Successful rechallenge with erlotinib in a patient with EGFR-mutant lung adenocarcinoma who developed gefitinib-related interstitial lung disease

Small-molecule tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) pathways are used clinically for patients with non-small cell lung cancer (NSCLC). It is well established that somatic mutations in the kinase domain of the EGFR (Lynch et al. in N Engl J Med 350:2129–2139, 2004; Paez et al. in Science 304:1497–1500, 2004) are strongly associated with the tumor response and clinical outcomes in patients with NSCLC receiving EGFR-TKIs (Mitsudomi and Yatabe in Cancer Sci 98:1817–1824, 2007). Although the most common adverse events are skin rash and diarrhea, the most serious adverse effect reported is drug-related interstitial lung disease (ILD) (Inoue et al. in Lancet 361:137–139, 2003; Ando et al. in J Clin Oncol 24:2549–2556, 2006). The precise mechanism underlying the development of drug-related ILD remains unknown. Here, we describe a case of EGFR-mutant NSCLC who was rechallenged with the small-molecule EGFR antagonist erlotinib after developing gefitinib-related ILD.     

Massive hemothorax due to diaphragmatic endometriosis after a laparoscopic cystectomy of an ovarian endometrioma in a patient without a history of thoracic endometriosis

Background

Severe hemothorax is a rare complication after laparoscopic surgery for endometriosis, and the causes and proper management are not well understood.

Case

We report here the extremely rare case with massive hemothorax after laparoscopic surgery for ovarian endometrioma. A 40-year-old woman, gravida 1, para 1, underwent laparoscopic cystectomy of ovarian endometrioma. On postoperative day 2, she had progressive anemia (Hb 5.3) as well as dyspnea. A chest X-ray and computed tomography showed massive fluid collection in the right thoracic cavity, suggestive of intrapleural bleeding.

Treatment

Thoracoscopic operation was performed and a total of 930?ml of blood retention in the right thoracic cavity was found. Scattered small endometriotic lesions were present on the pleural surface of the right diaphragm; pulsatile active bleeding was confirmed from one of these. Furthermore, two endometriotic lesions had perforated into the intraperitoneal cavity. The diaphragm containing bleeding spots was thoracoscopically resected and sutured. After thoracoscopic surgery, the dyspnea and anemia resolved. On postoperative day 5, the patient left the hospital.

Conclusion

The present report reminds us of the importance of paying special attention to postoperative-thoracic complications caused by diaphragmatic endometriosis if the patient shows respiratory symptoms.     

Validation study of a health risk appraisal model and endoscopic screening for early esophageal cancer in men in specialized hospitals

Background

This study was designed to validate a health-risk appraisal (HRA) model for identifying Japanese men in specialized hospitals who were at high risk for esophageal cancer on the basis of their past and present facial flushing reactions after drinking alcohol, drinking and smoking status, and intake of vegetables and fruit.

Methods

We prospectively studied men 50 years or older with no history of head and neck cancer or esophageal cancer who presented at Kitasato University Hospital to undergo endoscopic examination from January 2011 to March 2013. The subjects responded to an HRA questionnaire before examination.

Results

Among the 164 patients enrolled, 157 were eligible for analysis. The median HRA score was 3 in patients aged 70–90 years and 6 in those aged 50 to 69 years. Early esophageal cancer was diagnosed on endoscopic examination in 3 subjects (1.9%, 3/157). Among 70 patients 70–90 years of age, 18 (25.7%, 18/70) had an HRA score of 7 or higher, and early esophageal cancer was detected in 2 (11.1%, 2/18) of these patients. Early esophageal cancer was not detected in 87 patients 50–69 years of age. Early esophageal cancer was detected in a 70-year-old patient with an HRA score of 2 who had no history of drinking alcohol or smoking.

Conclusions

Our results suggest that an HRA questionnaire is useful for identifying persons 70 years or older who are at high risk for alcohol-related esophageal cancer in specialized hospitals.

     

Expression analysis of the regenerating gene (Reg) family members Reg-IIIβ and Reg-IIIγ in the mouse during development

The regenerating gene/regenerating islet-derived (Reg) family is a group of small secretory proteins. Within this family, Reg type-III (Reg-III) consists of: Reg-IIIα, -β, -γ, and -δ. To elucidate the physiological relevance of Reg-III, we examined the localization and ontogeny of Reg-IIIβ and Reg-IIIγ in mice at different time points spanning from embryonic day 13.5 to 7 weeks old, using in situ hybridization and immunohistochemistry. Our results showed that Reg-IIIβ was expressed in specific subsets of primary sensory neurons and motor neurons, and that expression was transient during the embryonic and perinatal periods. Reg-IIIβ expression was also observed in absorptive epithelial cells of the intestine. In contrast, Reg-IIIγ expression was mainly observed in epithelial cells of the airways and intestine, but not in the nervous system, and expression levels showed a gradually increasing pattern along with development. In the airways Reg-IIIγ was expressed in goblet and Clara-like cells, whereas in the intestine Reg-IIIγ was expressed in the absorptive epithelial cells and Paneth cells, and was found to be expressed in development before these organs had been exposed to the outside world. The present findings imply that Reg-IIIβ and Reg-IIIγ expression is regulated along divergent pathways. Furthermore, we also suggest that expression of Reg-IIIγ in the airway and intestinal epithelia may occur to protect these organs from exposure to antigens or other factors (e.g., microbes) in the outer world, whereas the transient expression of Reg-IIIβ in the nervous system may be associated with the development of the peripheral nervous system including such processes as myelination.     

Sensorimotor factors affecting outcome following shoulder injury

When the shoulder is subjected to an injurious mechanism, a cascade of effects results. These effects include tissue pathology and the manifestation of pain. Sensorimotor alterations also manifest, most likely as a result of tissue pathology and pain. The combination of the tissue pathology, pain, and sensorimotor alterations all directly affect outcome following injury, and thus need to be addressed by the clinician treating the shoulder injury to fully restore function. This article discusses how the sensorimotor system contributes to shoulder function and how it is altered with shoulder injury, thereby affecting outcome.     

Selenoprotein expression in Hürthle cell carcinomas and in the human Hürthle cell carcinoma line XTC.UC1.

Hürthle cell carcinomas (HTC) are characterized by mitochondrial amplification and enhanced oxygen metabolism. To clarify if defects in enzymes scavenging reactive oxygen species are involved in the pathogenesis of HTC, we analyzed selenium (Se)-dependent expression of various detoxifying selenoproteins in the HTC cell line XTC.UC1. Glutathione peroxidase and thioredoxin reductase activity was found both in cell lysates and conditioned media of XTC.UC1 cells and was increased by Na(2)SeO(3). Western blot analysis demonstrated the presence of thioredoxin reductase both in cell lysates and conditioned media and of glutathione peroxidase 3 in conditioned media. Type I 5'-deiodinase, another selenoprotein that catalyzes thyroid hormone metabolism, was detectable only in cell lysates by enzyme assay and Western blot, and responded to stimulation by both Na(2)SeO(3) and retinoic acid. A selenoprotein P signal was detected in conditioned media by Western blot, but was not enhanced by Na(2)SeO(3) treatment. In situ hybridization revealed glutathione peroxidase mRNAs in HTC specimen; glutathione peroxidase 3 mRNA levels were reduced. These data suggest adequate expression and Se-dependent regulation of a couple of selenoproteins involved in antioxidant defense and thyroid hormone metabolism in XTC.UC1 cells, so far giving no evidence of a role of these proteins in the pathogenesis of HTCs.     

Changes in lipid peroxidation, Cu/Zn-superoxide dismutase and its mRNA following an intracerebroventricular injection of 6-hydroxydopamine in mice

A single i.c.v. injection of 6-hydroxydopamine (6-OHDA) in mice resulted in a biphasic increase in lipid peroxidation as assayed by the level of thiobarbituric acid-reacting substances (TBARS). An increase in Cu/Zn-superoxide dismutase (SOD) activity was temporally related with the first peak of TBARS but remained unchanged during the second TBARS peak. This suggests that a free radical species other than O₂⁻ may be involved in the late onset increase in TBARS. The level of Cu/Zn-SOD mRNA did not immediately reflect the change in Cu/Zn-SOD activity but rather increased gradually reaching significantly higher levels only 8 weeks after i.c.v. an injection of 6-OHDA. This increase in Cu/Zn-SOD mRNA likely occurs in response to a consumption of intrinsic SOD. Thus, short- and long-term increases in lipid peroxidation likely occur by different mechanisms and studies of both are needed to elucidate the neurodegenerative process.     

Evaluation of two prognostic indices for adult T‐cell leukemia/lymphoma in the subtropical endemic area,Okinawa, Japan

Aggressive adult T‐cell leukemia/lymphoma (ATL) has an extremely poor prognosis and is hyperendemic in Okinawa, Japan. This study evaluated two prognostic indices (PIs) for aggressive ATL, the ATL‐PI and Japan Clinical Oncology Group (JCOG)‐PI, in a cohort from Okinawa. The PIs were originally developed using two different Japanese cohorts that included few patients from Okinawa. The endpoint was overall survival (OS). Multivariable Cox regression analyses in the cohort of 433 patients revealed that all seven factors for calculating each PI were statistically significant prognostic predictors. Three‐year OS rates for ATL‐PI were 35.9% (low‐risk, n = 66), 10.4% (intermediate‐risk, n = 256), and 1.6% (high‐risk, n = 111), and those for JCOG‐PI were 22.4% (moderate‐risk, n = 176) and 5.3% (high‐risk, n = 257). The JCOG‐PI moderate‐risk group included both the ATL‐PI low‐ and intermediate‐risk groups. ATL‐PI more clearly identified the low‐risk patient subgroup than JCOG‐PI. To evaluate the external validity of the two PIs, we also assessed prognostic discriminability among 159 patients who loosely met the eligibility criteria of a previous clinical trial. Three‐year OS rates for ATL‐PI were 34.5% (low‐risk, n = 42), 9.2% (intermediate‐risk, n = 109), and 12.5% (high‐risk, n = 8). Those for JCOG‐PI were 22.4% (moderate‐risk, n = 95) and 7.6% (high‐risk, n = 64). The low‐risk ATL‐PI group had a better prognosis than the JCOG‐PI moderate‐risk group, suggesting that ATL‐PI would be more useful than JCOG‐PI for establishing and examining novel treatment strategies for ATL patients with a better prognosis. In addition, strongyloidiasis, previously suggested to be associated with ATL‐related deaths in Okinawa, was not a prognostic factor in this study.     

Lynch syndrome-associated chordoma with high tumor mutational burden and significant response to immune checkpoint inhibitors

Chordoma is a rare malignant bone tumor arising from notochordal tissue. Conventional treatments, such as radical resection and high-dose irradiation, frequently fail to control the tumor, resulting in recurrence and re-growth. In this study, genetic analysis of the tumor in a 72-year-old male patient with refractory conventional chordoma of the skull base revealed a high tumor mutational burden (TMB) and mutations in the MSH6 and MLH1 genes, which are found in Lynch syndrome. The patient and his family had a dense cancer history, and subsequent germline genetic testing revealed Lynch syndrome. This is the first report of a chordoma that has been genetically proven to be Lynch syndrome. Chordomas usually have low TMB; however, this is an unusual case, because the TMB was high, and immune checkpoint inhibitors effectively controlled the tumor. This case provides a basis for determining the indications for immunotherapy of chordoma based on the genetic analysis. Therefore, further extensive genetic analysis in the future will help to stratify the treatment of chordoma.