Pemetrexed/Erlotinib as a Salvage Treatment in Patients with High EGFR-Expressing Metastatic Colorectal Cancer Following Failure of Standard Chemotherapy: A Phase II Single-Arm Prospective Study.

BACKGROUND: Despite new agents to treat metastatic colorectal cancer (CRC), patients eventually progress and additional therapies are needed. OBJECTIVE: We intended to evaluate the combination of pemetrexed/erlotinib in patients with high epidermal growth factor receptor (EGFR)-expressing (2+ or 3 on immunohistochemistry) metastatic CRC who experienced disease progression after standard chemotherapy. PATIENTS AND METHODS: We investigated pemetrexed and erlotinib (pemetrexed 500 mg/m2 on Day 1 and erlotinib 100 mg/m2 on Days 1-21) as a salvage treatment, given every 3 weeks, until disease progression or intolerable toxicity. The primary outcome was overall response rate (RR). RESULTS: From May 2017 to April 2018, 29 metastatic CRC patients with high EGFR expression who had previously received standard therapies were enrolled into this trial. The regimen was well tolerated. Skin rash, vomiting, fatigue, and anorexia were common toxic effects but were mostly manageable and controllable side effects of grades 1 or 2 only. In an intent-to-treat analysis, three partial responses (PRs) were observed in enrolled patients, revealing an overall RR of 10.3%. This value supported the statistical hypothesis of this study. Fifteen patients had stable disease and the disease control rate (DCR) was 62.1%. All three patients who achieved a PR had a tumor EGFR expression of 3+. Among the eight patients with EGFR 3+ expression, the RR and DCR were 37.5% and 75.0%, respectively. CONCLUSION: This phase II trial using pemetrexed/erlotinib in metastatic CRC with high EGFR expression met the primary endpoint of tumor response. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov (number NCT03086538).

Effect of needle type on intravascular injection in transforaminal epidural injection: a meta-analysis.

BACKGROUND: Lumbosacral transforaminal epidural injection (TFEI) is an effective treatment for spinal disease. However, TFEI may have several types of complications, some of which can be attributed to intravascular injection. We reviewed studies to compare the intravascular injection rate among different needle types. METHODS: We searched the literature for articles on the intravascular injection rate among different needle types used in TFEI. The search was performed using PubMed, MEDLINE, the Cochrane Library, EMBASE, and Web of Science. RESULTS: A total of six studies comprising 2359 patients were identified. Compared with the Quincke needle, the Whitacre needle reduced the intravascular injection rate (OR = 0.57, 95% CI = [0.44-0.73], P < 0.001). However, compared with the Quincke needle, the Chiba needle did not reduce the intravascular injection rate (OR = 0.80, 95% CI = [0.44-1.45], P = 0.46). In one study, the intravascular injection rate using a blunt-tip needle was lower than that using a sharp needle. In another study, the Whitacre and the blunt-tip needle have similar intravascular injection rates, while, the catheter-extension needle showed a reduced intravascular injection rate. CONCLUSIONS: This meta-analysis showed that the Whitacre needle reduced the intravascular injection rate as compared with the Quincke needle, but failed to establish that the Chiba needle can decrease the intravascular injection rate in TFEI. Moreover, the blunt-tip needle can reduce the intravascular injection rate compared with the Quincke needle, and the catheter-extension needle can reduce the intravascular injection rate compared with the Whitacre and the blunt-tip needle.

Phase II study of a cremophor-free, polymeric micelle formulation of paclitaxel for patients with advanced urothelial cancer previously treated with gemcitabine and platinum.

INTRODUCTION: Genexol-PM is a novel Cremophor® EL (CrEL)-free polymeric micelle formulation of paclitaxel. This multicenter phase II study was designed to evaluate the efficacy and safety of Genexol-PM monotherapy in patients with advanced urothelial carcinoma who developed disease progression after gemcitabine and cisplatin combination chemotherapy. PATIENTS AND METHODS: Patients received Genexol-PM 240 mg/m(2) intravenously over 3 h every 3 weeks without premedication. Intra-patient dose escalation to 300 mg/m(2) was allowed during the second and subsequent cycles if pre-specified toxicities were not observed during the first cycle. The primary endpoint was response. RESULTS: Thirty-seven patients were enrolled in this study. Platinum-free interval was less than 6 months in 27 (73%) patients, and 24 (64%) were categorized as having intermediate or poor prognosis according to Bajorin's criteria. Of 34 evaluable patients, there were 7 responses (21%; 95% CI, 7-34%), including one complete response (CR), with a median response duration of 6.5 months (95% CI, 3.5-9.6 months). The median time to progression was 2.7 months (95% CI, 0.9-4.6 months) with a median overall survival of 6.5 months (95% CI, 5.0-8.0 months). The most common grade 3/4 non-hematologic toxicities were peripheral neuropathy (sensory type 5.9%; motor type 8.8%) and infection (5.9%). Grade ≥3 hematologic toxicities occurred in only one patient. CONCLUSION: Genexol-PM was generally well tolerated and demonstrated sufficient antitumor activity to warrant further development when used as second-line chemotherapy after gemcitabine-cisplatin failure in patients with urothelial carcinoma (NCT01426126).

Classification of trace patterns of 226- and 1000-Hz tympanometry in healthy neonates.

OBJECTIVE: Accurate evaluation of middle ear function is a challenge especially in babies referred from newborn hearing screening programs. The aim was to assess the feasibility of tympanometry using 226- and 1000-Hz probe tones in neonates. METHODS: Hearing was evaluated by transient evoked otoacoustic emission (TEOAE) in 96 ears of healthy neonates in well-baby nursery. Babies with risk factors for hearing loss as identified in Joint Committee on Infant Hearing (JCIH, 1994) were excluded. Tympanograms recorded with 226 and 1000Hz probe tones were analyzed and classified. RESULTS: Tympanograms were classified according to Method A (Jerger/Liden) and visual classification systems, Method B (adapted from Marchant et al.) and Method C (adapted from Kei et al.), without difficulty. In 72 ears with normal TEOAE, 226Hz tympanograms were classified as normal in 72 ears in Methods A and B, and 16 ears in Method C. 1000Hz tympanograms were normal in 68 ears in Method A, 72 ears in Method B and 68 ears in Method C. In 24 ears with abnormal TEOAE, 226Hz tympanograms were interpreted as normal in most ears (23 ears in Method A, 24 ears in Method B), whereas 1000Hz tympanograms were abnormal in 13 ears in Method A and 6 ears in Method B, possibly reflecting middle ear dysfunction. CONCLUSION: In healthy neonates without risk factors for hearing loss, 1000Hz tympanograms can be recorded and interpreted. A single-peaked tympanograms was most common in ears with normal TEOAE. In ears with abnormal TEOAE, tympanograms were classified as abnormal more frequently using 1000Hz than 226Hz. Implementation of tympanometry using 1000Hz probe tone in newborn hearing screening programs may provide valuable information regarding middle ear dysfunction that may cause transient conductive hearing loss.

Oleanane-type triterpene saponins from the bark of Aralia elata and their NF-κB inhibition and PPAR activation signal pathway.

Two new oleanane-type triterpene saponins, tarasaponin IV (1) and elatoside L (2), and four known; stipuleanoside R(2) (3), kalopanax-saponin F (4), kalopanax-saponin F methylester (5), and elatoside D (6) were isolated from the bark of Aralia elata. Kalopanax-saponin F methyl ester was isolated from nature for the first time. Their chemical structures were elucidated using the chemical and physical methods as well as good agreement with those of reported in the literature. Oleanane-type triterpene saponins are the main component of A. elata. All compounds were investigated the anti-inflammatory activity. We measured their inhibition of NF-κB and activation of PPARs activities in HepG2 cells using luciferase reporter system. As results, compounds 2 and 4 were found to inhibit NF-κB activation stimulated by TNFα in a dose-dependent manner with IC(50) values of 4.1 and 9.5 µM, respectively, when compared with that of positive control, sulfasalazine (0.9 µM). Compounds 2 and 4 also inhibited TNFα-induced expression of iNOS and COX-2 mRNA. Furthermore, compounds 1-6 were evaluated PPAR activity using PPAR subtype transactivation assays. Among of them, compounds 4-6 significantly increased PPARγ transactivation. However, compounds 4-6 did not activate in any other PPAR subtypes.

A prospective phase II study of cetuximab in combination with XELOX (capecitabine and oxaliplatin) in patients with metastatic and/or recurrent advanced gastric cancer.

BACKGROUND: We evaluated the efficacy and safety of cetuximab in combination with XELOX [XELoda® (capecitabine) and OXaliplatin] in advanced gastric cancer (AGC) patients. The objectives were to evaluate overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety of cetuximab plus XELOX. METHODS: Previously untreated AGC patients received intravenous infusion of cetuximab 400 mg/m² on day 1 followed by weekly infusions of 250 mg/m². Oxaliplatin 130 mg/m² was administered intravenously on day 1 and capecitabine 1,000 mg/m² bid was administered orally for 14 days of a 3-week cycle. Chemotherapy was given until disease progression or intolerable toxicities. On completing maximum 8 cycles of chemotherapy, patients were allowed weekly cetuximab until progression. Response evaluations were done every two cycles and toxicities were assessed at each visit. RESULTS: Forty-four patients (29 male) were enrolled; median age was 57.5 years (range 36-70). In total, 253 cycles of XELOX chemotherapy (range 1-8, median 6.5 cycles) and 917 cetuximab infusions (range 1-58, median 19.0) were delivered. Overall RR was 52.3%. Median PFS and OS were 6.5 months (95% CI, 4.9-8.4) and 11.8 months (95% CI, 6.7-16.8), respectively. The most common toxicities of all grades were anemia (81.8% of patients), asthenia (81.8%), anorexia (79.6%), hand-foot syndrome (79.6%), acneiform skin eruption (77.2%), and sensory neuropathy (75.0%), and they were mostly grade 1 or 2. Grade 3-4 hematologic toxicities were uncommon (anemia, 6.8%; thrombocytopenia, 2.3%). CONCLUSIONS: Cetuximab in combination with XELOX chemotherapy was active and safe as first-line treatment of metastatic and/or recurrent AGC patients.

Multi-institutional phase II study of S-1 monotherapy in advanced gastric cancer with pharmacokinetic and pharmacogenomic evaluations.

This study describes the first phase II study of S-1, a novel oral fluoropyrimidine, in a non-Japanese Asian population with advanced gastric cancer. S-1 was administered twice daily for 28 days every 6 weeks. A pharmacokinetic study was performed on day 28 of cycles 1 and 3. Genomic DNA from peripheral mononuclear cells was analyzed using a cDNA microarray-based comparative genomic hybridization (CGH) method. Thirty-one patients were initially given a dose of 35 mg/m(2) twice daily (bid) (group 1); then, the protocol was amended by increasing the dose to 40 mg/m(2) bid for an additional 31 patients (group 2) because of good tolerability to S-1. The overall response rate was 19.3% (95% confidence interval, 9.2%-29.5%). Over a median follow-up duration of 265 days, the median time to progression and overall survival time were 126 and 264 days, respectively. The 1-year survival rate was 34%. There was no grade 4 toxicity and the major adverse event was anemia. Pharmacokinetic parameters were similar to those of the previous Japanese reports. Microarray CGH identified 18 genes with copy number changes that were associated with hemoglobin reduction with S-1 treatment. A logistic regression analysis, integrating one clinical parameter (initial hemoglobin level) combined with three genetic copy number variations (HIST1H2BL, C10orf127, and XPNPEP2), provided a predictive model for the development of severe hemoglobin reduction. In conclusion, this study showed the feasibility of using S-1 at 35 mg/m(2) bid in gastric cancer. We suggest that the pharmacogenomic markers identified in this study may be potential candidates for predicting anemia after S-1 treatment.

Randomized phase II study of gemcitabine plus cisplatin versus etoposide plus cisplatin for the treatment of locally advanced or metastatic non-small cell lung cancer: Korean Cancer Study Group experience.

BACKGROUND: Several randomized trials have demonstrated superior response rates and survivals for new agent platinum doublets than for older platinum doublets in advanced non-small cell lung cancer (NSCLC), however, few trials have been performed in Asian populations. Thus, we conducted a randomized study to compare gemcitabine-cisplatin (GP) with etoposide-cisplatin (EP) in Korean patients with advanced NSCLC. METHODS: Patients with histologically confirmed, locally advanced or metastatic NSCLC were randomized to receive either gemcitabine 1250 mg/m2 on days 1 and 8 plus cisplatin 75 mg/m2 on day 1, or etoposide 100 mg/m2 on days 1-3 plus cisplatin 75 mg/m2 on day 1. Treatment was repeated every 21 days in both groups. The primary endpoint was response rate. RESULTS: Between May 2000 and December 2001, 83 patients at 9 Korean centers were enrolled in this study. The GP arm showed a significantly higher response rate (52.6% versus 19.4%; P = 0.002), a longer time to progression (4.3 months in both arms; P = 0.018) and a marginally significant prolongation of overall survival (18.3 months versus 10.9 months; P = 0.059) than the EP arm. Grades 3 and 4 thrombocytopenia (18% versus 0%) was more common in the GP arm whereas grades 3 and 4 neutropenia was more common in EP arm (48.7% versus 71.8%). Other toxicities were comparable in both arms. CONCLUSION: GP provided a significantly higher response rate and a longer time to progression than EP and should be considered a standard treatment in advanced NSCLC in Korean population.

Is postoperative radiotherapy useful for the rectal carcinoma in the era of total mesorectal excision?

BACKGROUND/AIMS: The exact role of postoperative radiotherapy following curative surgery of rectal carcinoma has been debated. In this retrospective study, we examined the effect of radiotherapy on the survival and recurrence rate of rectal cancer patients who underwent total mesorectal excision. METHODOLOGY: Since June 1994, stage II and III rectal cancer patients have been recommended to receive postoperative chemoradiation. Among 175 consecutive patients who had undergone total mesorectal excision, 120 completed postoperative chemoradiation (group A) and 55 patients declined to receive radiation therapy (group B). For the two groups, survival and recurrence rates were compared. Mean follow-up time was 24.7 months. There was no difference between two groups with regard to sex, mean age, stage of the disease, mean tumor height, type of operation and mean follow-up duration. RESULTS: Overall recurrence rate showed no difference between the two groups (24.0% vs. 25.0%, P = 0.28). Local recurrence rate was also similar (10.0% vs. 6.0%, P = 0.11). There was no significant difference in duration to initial recurrence (14.0 months vs. 11.0 months, P = 0.18). The 5-year disease-free survival was 57% in group A and 63% in group B (P = 0.33). Disease-free survival in stage II was significantly better than in stage III. (78% vs. 42% overall, 70% vs. 37% in group A, 92% vs. 44% for group B, P < 0.01). CONCLUSIONS: In this study, we found no beneficial effect of postoperative radiation therapy following total mesorectal excision for the rectal cancer. So far, the prognosis was critically dependent on the stage rather than presence or absence of radiotherapy after total mesorectal excision.