Phase II study of nanoparticle albumin-bound paclitaxel monotherapy for relapsed non-small cell lung cancer with patient-reported outcomes (NLCTG1302).

Background: This multicenter, open-label, single-arm phase II study [Niigata Lung Cancer Treatment Group (NLCTG) 1302] was conducted to evaluate the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) monotherapy for previously treated patients with advanced non-small cell lung cancer (NSCLC). We also investigated chemotherapy-induced peripheral neuropathy (CIPN) to evaluate the quality of life (QOL). Methods: Sixty-five patients with advanced NSCLC from 14 participating institutions who had previously undergone one or two cytotoxic chemotherapy regimens were enrolled in this study. The patients received 100 mg/m2 nab-paclitaxel intravenously on days 1, 8, and 15, every 4 weeks. The primary endpoint was overall objective response rate. CIPN symptoms were prospectively assessed using the Patient Neurotoxicity Questionnaire (PNQ) and Common Terminology Criteria for Adverse Events (CTCAE). Results: The overall response rate (ORR) was 18.5% [95% confidence interval (CI): 10.9-29.6%], and the median progression-free survival (PFS) was 3.4 (95% CI: 2.5-4.3) months. Median overall survival (OS) was 8.6 (95% CI: 7.1-10.2) months. The most common non-hematologic grade ≥3 adverse events were infection (7.7%) and hyponatremia (4.6%). Neutropenia was the most common grade 3 or 4 adverse event (30.8%), and febrile neutropenia developed in 6.2% patients. The PNQ and CTCAE scores for motor peripheral neuropathy were low (kappa =0.10). Conclusions: The primary endpoint was achieved. Nab-paclitaxel was well tolerated and showed anti-tumor activity in patients with previously treated NSCLC. This study demonstrates a low degree of concordance in CIPN grading between physicians and patients. Trial Registration: University hospital Medical Information Network Clinical Trial Registry (ID: UMIN000012343).

Case report: pulmonary nocardiosis caused by Nocardia exalbida in an immunocompetent patient.

BACKGROUND: Nocardiosis is known as an opportunistic infection in immunocompromised hosts, but it occasionally has been reported in immunocompetent patient. The Nocardia exalbida is first-reported in 2006 from Japan, and a few cases of have been reported in only immunocompromised host, and the characteristic is still unclear. We herein describe the first case of pulmonary nocardiosis caused by N. exalbida in an immunocompetent patient. CASE PRESENTATION: A77 -year-old Japanese man was admitted to our hospital on November 2, 2018. He was a lifelong non-smoker with no childhood history of respiratory disease. He had a medical history of dyslipidemia. One month before this admission fevers, sputum, mild cough were developed and he was evaluated in a clinic near our hospital. His diagnosis was community acquired pneumonia within his right middle lobe. He was treated with ceftriaxone 1 g/day intravenously for a week, however his symptoms relapsed a few days later. So, the physician retried ceftriaxone for another 3 days, but his symptoms did not improve. He was referred to our hospital. He was treated with sitafloxacin as an outpatient for a week, however his symptoms got worse. The chest CT showed consolidation and atelectasis in his right middle lobe. Low density area was scattered in consolidation, and right pleural effusion was observed. The patient was diagnosed with pulmonary abscess and he was admitted. Administration of piperacillin/tazobactam improved his condition. We switched antibiotics to amoxicillin/clavulanate, and he was discharged. After 2 weeks, he relapsed and was admitted again. After administration of piperacillin/tazobactam for 3 weeks, we perform bronchoscopy and Nocardia species were cultured from samples of the bronchial wash. The isolates were identified as N. exalbida using 16S rRNA gene sequencing. We prescribed Trimethoprim / Sulfamethoxazole (TMP/SMX) for 4 months. Then we switched to minocycline for renal dysfunction caused from TMP-SMX for 1 more month. After 5 months therapy, Consolidation on CT disappeared, and Nocardiosis was cured. CONCLUSION: we reported the first case of pulmonary nocardiosis caused by N. exalbida in an immunocompetent patient. N. exalbida infection might be associated with a good response to treatment.

A prospective phase II study of multimodal prophylactic treatment for afatinib-induced adverse events in advanced non-small cell lung cancer (Niigata Lung Cancer Treatment Group 1401).

BACKGROUND: Afatinib has shown clinical benefits in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Many patients treated with afatinib experience skin or gastrointestinal toxicity. However, an effective management strategy has not been established. This prospective study was conducted to evaluate the efficacy of multimodal prophylactic treatment for afatinib-induced toxicity. METHODS: This single-arm prospective study was conducted to evaluate the efficacy of multimodal prophylactic treatment for afatinib-induced toxicity in patients with EGFR mutation positive advanced NSCLC who planned to receive a 40 mg dose of afatinib. Eligible patients were treated with oral loperamide (2 mg twice per day), prophylactic minocycline (100 mg once per day), topical medium-class steroids, and gargling with sodium azulene. The primary endpoint was the ability of prophylactic loperamide to prevent severe or intolerable diarrhea during the 4 weeks after the initial administration of afatinib. The incidence, severity and time to occurrence of diarrhea, rash, oral mucositis and paronychia were evaluated based on a daily patient questionnaire. RESULTS: Forty-six patients were enrolled. The primary endpoint analysis was performed in 35 patients as the per-protocol (PP) population. The 4-week successful prophylaxis rate for severe or intolerable diarrhea was 82.9% (90% confidence interval: 70.1-91.9%). In the total population, the incidences of grade 3 or higher rash, oral mucositis and paronychia within 4 weeks were 4%, 2% and 4%, respectively. CONCLUSIONS: Prophylactic loperamide administration was not effective in preventing severe or intolerable diarrhea during afatinib treatment. Adequate dose reduction will be a better approach to manage afatinib-induced diarrhea. Multimodal prevention using minocycline, topical steroids and gargling with sodium azulene may be helpful to maintain compliance with afatinib treatment (UMIN000016167).

Efficacy of EGFR-TKIs with or without upfront brain radiotherapy for EGFR-mutant NSCLC patients with central nervous system metastases.

BACKGROUND: Although the clinical efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) patients has been demonstrated, their efficacy in EGFR-mutant NSCLCs with central nervous system (CNS) metastases and the role of radiotherapy remain unclear. This study aimed to determine if it is preferable to add upfront cranial radiotherapy to EGFR-TKIs in patients with EGFR-mutant NSCLC with newly diagnosed brain metastases. METHODS: We retrospectively analyzed the data of EGFR-mutant NSCLC patients with CNS metastases who received EGFR-TKIs as a first-line therapy. RESULTS: A total of 104 patients were enrolled and 39 patients received upfront brain radiotherapy, while 65 patients received first and second generation EGFR-TKIs first. The median time to treatment failure (TTF) was 7.8 months (95% confidence interval [CI]: 6.3-9.4). The median survival time (MST) was 24.0 months (95% CI: 20.1-30.1). The overall response rate of the CNS was 37%. The median CNS progression-free survival (PFS) was 13.2 months (95% CI: 10.0-16.2). Brain radiotherapy prior to EGFR-TKI prolonged TTF (11.2 vs. 6.8 months, P = 0.038) and tended to prolong CNS-PFS (15.6 vs. 11.1 months, P = 0.096) but was not significantly associated with overall survival (MST 26.1 vs. 24.0 months, P = 0.525). Univariate and multivariate analyses indicated that poor performance status and the presence of extracranial metastases were poor prognostic factors related to overall survival. CONCLUSION: EGFR-TKI showed a favorable effect for EGFR-mutant NSCLC patients with CNS metastases. Prolonged TTF and CNS-PFS were observed with upfront brain radiotherapy.

Diagnosis of infective endocarditis with cardiac CT in an adult.

The diagnosis of infective endocarditis is based on modified Duke's criteria, which includes clinical, biological, and echocardiographic findings. However, computed tomography (CT) has not been mentioned as a diagnostic tool in the criteria. We report a case of infective endocarditis confirmed by cardiac CT in which we could identify vegetations and perivalvular abscess not on transthoracic echocardiography and transesophageal echocardiography. Cardiac CT was feasible imaging modality for evaluating and diagnosing infective endocarditis. Cardiac CT should be recommended in patients with clinical suspicion of infective endocarditis even when transthoracic echocardiography and transesophageal echocardiography is negative for infective endocarditis.

A case of aortic valve leaflet tear and perforations after neocuspidization.

Although aortic valve (AV) replacement is a curative procedure for severe aortic stenosis, prosthetic heart valves have many disadvantages and cause serious complications. A new promising surgical procedure-aortic valve neocuspidization (AVNeo)-has recently been developed; it is an original method of AV reconstruction with autologous pericardium. It has been reported to yield excellent medium-term results with respect to durability and complications. Herein, we encountered a first case of AV leaflet tear and perforations 27 months after AVNeo using autologous pericardium. AV leaflet tear or perforation is well recognized as a long-term serious complication of pericardial xenografts. Interestingly, however, AVNeo caused early structural valve deterioration in the current case. In the present case, an eccentric aortic regurgitation jet observed on colour flow imaging led us to reach the correct diagnosis. Finally, the patient showed complete recovery with redo AV replacement. This case highlights the importance of understanding the potential pitfalls of this new surgical technique and that of colour Doppler echocardiography in reaching a definite diagnosis.

A Phase II Study of Irinotecan for Patients with Previously Treated Small-Cell Lung Cancer.

OBJECTIVE: Chemotherapy with irinotecan plus cisplatin has shown promise in chemo-naïve small-cell lung cancer (SCLC) patients. However, irinotecan treatment for relapsed or refractory SCLC has not been adequately evaluated. This phase II study evaluated the appropriate treatment schedule of irinotecan as a single agent. This study was designed to determine the antitumor activity, toxicity, and survival in previously treated SCLC patients. METHODS: Previously treated SCLC patients with at least one platinum-based regimen received irinotecan (100 mg/m2) on days 1 and 8, every 3 weeks, until disease progression. The assessment of the response rate was the primary endpoint. RESULTS: Thirty patients were enrolled, with an objective response rate of 41.3% (95% confidence interval [CI] 25.5-59.3), and a disease control rate of 69%. Median progression-free and overall survival was 4.1 months (95% CI, 2.2-5.4) and 10.4 months (95% CI, 8.1-14), respectively. The grade 3/4 hematological toxicities were neutropenia (36.7%), thrombocytopenia (3.3%), anemia (13.3%), and febrile neutropenia (6.6%). There were no grade 4 nonhematological toxicities. Frequent grade 3 nonhematological toxicities included diarrhea (10%), anorexia (6.6%), and hyponatremia (6.6%). CONCLUSIONS: This phase II study showed a high objective response rate and long survival. Irinotecan monotherapy schedule used was well tolerated, and could be an active treatment option for these patients.

Segregation by size difference in binary suspensions of fluid droplets in channel flow.

In channel flow of multicomponent suspensions, segregation behavior of suspended components perpendicular to the flow direction is often observed, which is considered to be caused by the differential properties of the lateral migration depending on their shape, size, flexibility, and other characteristics. In the present study, we investigate the effect of size differences between suspended components on the segregation behavior, by a two-dimensional numerical simulation for binary dispersed suspensions of fluid droplets of two different sizes subjected to a plane Poiseuille channel flow. The small and large droplets are assumed to have equal surface tensions and equal viscosity ratios of internal to external fluids. The time evolutions of the lateral positions of large and small droplets relative to the channel centerline were computed by changing the area fraction of the small droplets in a mixture with a constant total area fraction. The large droplets are found to migrate closer to the channel centerline and the small droplets are found to migrate closer to the channel wall compared to the corresponding lateral positions in mono-dispersed suspensions at the same area fractions, although the mean lateral positions of the large and small droplets in mono-dispersed suspension are comparable. This segregation behavior as well as the margination of small droplets are enhanced when the size difference between large and small droplets is increased and the area fraction of large droplets is increased. These results may arise from higher tendencies for the large droplets to approach the channel centerline compared to the small droplets, which consequently expel small droplets from the central region toward the channel walls.

The efficacy of triplet antiemetic therapy with 0.75 mg of palonosetron for chemotherapy-induced nausea and vomiting in lung cancer patients receiving highly emetogenic chemotherapy.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) are some of the most problematic symptoms for cancer patients. Triplet therapy consisting of a 5HT3 receptor antagonist, aprepitant, and dexamethasone is a guideline-recommended antiemetic prophylaxis for highly emetogenic chemotherapy (HEC). The efficacy and safety of triplet therapy using a 0.75-mg dose of palonosetron have not yet been investigated. We performed a prospective phase II study using triplet antiemetic therapy with 0.75 mg of palonosetron. METHODS: Chemotherapy-naïve lung cancer patients scheduled to receive HEC were enrolled. The eligible patients were pretreated with antiemetic therapy consisting of the intravenous administration of 0.75 mg of palonosetron, and 9.9 mg of dexamethasone and the oral administration of 125 mg of aprepitant on day 1, followed by the oral administration of 80 mg of aprepitant on days 2-3 and the oral administration of 8 mg of dexamethasone on days 2-4. The primary endpoint was the complete response rate (the CR rate; no vomiting and no rescue medication) during the overall phase (0-120 h). RESULTS: The efficacy analysis was performed in 63 patients. The CR rates during the overall, acute and delayed phases were 81.0, 96.8, and 81.0%, respectively. The no nausea and no significant nausea rate during the overall phase were 54.0 and 66.7%, respectively. The most common adverse event was grade 1 or 2 constipation. CONCLUSIONS: Triplet antiemetic therapy using a 0.75-mg dose of palonosetron shows a promising antiemetic effect in preventing CINV in lung cancer patients receiving HEC.

Multicenter safety study of mFOLFOX6 for unresectable advanced/recurrent colorectal cancer in elderly patients.

BACKGROUND: Combination chemotherapy with oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX) has become a standard regimen for colorectal cancer. An increase of adverse events with combination chemotherapy is predicted in elderly patients, and it remains controversial whether they should receive the same chemotherapy as younger patients. Accordingly, this study of modified FOLFOX6 (mFOLFOX6) therapy was performed to compare its safety between elderly and non-elderly patients. METHODS: We prospectively studies 14 non-elderly patients aged <70 years old and 8 elderly patients aged >or= 70 years with unresectable advanced/recurrent colorectal cancer who received mFOLFOX6 therapy during the period from March 2006 to March 2007. Adverse events and the response to treatment were compared between the elderly and non-elderly groups. RESULTS: The main adverse events were neutropenia and peripheral neuropathy, which occurred in 62.5% (>or= grade 3) and 87.5% (>or= grade 1) of elderly patients. The grade and frequency of adverse events were similar in the elderly and non-elderly groups. In some patients with neutropenia, treatment could be continued without reducing the dose of oxaliplatin by deleting bolus 5-fluorouracil. A correlation was found between the cumulative dose of oxaliplatin and the severity of neuropathy, and there were 2 elderly and 3 younger patients in whom discontinuation of treatment was necessary due to peripheral neuropathy. The median number of treatment cycles was 10.0 and 9.5 in the non-elderly and elderly groups, respectively. The response rate was 60.0% in the non-elderly and 50.0% in the elderly group, while the disease control rate was 100% and 83.3% respectively, showing no age-related difference. CONCLUSION: mFOLFOX6 therapy was well-tolerated and effective in both non-elderly and elderly patients. However, discontinuation of treatment was sometimes necessary due to peripheral neuropathy, which is dose-limiting toxicity of this therapy.

Electrokinetic boundary condition compatible with the Onsager reciprocal relation in the thin double layer approximation.

The boundary condition, which has been used in the conventional electrokinetic calculation in the thin double layer approximation, has a flaw that it does not give the Onsager reciprocal relation for the sedimentation of charged particle. We propose a new boundary condition, which satisfies the reciprocal relation, and derive a general form for the mobility matrix for the motion of a charged particle under the action of external force, torque, and electric field. We then calculate the mobility matrix explicitly for homogeneously charged spherical particle and discuss the effect of the surface slippage and the surface conductivity on the particle mobility and electric conductivity.

Prognostic significance of receptor-binding cancer antigen expressed on SiSo cells (RCAS1) expression in relation to cadherin expression in patients with colorectal carcinoma.

PURPOSE: This study was designed to assess the prognostic value of receptor-binding cancer antigen expressed on SiSo cells expression and its relationship with cadherin expression in patients with colorectal cancer. METHODS: The expressions of receptor-binding cancer antigen expressed on SiSo cells and E-cadherin were analyzed with special reference to prognosis in 105 patients with colorectal cancer. RESULTS: Receptor-binding cancer antigen expressed on SiSo cells immunoreactivity was detected in the membrane and cytoplasm of tumor cells and considered to be positive in 48 patients (45.7 percent). The expression of receptor-binding cancer antigen expressed on SiSo cells was significantly correlated with lymph node metastasis (P = 0.0004), venous invasion (P = 0.0062), Dukes stages (P < 0.0001), and serum levels of carcinoembryonic antigen (P = 0.014). Furthermore, receptor-binding cancer antigen expressed on SiSo cells expression was significantly correlated with a poor prognosis (P < 0.001), and multivariate analysis indicated that it was an independent prognostic indicator. The expression of receptor-binding cancer antigen expressed on SiSo cells was more frequently found in tumors with reduced or abnormal expression of E-cadherin. The survival time of patients with reduced/abnormal E-cadherin expression was significantly shorter than that of patients with normal E-cadherin expression among patients with receptor-binding cancer antigen expressed on SiSo cells expression (P = 0.0043) but did not differ for those without receptor-binding cancer antigen expressed on SiSo cells expression (P = 0.17). Furthermore, multivariate analysis revealed that reduced/abnormal expression of E-cadherin was an independent prognostic factor in patients with receptor-binding cancer antigen expressed on SiSo cells expression but not in those without receptor-binding cancer antigen expressed on SiSo cells expression. CONCLUSIONS: Receptor-binding cancer antigen expressed on SiSo cells expression is significantly correlated with tumor progression and poor prognosis in patients with colorectal cancer. Both reduced E-cadherin and enhanced receptor-binding cancer antigen expressed on SiSo cells expression may be critical for the mechanism of metastasis and recurrence in human colorectal cancer.

Simulation of DNA motion in a microchannel using stochastic rotation dynamics.

The authors propose a method to simulate the DNA motion in microchannels of complex geometry. It is based on stochastic rotation dynamics using a new scheme for the boundary condition. The method enables them to define a boundary wall of arbitrary shape and to describe a wall moving at an arbitrary velocity. As an application, they simulate the motion of DNA in Poiseuille flow between two parallel planes and show that DNA molecules tend to concentrate near the center of the channel in agreement with experimental results.

Involvement of reactive oxygen intermediate in the enhanced expression of virulence-associated genes of Listeria monocytogenes inside activated macrophages.

Listeriolysin O encoded by 1,587 bp hly is the essential virulence factor of Listeria monocytogenes that replicates in the cytosolic space after escaping from phagosome of macrophages. By using murine macrophage-like J774.1 cells with or without activation by IFN-gamma plus LPS, the expression of both hly and its positive regulator prfA was monitored by means of RT-PCR. In activated J774.1 cells, the level of hly expression was enhanced although the multiplication of bacteria was significantly suppressed. The elevated expression of hly inside activated macrophage was abolished by addition of SOD and catalase, suggesting that reactive oxygen intermediates contribute to the upregulation of prfA and hly transcriptions. Moreover, we found that exposure of L. monocytogenes to H2O2 dramatically enhanced the expression of both prfA and hly mRNAs. Spontaneous ONOO- generator, SIN-1, also promoted the transcription to a certain level. These results suggested that oxygen radicals generated in activated macrophages provide a positive signal for up-regulation of virulence genes in L. monocytogenes.

[Two cases of acute respiratory failure associated with pneumonia requiring mechanical ventilation before diagnosis of amyotrophic lateral sclerosis].

We present two cases of acute respiratory failure requiring mechanical ventilation before diagnosis of amyotrophic lateral sclerosis (ALS). The patients were men of 60 (patient 1) and 74-years old (patient 2), both of whom exhibited acute respiratory failure requiring mechanical ventilation. Diagnoses of ALS were made because of continuous aspiration caused by bulbar palsy in patient 1, and, in patient 2, because of the progressive muscle atrophy that occurred during unsuccessful attempts to wean the patient from ventilatory support. Physicians should be aware of the possibility of ALS in cases of acute respiratory failure, CO2 narcosis, continuous aspiration, and difficulty of weaning from mechanical ventilation.

Immunohistochemical dihydropyrimidine dehydrogenase expression is a good prognostic indicator for patients with Dukes' C colorectal cancer.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) is an enzyme that catabolizes 5-fluorouracil (5-FU), which is widely used for chemotherapy in patients with advanced colorectal cancer (CRC). However, the clinical importance of tumor dihydropyrimidine dehydrogenase (DPD) expression in patients with CRC treated with 5-FU remains unclear. MATERIALS AND METHODS: We investigated DPD activities in normal mucosa (N) and tumors (T) by enzyme-linked immunosorbent assay (ELISA) in 64 surgically resected patients with Dukes' C CRC who were treated orally with postoperative adjuvant FU-based chemotherapy. We also immunohistochemically investigated DPD expression in these specimens. The clinicopathological importance of DPD activity and expression was evaluated in the patients. RESULTS: Positive DPD expression was detected in 28 tumors (43.8%) and tumor DPD activity significantly correlated with tumor DPD immunoreactivity (p=0.0121). Further, tumor DPD activity and immunoreactivity also correlated with lymph node metastatic status (p=0.0409). The disease-free survival rate of patients with positive-tumor DPD expression was significantly worse than that of patients with negative-tumor DPD expression (39.3% vs. 72.2%, p=0.0127). However, DPD activity in tumors or normal mucosa did not correlate with patient prognosis. Tumor DPD expression appeared to be an important poor prognostic factor in patients with Dukes' C CRC by multivariate analysis (p=0.013). CONCLUSION: Immunohistochemical DPD expression in tumors is a useful prognostic parameter in patients with Dukes' C CRC treated with postoperative adjuvant FU-based chemotherapy.

Thymidine phosphorylase and dihydropyrimidine dehydrogenase activity in colorectal carcinoma and patients prognosis.

BACKGROUND AND AIMS: 5-Fluorouracil (5-FU) is a widely used for colorectal carcinoma. However, the therapeutic effect of 5-FU differs among patients. This difference may be based on the difference in sensitivity of carcinoma cells to 5-FU. The activities of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) are reported to be correlated with cancer cell sensitivity against 5-FU in vitro. We evaluated whether TP and DPD are useful markers of tumor sensitivity for 5-FU in colorectal carcinomas. PATIENTS AND METHODS: We analyzed the TP and DPD in 189 patients with colorectal carcinoma using an enzyme-linked immunosorbent assay in relation to patients prognosis. RESULTS: The tumors' mean TP activity was significantly higher than that of noncancerous tissues (100 vs. 47 U/mg protein), but the tumors' mean DPD activity was significantly lower than that of noncancerous tissues (58 vs. 84 U/mg protein). Tumor TP, DPD, and TP/DPD values were not correlated with tumor location or histological types of tumors. Even tumor TP and TP/DPD values in Dukes' stage A tumors were lower than those of other stages; DPD values were not correlated with tumor stages. In 100 patients who underwent intravenous adjuvant 5-FU chemotherapy, prognosis was not correlated with tumor-TP, DPD, or TP/DPD values. Moreover, in 20 patients with synchronous liver metastasis who underwent postoperative 5-FU therapy through the hepatic artery, the survival times of patients was not correlated with tumor-TP, DPD, or TP/DPD values. CONCLUSIONS: These findings indicate that it is questionable to decide the indication of 5-FU chemotherapy according to tumor TP or DPD status in patients with colorectal cancer.

Expression of heavy subunit of gamma-glutamylcysteine synthetase (gamma-GCSh) in human colorectal carcinoma.

Gamma-glutamylcysteine synthetase (gamma-GCS) is a heterodimer consisting of heavy (gamma-GCSh) and light (gamma-GCSl) subunits. gamma-GCS catalyzes the rate-limiting de novo biosynthesis of glutathione (GSH), an abundant physiological antioxidant that plays important roles for regulating oxidative stress. Expression of gamma-GCSh and gamma-GCSl are sensitive to oxidative stress. To investigate whether expression of gamma-GCS is correlated with tumor progression, we used immunohistochemical approaches to examine 16 human colorectal adenomas and resected 57 carcinomas from untreated patients. In adjacent normal colorectal epithelium, levels of gamma-GCSh expression were low. Strong cytoplasmic staining for gamma-GCSh was detected in 3 (18.8%) adenoma and 48 (84.2%) carcinomas. The frequency of gamma-GCSh expression in carcinoma was significantly higher than in adenoma (p<0.0001). We used RNase protation assay and Western blot to determine levels of gamma-GCSh mRNA and protein from 10 pairs of matched carcinomas with adjacent normal controls. Elevated expression of both gamma-GCSh mRNA and protein were found in 6 cases, suggesting that transcriptional and/or posttranscriptional regulation play an important role in the upregulation of gamma-GCS during colorectal carcinogenesis. We also examined the expression of another redox-regulated gene, multidrug resistance protein 1 (MRP1). Strong staining for MRP1 was detected in 1 (6.3%) adenoma and 40 (70.2%) carcinomas. The frequency of MRP1 expression in carcinoma was significantly higher than in adenoma ( p<0.0001). Nuclear p53 expression was detected in 30 (52.6%) of carcinomas. There is a significant correlation between gamma-GCSh and MRP1 expression (p=0.013) but not between gamma-GCSh and p53. Since gamma-GCS is a sensor of oxidative stress, these results are consistent with the notion that oxidative stress is associated with colorectal tumor progression.