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Pneumatosis intestinalis induced by osimertinib in a patient with lung adenocarcinoma harbouring epidermal growth factor receptor gene mutation with simultaneously detected exon 19 deletion and T790 M point mutation: a case report

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BMC Cancer201919:186

https://doi.org/10.1186/s12885-019-5399-5

  • Received: 13 December 2018
  • Accepted: 20 February 2019
  • Published:
Open Peer Review reports

Abstract

Background

Pneumatosis intestinalis is a rare adverse event that occurs in patients with lung cancer, especially those undergoing treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). Osimertinib is the most recently approved EGFR-TKI, and its usage is increasing in clinical practice for lung cancer patients who have mutations in the EGFR gene.

Case presentation

A 74-year-old woman with clinical stage IV (T2aN2M1b) lung adenocarcinoma was determined to have EGFR gene mutations, namely a deletion in exon 19 and a point mutation (T790 M) in exon 20. Osimertinib was started as seventh-line therapy. Follow-up computed tomography on the 97th day after osimertinib administration incidentally demonstrated intra-mural air in the transverse colon, as well as intrahepatic portal vein gas. Pneumatosis intestinalis and portal vein gas improved by fasting and temporary interruption of osimertinib. Osimertinib was then restarted and continued without recurrence of pneumatosis intestinalis. Overall, following progression-free survival of 12.2 months, with an overall duration of administration of 19.4 months (581 days), osimertinib was continued during beyond-progressive disease status, until a few days before the patient died of lung cancer.

Conclusions

Pneumatosis intestinalis should be noted as an important adverse event that can occur with administration of osimertinib; thus far, such an event has never been reported. This was a valuable case in which osimertinib was successfully restarted after complete recovery from pneumatosis intestinalis, such that further extended administration of osimertinib was achieved.

Keywords

  • Receptor, epidermal growth factor
  • Protein kinase inhibitors
  • Lung neoplasms
  • Osimertinib
  • Pneumatosis intestinalis

Background

Pneumatosis intestinalis is a disease in which air-containing cysts form within the submucosa or serosa of the intestinal tract [1]. Although the detailed pathogenesis or aetiology of intra-mural gas formation remains unknown, several mechanisms have been proposed, such as a bacterial theory and a mechanical theory [2, 3]. Overall, the development of pneumatosis intestinalis is believed to be multifactorial in individual patients, because the underlying diseases or medical conditions in each reported case have been considerably different [2]. Pneumatosis intestinalis can be secondary to several conditions such as digestive tract obstruction, ischemic bowel disease, inflammatory bowel disease, autoimmune disease, infectious enteritis, intestinal tumour, and trauma [3]. The severity varies from benign to life-threatening disease [4]. Pneumatosis intestinalis can also be secondary to some drugs, such as molecular targeted therapy agents [5], corticosteroids [4], and alpha-glucosidase inhibitors [6].

Pneumatosis intestinalis occurring during treatment for lung cancer has been reported previously, especially in patients receiving epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib [715]. In addition, pneumatosis intestinalis has been reported in patients treated with cytotoxic agents, such as amrubicin [16], S-1 plus oral leucovorin combination [17], carboplatin plus irinotecan combination [18], and cisplatin + irinotecan combination [19]. Osimertinib is the most recently approved third-generation EGFR-TKI, which can be effective in patients with advanced-stage lung adenocarcinoma harbouring an EGFR gene mutation and an acquired drug-resistant mutation, such as the exon 20 T790 M point mutation [20]. Furthermore, clinical benefits for use of osimertinib as first-line treatment in patients harbouring so-called common EGFR gene mutations (the exon 21 L858R point mutation and the exon 19 deletions) were proven in the FLAURA study [21]; subsequently, an increasing number of patients with anticancer therapy naïve, EGFR gene mutation positive advanced non-small cell lung cancer have received osimertinib. Here, we report a case of osimertinib-induced pneumatosis intestinalis.

Case presentation

A 69-year-old Japanese woman who had never smoked was initially diagnosed with clinical stage IV (T2aN2M1b in 7th edition) lung adenocarcinoma with pleural and bone metastasis. She had no history of chronic obstructive pulmonary disease, diabetes mellitus, or any colonic diseases (such as constipation). At the initial diagnosis, no EGFR gene mutation was detected in malignant pleural effusion by real-time polymerase chain reaction (PCR). A combination regimen with carboplatin, paclitaxel, and bevacizumab was started as the first-line treatment (Fig. 1). Next, pemetrexed, erlotinib, and docetaxel were administered as second-, third-, and fourth-line treatments, respectively. Each regimen was changed because of disease progression. Lung cancer progressed with increased pleural effusion after one cycle with gemcitabine (fifth-line treatment). Therefore, EGFR gene mutation was studied in pleural effusion, using the PCR fragment analysis/PCR clamp method, because the progression-free survival (PFS) of erlotinib was 24.7 months. Two EGFR gene mutations were detected, namely a deletion in exon 19 and a T790 M point mutation in exon 20. Based on the genetic results, afatinib was started as the sixth-line treatment, as recommended in the LUX-Lung-4 study [22]. Osimertinib was not an option because it was not yet approved at that time. The PFS of afatinib was 4.0 months. Treatment with afatinib was continued for 15.3 months (458 days) until osimertinib was approved.
Fig. 1
Fig. 1

Timeline of anticancer treatments. Progression-free survival and best objective response of each regimen are summarized. Abbreviations: ORR: objective response rate, PD: progressive disease, PFS: progression-free survival, PR: partial response, SD: stable disease

Osimertinib (80 mg/day) was started as the seventh-line treatment at her age of 74, when the patient had a body mass index of 16.2 kg/cm2 and a performance status of 1. The adverse events, cutaneous pruritus and stomatitis, were graded with Common Terminology Criteria for Adverse Events (CTCAE, ver 4.0) as grade 1. However, there was gradual improvement in the shoulder pain that had resulted from bone metastasis, and oral administration of oxycodone was successfully stopped on the 87th day after osimertinib was started. The best response of osimertinib was stable disease. In follow-up computed tomography (CT) at day 97 after treatment with osimertinib, intra-mural air in the transverse colon and intra-hepatic portal vein gas were incidentally observed. Intra-mural air in the bowel intestine was considered to be pneumatosis intestinalis. However, no evidence of perforation was observed because free air was absent from the abdominal cavity (Figs. 2a, b and 3). Progression of lung cancer was not recognized.
Fig. 2
Fig. 2

Abdominal computed tomography. a Intra-mural gas (arrows) in the wall of the transverse colon. b Intra-hepatic portal vein gas (arrowhead) in the peripheral area of the liver. c, d After treatment, both of these findings were improved

Fig. 3
Fig. 3

Chest and abdominal X-ray. a Right-sided pleural effusion due to lung cancer. No evidence of free air in the abdominal cavity. b No evidence of overt gas along the wall of the intestinal tract

Because of the close association between pneumatosis intestinalis and EGFR-TKI usage [5], pneumatosis intestinalis was considered to have been induced by osimertinib, which had been most recently administered. There were no subjective symptoms, such as abdominal pain. Her white blood cell count was 3500/μL (normal range: 3400-9200/μL), serum C-reactive protein was 0.0 mg/dL (normal range: 0.0–0.3 mg/dL), and creatinine kinase (CK) was 48 IU/L (normal range: 62–287 IU/L). Therefore, there were no findings to indicate inflammatory response, such as infection or intestinal necrosis.

We put the patient on fasting conservatively and interrupted osimertinib on the first day of fasting, monitoring her condition carefully. She received neither antibiotics, nor an oxygen supply. After improvement of pneumatosis intestinalis and intra-hepatic portal vein gas on abdominal CT taken on day 7 (Fig. 2c, d), we resumed meals orally on day 7 and osimertinib (80 mg/day) on day 10.

It had been possible to continue osimertinib successfully. With a PFS of 12.2 months, osimertinib was continued with beyond-progressive disease status. Our patient was administered osimertinib until a few days before she died of lung cancer. The total duration of osimertinib administration was 19.4 months (581 days) (16.1 months [484 days] since complete recovery from pneumatosis intestinalis). Her overall survival was 79.3 months.

Discussion and conclusions

Here, we report a case of pneumatosis intestinalis and intra-hepatic portal vein gas that occurred during administration of osimertinib to a patient with advanced-stage lung adenocarcinoma harbouring EGFR gene mutations (a deletion in exon 19 and a T790 M point mutation in exon 20). Pneumatosis intestinalis was resolved by conservative treatment and temporary interruption of osimertinib. Even after osimertinib had been restarted, no recurrence was observed during the remaining follow-up period.

Pneumatosis intestinalis is a disease in which air-containing cysts form within the submucosa or serosa of the intestinal tract [1]. Some theories that air intrudes to the intestinal wall have been proposed [3, 23]: i) according to the mechanical theory, some mechanical triggers, such as drugs or immune dysfunction, may lead to disruption of the submucosa, fragility of integration of mucosal epithelia, intestinal wall injury, and increased intestinal pressure; ii) according to the bacterial theory, the bacilli invading the submucosa may promote mucosal breaks, increase submucosal permeability, and contribute to the production of gas within the submucosa; iii) according to the chemical/nutritional deficiency theory, some medicines such as alpha-glucosidase inhibitors, or malnutrition, may change the bacterial flora in the bowel intestine, leading to an increase in gas production; and iv) according to the pulmonary theory, the rupture of alveolar structures may increase the entry of air into the mesenteric vessels via the pneumomediastinum. Although the details of the mechanisms remain unknown, multifactorial triggers may cause pneumatosis intestinalis.

The detailed mechanism by which EGFR-TKIs cause pneumatosis intestinalis is not fully understood. However, a previous report has suggested that EGFR-TKIs could lead to pneumatosis intestinalis through the following process: i) the basic fibroblast growth factor, one of the growth factors expressed in the gastrointestinal tract, is involved in maintaining the gastrointestinal mucosa (epithelium) in a murine model [24]; and ii) gefitinib damages the gastrointestinal mucosa and impairs its defence and repair function [9]. These pharmacological actions of EGFR-TKIs may ultimately cause pneumatosis intestinalis. EGFR-TKIs, including osimertinib, may share a similar mechanism that impairs the turnover of intestinal epithelial cells.

Our patient had none of the other risk factors for pneumatosis intestinalis that have been reported previously, such as diabetes mellitus, steroid or narcotic use, underlying colonic disease, and pre-existing acute colonic infection. Although she had undergone long-term administration of multiple potentially causative agents for pneumatosis intestinalis, including other EGFR-TKIs and bevacizumab (Fig. 1), her first episode of pneumatosis intestinalis did not occur until osimertinib treatment was initiated. Because oxycodone was successfully stopped only 10 days before the diagnosis of pneumatosis intestinalis, the patient’s risk of pneumatosis intestinalis had been reduced at the time that pneumatosis intestinalis was diagnosed.

Mild disease is usually asymptomatic and pneumatosis intestinalis is detected by routine CT study incidentally with median duration until detection with less than 3 months [5]. Mild disease usually improves with conservative treatment and withdrawal of EGFR-TKI treatment. The typical symptoms of pneumatosis intestinalis are abdominal pain, diarrhoea, distention, nausea/vomiting, bloody/mucous stool, and constipation [5]. These symptoms may be observed in severe disease, especially when both intestinal perforation and peritonitis occur. These manifestations may lead the patients to emergency surgery [2, 25]. The current case has neither overt symptoms nor any laboratory findings suggestive of intestinal necrosis or severe disease.

Radiologically, the characteristic findings have been investigated. Abdominal CT features suggestive of severe life-threatening disease have been reported as bowel wall thickening, mesenteric stranding, ascites, bowel dilatation, location confined to small bowel, and portomesenteric venous gas [4]. In the current case, none of the aforementioned CT features suggestive of life-threatening disease were observed (Fig. 2a, b).

Intra-hepatic portal vein gas is probably air that intrudes into the portal vein via the intestinal tract [26]. It is commonly observed in combination with pneumatosis intestinalis [9]. Furthermore, its identification is usually, but not always, helpful to distinguish severe from mild disease, and it is strongly associated with mesenteric ischemia [1]. In the current case, the extent of intra-hepatic portal vein gas was very mild (Fig. 2b). This may be the reason why the presence of intra-hepatic portal vein gas was not associated with severe mesenteric ischemia in this case.

There are reports of nine cases of patients with pneumatosis intestinalis caused by EGFR-TKI usage (Table 1) [715]. Gefitinib and erlotinib were used in six and three patients, respectively. Among all but one, conservative observation and withdrawal of EGFR-TKIs were chosen as the major treatments (Table 1). Iwasaku et al. [8], Otsubo et al. [11], and Maeda et al. [12] reported patients who were re-administered EGFR-TKIs after the symptom of mild abdominal pain improved. Yamamoto et al. [14] reported another case of pneumatosis intestinalis that was resolved without interruption of EGFR-TKI treatment. In that case, none of the aforementioned clinical and radiological findings suggestive of life-threatening disease were observed, and the extent of the involved areas was limited in our case. All prior cases have occurred in Asian countries, primarily Japan [715]. It is well-known that there is an ethnic difference in the prevalence of EGFR positive lung cancer between Western and Asian populations [27, 28]. The prevalence of pneumatosis intestinalis may correspond to that of EGFR gene mutation positive lung cancer. Upon review of prior case reports with regard to Asian patients, no risk factors other than those previously reported to cause pneumatosis intestinalis were found.
Table 1

Reported cases of pneumatosis intestinalis in patients with lung cancer who received treatment with EGFR-TKIs

Drug

First author

Publication year

Age/sex

Treatment

Symptoms

Complication

Outcome

Restart of EGFR-TKI treatment

Recurrence

Gefitinib

Higashino (7)

2010

67/F

Observation/withdrawal

Mild abdominal pain

Intra-peritoneal free air

Improved

ND

Gefitinib

Iwasaku (8)

2012

82/F

Observation/withdrawal

Mild abdominal pain

None

Improved

Yes

Yes

Gefitinib

Lee (9)

2012

66/F

Observation/withdrawal

Vomiting, diarrhea, and abdominal distension

Intra-hepatic portal veinous gas with suggestive of liver infarction

Improved

No

Gefitinib

Wakabayashi (10)

2012

83/M

Surgery/ withdrawal

Fever, vomiting, diarrhea, and severe abdominal pain

Intra-peritoneal free air, remarkable elevation of inflammatory parameters

Improved

ND

Gefitinib

Otsubo (11)

2015

71/M

Observation/withdrawal

Vomiting, diarrhea, and abdominal pain

Intra-peritoneal free air

Improved

Yes

No

Gefitinib

Maeda (12)

2016

80/F

Observation/withdrawal

Anorexia, constipation, and abdominal distension

Intra-peritoneal free air, mild elevation of inflammatory parameters

Improved

Yes

Yes

Erlotinib + bevacizumab

Tsukita (13)

2014

69/M

Observation/withdrawal

No symptoms

Intra-peritoneal free air

Improved

ND

Erlotinib + pemetrexed

Yamamoto (14)

2014

70/F

Observation, continuation of erlotinib

Vomiting, anorexia, diarrhea, and abdominal pain

None

Improved

Erlotinib + bevacizumab

Saito (15)

2016

73/F

Observation/withdrawal

Anorexia and fatigue

Intra-peritoneal free air

Improved

No

Osimertinib

Current case

2018

73/F

Observation/withdrawal

No symptoms

Intra-hepatic portal vein gas

Improved

Yes

No

Abbreviations: EGFR-TKI epidermal growth factor receptor tyrosine kinase inhibitor, F female, M male, ND not described

Because our patient had already experienced six regimens of anticancer therapy, osimertinib was considered to be the singular option that had the potential to stabilize the progression of lung cancer. The restart and continuation of osimertinib under close observation was a meaningful approach, which resulting in the patient maintaining PFS for 19.4 months. Our patient had essentially no underlying risk factors, and the change of the EGFR-TKI from afatinib to osimertinib was the only way in which her condition was altered during the time that pneumatosis intestinalis developed. The absence of recurrence after restarting osimertinib might be explained by the use of dietotherapy that focused on ease of digestion and the avoidance of factors that could have exacerbated pneumatosis intestinalis, such as constipation.

Pneumatosis intestinalis is a rare adverse event that can occur in patients with lung cancer treated with osimertinib. In this case, it was a valuable and successful option to restarted osimertinib after the patient had completely recovered from pneumatosis intestinalis without deterioration, resulting in extended administration of osimertinib.

Abbreviations

CK: 

Creatinine kinase

CT: 

Computed tomography

CTCAE: 

Common terminology criteria for adverse event

EGFR: 

Epidermal growth factor

ORR: 

Objective response rate

PCR: 

Polymerase chain reaction

PD: 

Progressive disease

PFS: 

Progression-free survival

PR: 

Partial response

SD: 

Stable disease

TKI: 

Tyrosine kinase inhibitor

Declarations

Acknowledgements

None.

Funding

No funding was used to acquire the information/data described in this case report.

Availability of data and materials

Data sharing is not applicable for this case report, as no datasets were generated during the current study, which was based on clinical observations.

Authors’ contributions

YN, AM, SM1, SM2, YT, KO, KM, SH, HU, HT, NM, and KK collected the patient’s data, provided the figures and table, and gave critical interpretation of the manuscript. KK provided final approval for the version to be published. The final version of the manuscript was read and approved by all authors.

Ethics approval and consent to participate

This case report was approved by the local ethics committee of Toranomon Hospital (approval number #1753-B, 2018/12/11).

Consent for publication

Written informed consent for publication of this case report and the associated images was obtained from the patient.

Competing interests

The authors declare that they have no competing interests.

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Authors’ Affiliations

(1)
Department of Respiratory Medicine, Toranomon Hospital (Branch), 1-3-1 Kajigaya Takatsu-ku, Kawasaki-shi Kanagawa, 213-8587, Japan
(2)
Department of Respiratory Medicine, Respiratory Center, Toranomon Hospital, 2-2-2 Toranomon Minato-ku, Tokyo 105-8470, Japan

References

  1. Ho LM, Paulson EK, Thompson WM. Pneumatosis intestinalis in the adult: benign to life-threatening causes. AJR Am J Roentgenol. 2007;188:1604–13.View ArticleGoogle Scholar
  2. St Peter SD, Abbas MA, Kelly KA. The spectrum of pneumatosis intestinalis. Arch Surg. 2003;138:68–75.View ArticleGoogle Scholar
  3. Khalil PN, Huber-Wagner S, Ladurner R, Kleespies A, Siebeck M, Mutschler W, et al. Natural history, clinical pattern, and surgical considerations of pneumatosis intestinalis. Eur J Med Res. 2009;14:231–9.View ArticleGoogle Scholar
  4. Lee KS, Hwang S, Hurtado Rúa SM, Janjigian YY, Gollub MJ. Distinguishing benign and life-threatening pneumatosis intestinalis in patients with cancer by CT imaging features. AJR Am J Roentgenol. 2013;200:1042–7.View ArticleGoogle Scholar
  5. Shinagare AB, Howard SA, Krajewski KM, Zukotynski KA, Jagannathan JP, Ramaiya NH. Pneumatosis intestinalis and bowel perforation associated with molecular targeted therapy: an emerging problem and the role of radiologists in its management. AJR Am J Roentgenol. 2012;199:1259–65.View ArticleGoogle Scholar
  6. Yamashita T, Yoneda M. A case of pneumatosis cystoides intestinalis induced by α-glucosidase inhibitor. Kyotofuritsuikadaigaku Zasshi. J Kyoto Prefectural Uni Med. 2014;123:255–62 (in Japanese).Google Scholar
  7. Higashino M, Hirano S, Uemura M, Fujita Y, Sugiyama E, Ishihara S, et al. Consideration of two cases with intestinal emphysema during lung cancer treatment. Haigan. Jpn J Lung Cancer. 2010;50:727 (in Japanese)(Abstract).Google Scholar
  8. Iwasaku M, Yoshioka H, Korogi Y, Kunimasa K, Nishiyama A, Nagai H, et al. Pneumatosis cystoides intestinalis after gefitinib therapy for pulmonary adenocarcinoma. J Thorac Oncol. 2012;7:257.View ArticleGoogle Scholar
  9. Lee JY, Han HS, Lim S, Shim YK, Choi YH, Lee OJ, et al. Pneumatosis intestinalis and portal venous gas secondary to gefitinib therapy for lung adenocarcinoma. BMC Cancer. 2012;12:87.View ArticleGoogle Scholar
  10. Wakabayashi H, Yamada T, Yokoi K, Tanaka N, Yokomuro S, Uchida E. Possible cause of gefitinib, pneumatosis cystoides intestinalis cases that were difficult to differentiate from gastrointestinal perforation. Nihon Rinshou Geka Gakkai Zassi. J Jpn Surg Assoc. 2012;73:735 (in Japanese)(Abstract).Google Scholar
  11. Ohtusbo A, Watanabe S, Tanaka T, Morita A, Takeda Y, Uruga K, et al. A case of lung adenocarcinoma successfully treated with erlotinib after recovering from pneumatosis cystoides intestinalis caused by gefitinib. Niigata Igakukai Zassi. Niigata Med J. 2015;129:534–8 (in Japanese).Google Scholar
  12. Maeda A, Nakata M, Shimizu K, Yukawa T, Saisho S, Okita R. Pneumatosis intestinalis after gefitinib therapy for pulmonary adenocarcinoma: a case report. World J Surg Oncol. 2016;14:175.View ArticleGoogle Scholar
  13. Tsukita Y, Watanabea K, Morita M, Watanuki R, Suzuki A, Fukuhara T, et al. Pneumatosis intestinalis associated with treatment of pulmonary adenocarcinoma with bevacizumab and erlotinib. Nihon Kokyuuki Gakkaishi. Ann Jpn Respir Soc. 2014;3:442–5 (in Japanese).Google Scholar
  14. Yamamoto A, Kikuchi N, Isobe K, Wada T, Shibuya K, Homma S. A case of lung cancer complicating pneumatosis intestinalis during beyond progressive disease therapy. Nihon Kokyuuki Gakkaishi. Ann Jpn Respir Soc. 2014;3:548–52 (in Japanese).Google Scholar
  15. Saito A, Watanabe S, Yabe H, Yamazoe M, Takahashi R, Tanaka Y. A case of pulmonary adenocarcinoma developing pneumatosis intestinalis during chemotherapy combined with erlotinib and bevacizumab. Dounan Igakkaishi. J Med Assoc South Hokkaido. 2016;69:79 (in Japanese)(Abstract).Google Scholar
  16. Ishiwata T, Suda A, Abe M, Kantake M, Shinozaki T. A case of pneumatosis cystoides intestinalis during systemic chemotherapy for small-cell lung cancer. Haigan. Jpn J Lung Cancer. 2013;53:144–9 (in Japanese).View ArticleGoogle Scholar
  17. Naito T, Seto T, Takeda K, Goto K, Okamoto I, Nakagawa K, et al. Phase II clinical trial of S-1 plus oral leucovorin in previously treated patients with non-small-cell lung cancer. Lung Cancer. 2014;86:339–3.View ArticleGoogle Scholar
  18. Uryu K, Umakoshi T, Hyakutake T, Hasegawa Y, Asano K, Harada H. Pneumatosis cystoides intestinalis in a patient with lung cancer. Nihon Kokyuuki Gakkai Zasshi. 2010;48:972–5 (in Japanese).Google Scholar
  19. Shimazu K, Ogata R, Tanio Y, Fushimi H. An autopsy case report of pneumatosis cystoides intestinalis in lung cancer patient undergoing chemotherapy. Shindan Byori. Jpn J Diagn Pathol. 2010;27:135–9 (in Japanese).Google Scholar
  20. Mok TS, Wu YL, Ahn MJ, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med. 2017;376:629–40.View ArticleGoogle Scholar
  21. Soria J-C, Ohe Y, Vansteenkiste J, Reungwetwattana T, Chewaskulyong B, Lee KH, et al. Osimertinib in untreated EGFR-mutated advanced non-small cell lung cancer. N Engl J Med. 2018;378:113–25.View ArticleGoogle Scholar
  22. Katakami N, Atagi S, Goto K, Hida T, Horai T, Inoue A, et al. LUX-lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both. J Clin Oncol. 2013;31:3335–41.View ArticleGoogle Scholar
  23. Wu LL, Yang YS, Dou Y, Liu QS. A systematic analysis of pneumatosis cystoids intestinalis. World J Gastroenterol. 2013;19:4973–8.View ArticleGoogle Scholar
  24. Matsuura M, Okazaki K, Nishio A, Nakase H, Tamaki H, Uchida K, et al. Therapeutic effects of rectal administration of basic fibroblast growth factor on experimental murine colitis. Gastroenterology. 2005;128:975–86.View ArticleGoogle Scholar
  25. Knechtle SJ, Davidoff AM, Rice RP. Pneumatosis intestinalis. Surgical management and clinical outcome. Ann Surg. 1990;212:160–5.View ArticleGoogle Scholar
  26. Kashima T, Ohno Y, Tachibana M. Pneumatosis intestinalis and hepatic portal venous gas in a patient receiving sorafenib. Int J Urol. 2012;19:1041–2.View ArticleGoogle Scholar
  27. Barlesi F, Mazieres J, Merlio JP, Debieuvre D, Mosser J, Lena H, et al. Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French cooperative thoracic intergroup (IFCT). Lancet. 2016;387:1415–26.View ArticleGoogle Scholar
  28. Soh J, Toyooka S, Matsuo K, Yamamoto H, Wistuba I, Lam S, et al. Ethnicity affects EGFR and KRAS gene alterations of lung adenocarcinoma. Oncol Lett. 2015;10:1775–82.View ArticleGoogle Scholar

Copyright

© The Author(s). 2019

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