.48; 95% CI, 0.36 to 0.64; P<0.001), whereas in the subgroup of 176 patients who were negative for the mutation, progression-free survival was significantly longer among those who received carboplatin–paclitaxel (hazard ratio for progression or death with gefitinib, 2.85; 95% CI, 2.05 to 3.98; P<0.001). The most common adverse events were rash or acne (in 66.2% of patients) and diarrhea (46.6%) in the gefitinib group and neurotoxic effects (69.9%), neutropenia (67.1%), and alopecia (58.4%) in the carboplatin–paclitaxel group. CONCLUSIONS Gefitinib is superior to carboplatin–paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib. (ClinicalTrials.gov number, NCT00322452.)

https://www.nejm.org/doi/pdf/10.1056/NEJMoa0810699

Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma

The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile.

/pdf/the-cancer-genome-atlas-pan-cancer-analysis-project-gw3srsikvs.pdf

The cancer genome atlas pan-cancer analysis project

Patients with stage IIIB or IV non–small-cell lung cancer, with performance status from 0 to 3, were eligible if they had received one or two prior chemotherapy regimens. The patients were stratified according to center, performance status, response to prior chemotherapy, number of prior regimens, and prior platinum-based therapy and were randomly assigned in a 2:1 ratio to receive oral erlotinib, at a dose of 150 mg daily, or placebo. results The median age of the 731 patients who underwent randomization was 61.4 years; 49 percent had received two prior chemotherapy regimens, and 93 percent had received platinum-based chemotherapy. The response rate was 8.9 percent in the erlotinib group and less than 1 percent in the placebo group (P<0.001); the median duration of the response was 7.9 months and 3.7 months, respectively. Progression-free survival was 2.2 months and 1.8 months, respectively (hazard ratio, 0.61, adjusted for stratification categories; P<0.001). Overall survival was 6.7 months and 4.7 months, respectively (hazard ratio, 0.70; P<0.001), in favor of erlotinib. Five percent of patients discontinued erlotinib because of toxic effects. conclusions Erlotinib can prolong survival in patients with non–small-cell lung cancer after firstline or second-line chemotherapy.

/pdf/erlotinib-in-previously-treated-non-small-cell-lung-cancer-33prgcvyt1.pdf

Erlotinib in previously treated non-small-cell lung cancer.

The CDKN2 gene is located on the short arm of chromosome 9p and encodes two unrelated proteins, p16(INK4a) and p14(ARF), through the use of independent first exons and shared exons 2 and 3. p16(INK4a) is a cyclin-dependent kinase inhibitor, whereas p14(ARF) regulates the cell cycle through a p53 and MDM2-dependent pathway. We have examined the expression of p16(INK4a) and p14(ARF) using competitive RT-PCR in 60 non-small cell lung cancers (NSCLCs) and matching normal lung tissues. The intensities of bands for p16(INK4a) and p14(ARF) were nearly equal or the intensity of the p16(INK4a) band slightly exceeded that of p14(ARF) in the normal lung tissues (n = 60). In 38 tumors the intensity of the p16(INK4a) band was similar to or slightly weaker than that of p14(ARF). In 6 tumors the intensity of the p16(INK4a) band was weaker than that of p14(ARF). In 15 tumors the intensity of the p14(ARF) band was very strong and the p16(INK4a) band was barely visible. In only one tumor was the intensity of the p16(INK4a) band very strong, while the band of p14(ARF) was barely visible. The ratio of the intensity of p16(INK4a) to p14(ARF) had an interesting correlation with the tumor's clinicopathological characteristics. The p stage II - IV tumors had significantly lower p16(INK4a) to p14(ARF) ratios than the p stage I tumors (P = 0.036). The T2 - 4 tumors had significantly lower p16(INK4a) to p14(ARF) ratios than the T1 tumors (P = 0.005). The N1 - 3 tumors had significantly lower p16(INK4a) to p14(ARF) ratios than the N0 tumors (P = 0.014). Our results suggest that the ratio of expression of p16(INK4a) to p14(ARF) tends to decrease during the progression of NSCLC.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1349-7006.2002.tb01320.x

Ratio of expression of p16INK4a to p14ARF correlates with the progression of non-small cell lung cancer.

カルボプラチンを使用した気管支動脈注入 (broncho arterial injection, BAI) による薬剤性肺臓炎の1例を経験した.症例は80歳男性.右肺癌の治療目的にてカルボプラチンのBAI治療を行った.その後発熱, 呼吸困難等出現し, 胸部X線写真上両肺野に網状影が出現した.ステロイド使用後胸部X線所見が一旦改善するも徐々に増悪し, BAI施行後20日目に死亡した.カルボプラチンによる薬剤性肺臓炎は本症例が1例目である.

https://www.jstage.jst.go.jp/article/jacsurg1992/11/4/11_4_537/_pdf

Drug induced pneumoniae in a patient treated by BAI with carboplatin

Cardiac metastasis of lung cancer presented as mimicking ST-elevation myocardial infarction with reciprocal electrocardiographic changes.

症例は72歳，女性．腹痛を主訴に平成14年4月中旬当院救急外来を受診した．外来で点滴加療中に大量の血便とともに，ショック状態となった．腹部は軽度膨満し，全体に軽度の圧痛を認めた．右上腹部に約5横指肝を触知した．緊急CTを施行したところS状結腸壁肥厚とS状結腸内への造影剤の漏出，さらに肝右葉を占拠する約15cmの腫瘤を認めた．以上より肝転移を伴うS状結腸癌からの出血性ショックと診断し緊急開腹術を施行した．開腹所見は，骨盤内で回腸末端，回腸間膜，S状結腸腫瘍が一塊になっていた．S状結腸癌の回腸および回腸間膜浸潤と判断しこれを一塊に切除，回腸は端々吻合し，結腸は口側切離端を人工肛門としてHartmann手術を施行した．S状結腸に2型の腫瘍が存在し，その潰瘍底が回腸間膜に穿通していた．大量出血の原因は腫瘍の回腸間膜への浸潤および同部の血管の破綻と考えられた．本症例は，小腸間膜に大腸癌が浸潤，穿通し多量の血便をきたすというきわめて稀な症例であった．若干の文献的考察を加え報告した．

A case of sigmoid colon cancer with massive melena caused by penetration of a small intestinal mesenteric artery

Kaneda et al. described their experience of 43 patients with myasthenia gravis (MG) who underwent thymectomy. One group of 28 patients received high-dose oral prednisolone (up to 100 mg qod.). Another 15 patients did not receive preoperative oral steroid but were given 1 g of hydrocortisone on the day of the operation. The authors found a signifi cant difference in the proportion of patients who had respiratory insuffi ciency within 3 days of surgery. The title of the paper suggests that the authors were comparing the effect of preoperative steroid with no steroid. However, the study was so designed that the no-steroid group actually received a high dose of steroid on the day of the operation. Thus, they were comparing preoperative oral steroid with a perioperative steroid pulse. It is of interest that fewer patients in the steroid group had thymus hyperplasia. Germinal center B cells are steroid-sensitive. Although the authors do not report the effect of steroid on the anti-acetylcholine receptor (AChR) antibody, the fall in the anti-AChR antibody titer may have affected the clinical course of the steroid patients. Alternatively, the course may have been affected by some action of the steroid other than that of suppressing the immune system. As the authors suggested, the unfavorable clinical course in some of the no-steroid group may have been an adverse effect of the high-dose intravenous steroid pulse. This may explain the extroadinarily high percentage of cases of postoperative respiratory insuffi ciency in the no-steroid group. Because 9 of the 15 no-steroid group patients had only ocular symptoms and were unlikely to have respiratory insuffi ciency, it is suggested that fi ve of six patients who were classifi ed as Osserman IIA or IIB had postoperative respiratory insuffi ciency. This suggests that steroid pulse therapy on the day of the operation may be contraindicated. Although the steroid was given in a clinical trial setting, I am not convinced that patients with ocular symptoms only should be treated with a high-dose steroid or steroid pulse. These patients are highly unlikely to experience postoperative respiratory insuffi ciency. In their article, postoperative respiratory insuffi ciency was defi ned as tracheal intubation or moderate or severe breathing diffi culty. Although they used the example of SpO2 < 94% with an FiO2 of 32%, it is likely that most of the patients were diagnosed as having respiratory insuffi ciency based on their clinical symptoms alone. To be more objective, respiratory insuffi ciency should be defi ned more accurately and preferably assessed by an independent physician (not by one of the authors). The study included fi ve patients with MG with negative anti-AChR antibody who underwent thyReceived: 9 November 2007 © The Japanese Association for Thoracic Surgery 2008

Yoshitaka Fujii

Papers

Ratio of expression of p16INK4a to p14ARF correlates with the progression of non-small cell lung cancer.

Drug induced pneumoniae in a patient treated by BAI with carboplatin

Cardiac metastasis of lung cancer presented as mimicking ST-elevation myocardial infarction with reciprocal electrocardiographic changes.

A case of sigmoid colon cancer with massive melena caused by penetration of a small intestinal mesenteric artery

Preoperative steroid therapy stabilizes postoperative respiratory condition in myasthenia gravis