TP53 signature predicts pathological complete response after neoadjuvant chemotherapy for breast cancer: Observational and confirmational study using prospective study cohorts.

The TP53 signature is considered a predictor of neoadjuvant chemotherapy (NAC) response and prognostic factor in breast cancer. The objective of this study was to confirm TP53 signature can predict pathological complete response (pCR) and prognosis in cohorts of breast cancer patients who received NAC in prospective studies. Development cohorts (retrospective [n = 37] and prospective [n = 216] cohorts) and validation cohorts (NAC administered prospective study cohorts [n = 407] and retrospective perioperative chemotherapy (PC)-naïve, hormone receptor (HrR)-positive cohort [PC-naïve_HrR+ cohort] [n = 322]) were used. TP53 signature diagnosis kit was developed using the development cohorts. TP53 signature predictability for pCR and the relationship between recurrence-free survival (RFS), overall survival (OS), and the TP53 signature were analyzed. The pCR rate of the mutant (mt) signature group was significantly higher than that of the wild-type (wt) signature group (odds ratio, 5.599; 95 % confidence interval = 1.876-16.705; P = 0.0008). The comparison of the RFS and OS between the HrR+ and HER2- subgroup of the NAC cohort and of the PC-naïve_HrR+ cohort indicated that the RFS and OS benefit of NAC was greater in the mt signature group than in the wt signature group. From post hoc analyses, the RFS and OS benefit from adding capecitabine to FEC+T as NAC might be observed only in the mt signature group. The TP53 signature can predict the pCR after NAC, and the RFS and OS benefit from NAC may be greater in the mt signature group than in the wt signature group.

The Oxygen Reserve Index as a determinant of the necessary amount of postoperative supplemental oxygen.

BACKGROUND: Although blood gas analysis (BGA) is important for supplemental oxygen titration, it is invasive, intermittent, costly, and burdensome for staff. We assessed whether the Oxygen Reserve Index (ORi™), a novel pulse oximeter-based index that reflects the partial pressure of oxygen (PaO2), could determine the amount of postoperative supplemental oxygen. We also evaluated the extent of hyperoxia and hypoxia. METHODS: Fifty patients scheduled to undergo breast surgery were randomly assigned to receive ORi-based oxygen (group O) or conventional postoperative oxygen (group C) treatments. Postoperatively, patients were transported to the Post-Anesthesia Care Unit (PACU) and then to general wards. In group O, oxygen was administered at 4 L·min-1 in the operation room after extubation and was decreased if the ORi was >0.00 until a continuous index of 0.00 was achieved for 30 min in the PACU and wards. In group C, oxygen was administered at 4 L·min-1 throughout the evaluation period. BGA was performed 1 h after anesthesia induction (T0), after extubation (T1), before PACU exit (T2), and on the first postoperative morning (T3). Percutaneous oxygen saturation was measured every two seconds from 9 PM after surgery to 6 AM the next morning. RESULTS: The supplemental oxygen amount and PaO2 were significantly lower in group O than group C at T2 (1.5 [0.5-3.0] vs. 4.0 [4.0-4.0] L/min, 117.3 [26.8] vs. 170.0 [42.8] mmHg) and T3 (1.0 [0.5-3.0] vs. 4.0 [4.0-4.0] L/min, 107.5 [16.5] vs. 157.1 [28.4] mmHg; median [interquartile ranges] and mean [1 SD]; P<0.01). No patient exhibited hypoxia. CONCLUSIONS: Based on our results, ORi might be useful to titrate postoperative oxygen supplementation.

A survey on the current status of clinical resources for diagnosis and treatment of breast cancer in rural hospitals of the Tohoku region in Japan.

BACKGROUND: We administered a questionnaire survey to assess the available clinical resources for the diagnosis and treatment of breast cancer and identify the issues faced by rural hospitals in the Tohoku region in Japan. METHODS: The term rural hospital was defined by the following three criteria: the facility is a certified regional cancer center and hospital, no breast specialist is on staff, and ≥ 10 breast surgeries per year have been performed. Thirty-eight rural hospitals were eligible, and each was sent a self-administered questionnaire consisting of 26 questions by mail. RESULTS: Responses were received from 29 of the 38 hospitals. Most of the hospitals had adequate facilities for diagnosis and treatment, but they needed specialists' support for ≥ 2 days per month. Approximately half of the hospitals indicated that applying resources for diagnosis and treatment of breast cancer, especially during planning of treatment and management of advanced breast cancer patients, was a burden. Interestingly, the hospitals felt that being able to provide treatment to their patients was more ideal rather than referring them to urban hospital like the prefectural cancer center and hospital providing specialized cancer treatment. CONCLUSIONS: The surveyed rural hospitals needed practical and knowledge-based support from specialists. Unfortunately, the number of specialists is currently insufficient in Tohoku. Increased number of certified physicians, clinical pathways for sharing patient's information and updated knowledge, and information and communication technology for treatment with specialists' intervention in rural hospitals may solve issues in Tohoku.

The C-reactive protein to albumin ratio predicts postoperative complications in oldest-old patients with colorectal cancer.

PURPOSE: The C-reactive protein to albumin ratio (CAR) is a simple and useful score for predicting the outcomes of patients with various cancers. The aim of this study was to evaluate the CAR and short-term outcomes in oldest-old patients with colorectal cancer. METHODS: A total of 126 patients aged 85 years and older with colorectal cancer who underwent resection for primary colon cancer from April 2015 to December 2018 were included. The preoperative cutoff value of the CAR for predicting postoperative complications was 0.19 on receiver operating characteristic curve analysis. Clinical characteristics and inflammation-based scores were compared between patients with a high CAR (CAR ≥ 0.19, n = 44) and a low CAR (CAR < 0.19, n = 82). RESULTS: A high preoperative CAR level (≥ 0.19) was significantly associated with stoma construction (p = 0.004), blood loss (p = 0.003), postoperative complications (p = 0.016), and systemic inflammation marker levels, including a low neutrophil to lymphocyte ratio (p = 0.006), a low platelet to lymphocyte ratio (p = 0.005), a low prognostic nutritional index (p < 0.001), and a high modified Glasgow prognostic score (p < 0.001). On univariate and multivariate analyses, only the CAR was an independent predictor of postoperative complications (HR 2.864, p = 0.029). CONCLUSIONS: A high CAR was significantly associated with postoperative complications for oldest-old patients with colorectal cancer.

Deterioration of Glycemic Control Contributes to the Prevalence of Proteinuria among Bevacizumab-Treated Cancer Patients with Type 2 Diabetes Mellitus.

The objective of this study was to investigate whether improving glycemic control reduces the prevalence and progression of proteinuria among bevacizumab (BEV)-treated cancer patients with type 2 diabetes mellitus (DM). We retrospectively reviewed the medical records of 55 patients with type 2 DM who were treated with BEV between July 1 2011 and May 31 2018 at Iwate Medical University Hospital. The patients were classified based on changes in glycated hemoglobin (HbA1c) level during the 3 months following BEV administration into the "HbA1c elevated" group (+0.5% or above, n=24) and the "HbA1c non-elevated" group (indicating no change or decrease; n=31). At 3 months following BEV administration, the means of HbA1c and its change rate in the 'HbA1c elevated' group was significantly higher than that in the 'HbA1c non-elevated' group, and the prevalence of proteinuria in the 'HbA1c elevated' group was significantly higher than that in the 'HbA1c non-elevated' group. Additionally, our subjects were classified into the proteinuria group and non-proteinuria group. The mean HbA1c level in the proteinuria group was significantly higher than that in the non-proteinuria group at 3 months following BEV administration. Furthermore, the mean rates of change of HbA1c level in patients experiencing grades 1 and 2 proteinuria were +9.97±2.26 and +14.0±3.82%, respectively. These values were significantly higher than those of patients with no proteinuria (-2.15±1.96%). Our results suggest that deterioration of glycemic control contributes to the prevalence of proteinuria among BEV-treated cancer patients with type 2 DM.

The efficacy of sodium azulene sulfonate L-glutamine for managing chemotherapy-induced oral mucositis in cancer patients: a prospective comparative study.

BACKGROUND: The efficacy of sodium azulene sulfonate L-glutamine (GA) in treating oral mucositis caused by the administration of anticancer agents has not been previously elucidated. Therefore, this prospective comparative study was conducted to evaluate the efficacy of GA in treating oral mucositis caused by chemotherapy regimens involving fluorinated pyrimidine anticancer drugs. METHODS: The subjects of this study were patients with oral mucositis of grade 2 or higher while on outpatient chemotherapy regimens involving fluorinated pyrimidine anticancer drugs for colorectal or breast cancer. The subjects were randomly divided into a group that received GA (the GA group) or a group that did not receive GA (the control group) by using the closed-envelope method. GA was administered three times a day every day from the first day of the regimen until the final day. The primary endpoint was the development of oral mucositis of grade 2 or higher. The secondary endpoint was the severity of oral pain, which was judged using an 11-stage numerical rating scale (NRS) ranging from 0 to 10. RESULTS: The proportion of patients with oral mucositis of grade 2 or higher was 32.4% in the GA group and 57.6% in the control group. The GA group had a significantly lower frequency of occurrence. The changes in the NRS scores before and after the trial began were - 2.9 ± 0.6 in the GA group and - 1.2 ± 0.5 in the control group. The NRS score decreased more significantly in the GA group than in the control group (P = 0.046). One patient stopped GA treatment voluntarily due to nausea; other than nausea, no GA-related side effects were observed. CONCLUSIONS: GA protects against oral mucositis and reduces the severity of prevailing oral mucositis symptoms. Our findings indicate that GA is a highly safe and convenient drug.

Effect of olanzapine for breast cancer patients resistant to triplet antiemetic therapy with nausea due to anthracycline-containing adjuvant chemotherapy.

OBJECTIVE: Triplet antiemetic therapy with neurokinin 1 receptor blocker, 5-hydroxytryptamine receptor blocker and steroids is commonly used in patients who are highly emetic after chemotherapy. However, an alternative antiemetic therapy for patients who are resistant to triplet antiemetic therapy is not established. Olanzapine is recommended in the guidelines as an optional antiemetic drug. However, the effectiveness of adding olanzapine to triplet antiemetic therapy is unknown. In this study, the effectiveness and safety of adding olanzapine to triplet antiemetic therapy with aprepitant, palonosetron and dexamethasone as highly emetic anthracycline-containing adjuvant chemotherapy for primary breast cancer patients were prospectively investigated. METHODS: Forty-five patients with breast cancer who experienced >Grade 1 nausea or any vomiting after the first cycle of chemotherapy using both epirubicin and cyclophosphamide were included. Low-dose olanzapine (2.5 mg/day) was administered orally from the first day of chemotherapy for 4 days, and the number of episodes of vomiting, scale of nausea, dietary intake and somnolence were compared with the symptoms after the first cycle. RESULTS: As the primary endpoint, the nausea grade was significantly improved by adding olanzapine (P < 0.05). As the secondary endpoints, mean nausea scale (3.2→1.9, Day 1; 3→1.3-1, Days 2-6) and dietary intake (33.6→53.8%, Day 1; 42.0→60.7-78.1%, Days 2-6) were improved by adding olanzapine. Only four patients withdrew due to somnolence and/or dizziness. CONCLUSIONS: This study demonstrated the effectiveness and tolerability of adding low-dose olanzapine for patients with insufficient nausea relief with triplet antiemetic therapy consisting of palonosetron, steroid and aprepitant.

Pulmonary hilar lymph node metastasis of breast cancer induced bronchopleural fistula and superior vena cava syndrome.

BACKGROUND: It is extremely rare for pulmonary hilar lymph node metastasis (PHLNM) of a cancer to be independently lethal. Here, we report an exceedingly rare case of cavitation in PHLNM from breast cancer triggering broncho-pleural fistula and empyema (BPFE), complicated with superior vena cava syndrome (SVCS). CASE REPORT: A 56-year-old woman who had undergone left segmental mastectomy and axillary lymph node dissection due to left breast cancer was then treated for 1 year with postoperative adjuvant chemotherapy. Recurrence of right PHLNM was observed 2 years after the operation, for which 3 courses of bevacizumab (BEV) and paclitaxel combination chemotherapy were administered. The woman had dyspnea and fever during the washout period, and CT examination revealed fistula formation between the right PHLNM cavitation and right main bronchus, so she was admitted for further treatment. This fistula rapidly progressed to BPFE, and contralateral aspiration was observed to cause pneumonia of the left lung. In addition, edema of both upper limbs and head and neck were observed, and CT examination revealed SVCS caused by re-enlargement of PHLNM. Active treatment was performed, but the recommencement of chemotherapy was not possible, and she died on Day 150 of admission. CONCLUSIONS: We think that PHLNM deteriorated to central necrosis due to chemotherapy with BEV taking effect, leading to formation of BPFE. The case was also made more difficult due to the complication of SVCS caused by the re-enlarged PHLNM.

A phase I study of capecitabine combined with CPT-11 in metastatic breast cancer pretreated with anthracyclines and taxanes.

OBJECTIVE: A dose escalation study of biweekly irinotecan (CPT-11) combined with capecitabine was performed to determine the maximum tolerated dose (MTD) and recommended dose (RD) for metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes. METHODS: Escalating doses of CPT-11 (80-120 mg/m(2)) were administered on days 1 and 15. Capecitabine was administered at a fixed dose of 1,657 mg/m(2)/day for 21 consecutive days, followed by 7 days of rest. We treated 3-6 patients at a particular dose level until the MTD was determined. RESULTS: Twenty patients were treated. The MTD was determined to be 100 mg/m(2), as 3 of 6 patients developed dose-limiting toxicities, grade 3 leukopenia, neutropenia, photophobia, fatigue and diarrhea. The RD for the phase II study was thus determined to be 90 mg/m(2). The response rate was 41.7%. CONCLUSIONS: Combination therapy with CPT-11 and capecitabine was well tolerated with a promising response rate for MBC that had been treated previously with anthracyclines and taxanes. A multi-center phase II study is warranted to evaluate the efficacy and safety of this combination therapy with pharmacokinetic assessment.

Long-term complete remission of metastatic breast cancer, induced by a steroidal aromatase inhibitor after failure of a non-steroidal aromatase inhibitor.

PATIENT: Female, 56 FINAL DIAGNOSIS: Breast cancer Symptoms: Solid mass in the right breast Medication: Exemestane Clinical Procedure: - Specialty: Oncology. OBJECTIVE: Unusual clinical course. BACKGROUND: The efficacy of third-generation aromatase inhibitors for hormone receptor-positive postmenopausal metastatic breast cancer is well established. Although several clinical trials have reported incomplete cross-resistance between different aromatase inhibitors, few cases of complete responses of recurrent metastatic breast cancer occurring after substituting a second aromatase inhibitor have been reported. We here present a rare case of non-steroidal aromatase inhibitor-tolerant metastatic breast cancer with long-term complete remission following substitution of a steroidal aromatase inhibitor. CASE REPORT: We present the case of a 56-year-old Japanese woman who underwent right breast-conserving surgery for breast cancer, TNM staging T1, N0, M0, Stage I. She received adjuvant chemotherapy with 6 cycles of FEC100 and radiation therapy, and then began hormonal therapy with anastrozole. Twelve months postoperatively, computed tomography (CT) revealed multiple lung metastases. Exemestane was substituted for anastrozole. After 3 months of exemestane, CT showed that all lung metastases had completely resolved. Her complete response was maintained for 5 years: she died during a tsunami 6 years after the initial surgery. CONCLUSIONS: Substitution of a steroidal for a non-steroidal aromatase inhibitor produced a sustained complete remission in a patient with hormonal receptor-positive postmenopausal recurrent breast cancer. Achieving complete response after switching from a non-steroidal to a steroidal aromatase inhibitor in a hormonal receptor-positive postmenopausal recurrent breast cancer contributed to a higher quality of life for the patient. Further investigation is needed to identify the predictors of long-term remission following such a switch.

[Efficacy and safety of administration of low-dose unfractionated heparin (LDUH) for the prevention of pulmonary thromboembolism after surgery for lung cancer; the long term outcome].

We evaluated the efficacy and safety of the administration of low-dose unfractionated heparin(LDUH)for the prevention of pulmonary thromboembolism after lung cancer surgery. We operated on 206 patients with primary lung cancer for 8 years;128 males and 78 females, mean age:69.9±8.8 years. All patients were administrated LDUH 5,000 units every 12 hours from the operation day until the day when the patient could walk around the floor. No patients suffered from clinical pulmonary thromboembolism in this period. The duration of treatment was 4.6±2.6 days and the chest tube duration was 5.4±3.0 days. We experienced post-operative intra-thoracic bleeding in 2 patients during the previous 4 years. Based on this experience, we introduced new eligibility criteria;we discontinued LDUH administration on the operation day if diffuse adhesion in the thoracic cavity was observed at operation or intraoperative blood loss was over 500 ml. The dose of LDUH was decreased to 2,500 unit every 12 hours if the postoperative bleeding was over 400 ml on the operation day or the patient's body weight was less than 40 kg. After introduction of the new criteria, no severe bleeding complications occurred during the latter 4 years.

[A rare case of gallbladder cancer with giardiasis].

A 72-year-old man was referred to our hospital for suspected gallbladder cancer. We performed cholecystectomy with liver bed resection and lymph node dissection. Intraoperative cytological examination of the bile juice revealed some trophozoites of Giardia lamblia, and pathological examination revealed gallbladder cancer. Therefore, we diagnosed giardiasis associated with gallbladder cancer. We administered 750 mg per day metronidazole for 10 days. The patient was a farmer by occupation and used animal manure for agricultural purposes; he also consumed his own harvest, which was recognized as the infection route for his giardiasis. We reviewed the literature and found very few cases of giardiasis associated with gallbladder cancer.

[The ideal follow-up after breast cancer operation].

With the increase in breast cancer patients in Japan, therapy for breast cancer has progressed with evidence-based medicine (EBM), and most of it has shifted to outpatient clinics (OPC) except for surgery. With the specialization of surgical techniques and pharmacological treatments, i. e. sentinel node biopsy and advanced medical treatment, many patients now visit specialized cancer clinics, and the congestion has resulted in difficulty in follow-up after surgery, and the reconsideration of how to follow-up is under way. Although the clinical guideline issued by the Japanese Breast Cancer Society recommends performing a careful history, physical examination and annual mammography, each clinic has its own follow-up program with additional modalities different approaches in EBM. Here we investigate the recommendations of the clinical guideline, how they discuss evidence, and we attempt to pinpoint the problems when used at the daily clinical level while considering the characteristics of current breast cancer practice. Then, we considered the specific characteristics of breast cancer revealed by meta-analyses, the effect of long-term adjuvant endocrine therapy after surgery, and reflecting the patient's intent in follow-up in order to conduct an ideal follow-up with a view to cooperation between cancer specialized hospitals and community clinics.

[Palliative chemotherapy for metastatic breast cancer with capecitabine].

We examined 51 patients treated with Capecitabine for metastatic breast cancer. 51 patients achieved a 30.8% response rate, 59.6% a clinical benefit rate(59.6%)and 7.2 M of time to disease progression, as previously reported. Capecitabine therapy, single agent or combination therapy, should be considered a treatment of choice for metastatic breast cancer with certain response and general tolerability.

Angiotensin II and epidermal growth factor receptor cross-talk mediated by a disintegrin and metalloprotease accelerates tumor cell proliferation of hepatocellular carcinoma cell lines.

AIM: The cross-talk pathway between angiotensin II (AngII) and the epidermal growth factor receptor (EGFR) mediated by epidermal growth factor (EGF)-like ligands cleaved by a disintegrin and metalloprotease (ADAM) has been elucidated in several cell types. Even though the liver is a representative angiotensinogen-producing organ, such cross-talk has never been elucidated in hepatocellular carcinomas (HCCs). We investigated whether AngII exerted a mitogenic effect on HCC cell lines through the AngII-EGFR cross-talk pathway. METHODS: We determined the expression and/or phosphorylation status of AngII receptor type 1 (AGTR1), ADAM9, ADAM17, ERK1/2, STAT3, AKT and EGFR in five HCC cell lines using Western blotting. Proliferation and invasion activities were measured by ATP and Matrigel invasion assays, respectively. RESULTS: AGTR1 was expressed ubiquitously in HCC cell lines. EGFR expression in HepG2 was relatively weaker than that in the remaining HCC cell lines. The phosphorylation status of EGFR, ERK1/2, STAT3 and AKT was upregulated by AngII treatment in two EGFR-overexpressing cell lines (Huh7 and PLC/PRF/5), but not in HepG2 (showing weak EGFR expression). AngII stimulation significantly accelerated proliferation and invasion activities in Huh7 and PLC/PRF/5, and was inhibited by pretreatment with an ADAM inhibitor. A selective AGTR1 blocker significantly repressed proliferation activity in both cell lines, but did not significantly repress the invasion activity. Both chemical agents and neutralizing antibodies against ADAMs (ADAM9 and ADAM17) and EGF-like ligands suppressed EGFR transactivation and/or subsequent phosphorylation of ERK1/2, STAT3 and AKT. CONCLUSION: These results suggest that AngII-EGFR cross-talk signaling mediated by ADAMs is involved in the proliferation and invasion activities of several HCC cell lines.

A multicenter phase II study of biweekly paclitaxel and S-1 combination chemotherapy for unresectable or recurrent gastric cancer.

PURPOSE: This Phase II study assessed the activity and safety of biweekly paclitaxel and oral S-1 as treatment for unresectable and recurrent gastric cancer. The maximum tolerated dose for this regimen had been established previously in a Phase I study performed in Japanese patients. PATIENTS AND METHODS: Chemotherapy was performed using two anticancer agents, S-1 and paclitaxel. Oral S-1 (80 mg/m(2)) was administered twice a day after meals for two consecutive weeks from Day 1 to 14, followed by a 2 week recovery period; paclitaxel (120 mg/m(2)) was administered intravenously, biweekly, on Days 1 and 15. The patient received cycles of this regimen every 4 weeks (q 28-day cycles). The primary end point was the response rate according to the Response Evaluation Criteria in Solid Tumors. RESULTS: A total of 39 patients (median age, 65 years) were enrolled; 13 other patients were screened, but found to be ineligible. All patients had unresectable and recurrent gastric cancer. The most common treatment-related Grade 3/4 adverse events were neutropenia (37.5%), appetite loss, diarrhea, decreased sodium (each 5%), and anemia, increased alanine aminotransferase, general fatigue, and dizziness (each 2.5%). Almost all the patients experienced alopecia. Intent-to-treat analysis showed a response rate of 43.6%. With a median follow-up of 14 months (range 8-21 months), median survival was 256 days and the median time to progression was 4 months. CONCLUSION: A combination regimen of biweekly paclitaxel and oral S-1 was well tolerated and showed promising activity against unresectable and recurrent gastric cancer.

Downregulation of miR-138 is associated with overexpression of human telomerase reverse transcriptase protein in human anaplastic thyroid carcinoma cell lines.

Alterations of several microRNA (miRNA) have been linked to cancer development and its biology. To search for unique miRNA that might play a role in the development of anaplastic thyroid carcinoma (ATC), we examined the expression of multiple miRNA and their functional effects on target genes in human thyroid carcinoma cell lines. We quantitatively evaluated the expression of multiple miRNA in 10 ATC and five papillary thyroid carcinoma (PTC) cell lines, as well as primary tumors from 11 thyroid carcinoma patients (three ATC and eight PTC), using the stem-loop-mediated reverse transcription real-time polymerase chain reaction method. We also examined the target gene specificity of unique miRNA that showed differences in expression between ATC and PTC cell lines. One miRNA, miR-138, was significantly downregulated in ATC cell lines in comparison with PTC (P < 0.01). Eleven miRNA (including miR-138) potentially targeting the human telomerase reverse transcriptase (hTERT) gene were totally downregulated in both ATC and PTC cell lines in comparison with normal thyroid tissues. A tendency for an inverse correlation between miR-138 and hTERT protein expression was observed in the thyroid cancer cell lines, although this failed to reach significance (r = -0.392, P = 0.148). We demonstrated that overexpression of miR-138 induced a reduction in hTERT protein expression, and confirmed target specificity between miR-138 and the hTERT 3'-untranslated region by luciferase reporter assay. These results suggest that loss of miR-138 expression may partially contribute to the gain of hTERT protein expression in ATC, and that further multiple miRNA targeting hTERT mRNA might be involved in the development of thyroid carcinoma.

Detection of p53 gene mutations by nonisotopic RNase cleavage assay as a predictor of poor prognosis in colorectal cancers.

The present study was undertaken to evaluate p53 gene mutation as a prognostic factor in patients with colorectal cancer. Nonisotopic RNase cleavage assay (NIRCA), recently used for detecting gene mutations, was employed to detect p53 gene mutations in this study. In 15 samples of colorectal tumors, NIRCA was confirmed to be simple, accurate, and thus useful for clinical use, compared with polymerase chain reaction single-strand conformational polymorphism (PCR-SSCP). In another group of 79 cases of colorectal cancer analyzed for p53 gene mutation by using NIRCA, mutations were detected in 58 of 79 (73.4%) cases. Multivariate Cox proportional-hazards analysis showed that p53 gene mutation was a significant prognostic factor in patients with colorectal cancer. Our results showed that NIRCA is a simple and sensitive method, and thus useful for genetic screening of colorectal cancer. Furthermore, our results showed that p53 gene mutation is an independent predictor of poor prognosis in colorectal cancers.

Polymorphism in the thymidylate synthase promoter enhancer region is not an efficacious marker for tumor sensitivity to 5-fluorouracil-based oral adjuvant chemotherapy in colorectal cancer.

Thymidylate synthase (TS) is the target enzyme of 5-fluoropyrimidines. The TS gene promoter enhancer region (TSER) possesses tandem, repeated, regulatory sequences that are polymorphic in humans. This polymorphism has been reported to influence TS expression in vitro and in vivo. In this study, we assessed whether or not the TSER genotype is an efficacious marker for tumor sensitivity to 5-fluorouracil (5-FU)-based oral adjuvant chemotherapy for colorectal cancer. One hundred and thirty-five Japanese patients who received curative resection and 5-FU-based oral adjuvant chemotherapy were studied. TSER genotypes of the tumors were analyzed by PCR. The numbers of repeated sequences of representative bands were determined by direct sequence. The genotypes of two-/two-repeats (TSER 2/2), two-/three-repeats (TSER 2/3), three-/three-repeats (TSER 3/3), and three-/five-repeats (TSER 3/5) were found in 11 (8.1%), 32 (23.7%), 85 (63.0%), and 7 (5.2%) tumors, respectively. Patients were classified into two groups: TSER 2/2 or 2/3 group; and the TSER 3/3 group. The relationship between the TSER genotype group and disease-free intervals was analyzed by univariate and multivariate analyses. Five-year disease-free survivals of the TSER 2/2 or 2/3 group and the TSER 3/3 group were 77% and 75%, respectively (P = 0.89). Multivariate analysis revealed that stage was the only independent prognostic factor and that the TSER genotype did not have a prognostic significance (hazard ratio for TSER 3/3, 0.91; P = 0.84). In conclusion, TSER genotype is not an efficacious marker for tumor sensitivity to 5-FU-based oral adjuvant chemotherapy for Japanese colorectal cancer patients after curative resection.