Prognostic awareness in Japanese patients with advanced cancer: a follow-up cohort study.

BACKGROUND: Patients with advanced cancer have been reported to be more likely to receive goal-concordant care if they have accurate prognostic awareness. However, many patients do not have this awareness. This study aimed to examine the prognostic awareness among Japanese patients with advanced cancer. METHODS: This single-center, follow-up cohort study included Japanese patients with advanced cancer who received chemotherapy at Tohoku University Hospital between January 2015 and January 2016. Patients were surveyed at enrollment and followed up for clinical events for 5 years thereafter. We compared (i) the patients' prognostic awareness with both actual survival time and physician's prediction of survival and (ii) physician's prediction of survival time with actual survival. Factors associated with accurate prognostic awareness were identified by univariate analysis. RESULTS: Of the 133 patients eligible for the study, 57 patients were analyzed. Only 10 (17.5%) patients had accurate prognostic awareness. Forty-three patients (75.4%) were optimistic about their prognosis; >80% of patients were more optimistic than their physicians about their prognosis. The physicians' predictions were accurate in for patients (37.5%). Accurate prognostic awareness was associated with physician's explanation of the prognosis and patients' perception of a good death. CONCLUSIONS: A majority of the patients with advanced cancer in this study had prognostic awareness that was more optimistic in comparison with their actual survival, and most were more optimistic than their physicians about their prognosis. Further research is needed to develop programs to facilitate the discussion of life expectancy with patients in a manner that is consistent with their preferences.

Impact of palliative chemotherapy and best supportive care on overall survival and length of hospitalization in patients with incurable Cancer: a 4-year single institution experience in Japan.

BACKGROUND: This study aimed to analyze the determinants of patients' choice between palliative chemotherapy and best supportive care (BSC) and to investigate how this choice affects overall survival (OS) and length of hospitalization according to Eastern Cooperative Oncology Group (ECOG) performance status (PS). METHODS: An oncologist explained the palliative chemotherapy and BSC options to 129 patients with incurable cancer during their first consultation. Data on the ECOG PS, treatment decision, OS, and the length of hospitalization were retrospectively collected over 4 years. RESULTS: Patients with an ECOG PS of 0-2 chose palliative chemotherapy more often than those with an ECOG PS of 3-4 (P < 0.01). Patients with ≤70 years chose palliative chemotherapy more often than those with > 70 (P < 0.05). And patients with gastric cancer and colon cancer chose palliative chemotherapy more often than those with CUP (carcinoma of unknown primary) (P < 0.05, P < 0.05 respectively). Factors associated with a significantly poorer OS in an adjusted analysis included the ECOG PS and treatment decision (hazard ratios: 0.18 and 0.43; P < 0.001, P < 0.01 respectively). In patients with an ECOG PS of 0-2, palliative chemotherapy was not associated with a longer OS compared with BSC (median OS: 14.5 vs. 6.8 months, respectively; P = 0.144). In patients with an ECOG PS of 3-4, palliative chemotherapy resulted in a significant survival gain compared to with BSC (median OS: 3.8 vs. 1.4 months, respectively; P < 0.05). Strong positive correlations between OS and the length of hospitalization were observed in patients with an ECOG PS of 3-4 who underwent palliative chemotherapy (r2 = 0.683) and the length of hospitalization was approximately one-third of their OS. CONCLUSIONS: The determinants for treatment choice were age, ECOG PS and type of cancer, not sex difference. Oncologists should explain to patients that OS and the length of hospitalization vary according to the ECOG PS when selecting between palliative chemotherapy and BSC.

Loss of protein phosphatase 6 in mouse keratinocytes increases susceptibility to ultraviolet-B-induced carcinogenesis.

We previously reported that deficiency in the gene encoding the catalytic subunit of protein phosphatase 6 (Ppp6c) predisposes mouse skin tissue to papilloma formation initiated by DMBA. Here, we demonstrate that Ppp6c loss acts as a tumor promoter in UVB-induced squamous cell carcinogenesis. Following UVB irradiation, mice with Ppp6c-deficient keratinocytes showed a higher incidence of skin squamous cell carcinoma than did control mice. Time course experiments showed that following UVB irradiation, Ppp6c-deficient keratinocytes upregulated expression of p53, PUMA, BAX, and cleaved caspase-3 proteins. UVB-induced tumors in Ppp6c-deficient keratinocytes exhibited a high frequency of both p53- and γH2AX-positive cells, suggestive of DNA damage. Epidemiological and molecular data strongly suggest that UVB from sunlight induces p53 gene mutations in keratinocytes and is the primary causative agent of human skin cancers. Our analysis suggests that PP6 deficiency underlies molecular events that drive outgrowth of initiated keratinocytes harboring UVB-induced mutated p53. Understanding PP6 function in preventing UV-induced tumorigenesis could suggest strategies to prevent and treat this condition.

Aberrant splicing caused by a MLH1 splice donor site mutation found in a young Japanese patient with Lynch syndrome.

Lynch syndrome, also known as hereditary non-polyposis colorectal cancer, characterized by predisposition to colorectal cancer and other associated cancers, is an autosomal-dominant disorder mainly caused by germline mutations in DNA mismatch repair (MMR) genes such as MLH1, MSH2, and MSH6. Some mutations that disrupt splice donor or acceptor sites cause aberrant mRNA splicing. These mutations are generally considered as pathogenic ones, however, it is sometimes uneasy to accurately predict their pathogenicity without functional assays, particularly when the mutation is a single nucleotide substitution. In this report, we describe a 25-year-old patient with Lynch syndrome who carries a germline variant in a splice donor site of the MLH1 gene (c.790 + 5 G > T), which was first detected among Asian populations. The immunohistochemical analysis revealed loss of MLH1 protein expression in the tumor. Our splicing assay confirmed that the intronic MLH1 variant actually caused aberrant splicing, supporting its pathogenic effect. Our data accumulate more information on the genotype-phenotype relationships in patients with Lynch syndrome.

[Clinical characteristics of cancer of unknown primary (CUP)--a summary of 22 cases].

Cancer of unknown primary site (CUP) is not a rare entity and accounts for 3-5% of all malignant neoplasias. CUPs are diagnosed with metastatic lesion so they are all in the advanced stage. Systemic chemotherapy is applied in many cases, but the ideal therapeutic strategy has not yet been determined. CUP shows much histological and therapeutic heterogeneity. Histologically, half of CUPs are adenocarcinoma and the rest are undifferentiated carcinomas. We analyzed the clinical and therapeutic characteristics 22 cases of CUP patients. Most CUP patients are found from lymph node swelling. There is no significant tendency as to the site of lymph node metastasis. Bone metastases are frequently encountered. It seems undifferentiated carcinomas are more responsive to chemotherapy. Chemo-sensitive patients are likely to have a longer life expectancy. In our experience all of the chemo-responsive cases are treated with platinum-based chemotherapy. Today several platinum-based combination chemotherapies are reported, but there is no large-scale randomized study. Because of its variety, individualized therapy may be ideal for CUP.

Dose escalation study of docetaxel and nedaplatin in patients with relapsed or refractory squamous cell carcinoma of the esophagus pretreated using cisplatin, 5-fluorouracil, and radiation.

BACKGROUND: Definitive chemoradiation with cisplatin (CDDP) and 5-fluorouracil (5FU) has been playing an important role in the treatment of esophageal cancer, but some patients are not curable or have recurrent lesions. However, few chemotherapeutic regimens are available for such patients. Docetaxel and nedaplatin are active for esophageal cancer. We conducted a dose-escalation study of docetaxel and nedaplatin as second line-chemotherapy after definitive chemoradiation in patients with relapsed or refractory squamous cell carcinoma of the esophagus after chemoradiation. METHODS: Nedaplatin was administered on day 1 and docetaxel was administered on days 1 and 15, every 4 weeks. Dose escalation was based on the dose-limiting toxicity (DLT) observed during the first cycle. RESULTS: Twelve patients were enrolled. At a docetaxel dose of 30 mg/m(2) and a nedaplatin dose of 80 mg/m(2), one grade 4 neutropenia occurred and caused one treatment break longer than 2 weeks, but there were few DLTs. At doses of 35 and 80 mg/m(2), respectively, two grade 4 neutropenias and one grade 2 thrombopenia occurred and caused three treatment breaks longer than 2 weeks. Therefore, the maximum tolerated dose was established at this dose level. Two grade 3 anorexias and one grade 3 nausea occurred, but other non-hematological toxicities were generally mild. Responses were seen in one-fourth of the 12 patients, including one complete remission. CONCLUSION: The recommended doses of docetaxel and nedaplatin were 30 and 80 mg/m(2), respectively. This combination could be a potential second-line treatment for this target population.

[A case of malignant melanoma from the esophagus responding to weekly paclitaxel therapy].

A 44-year-old man had a tumor in the lower thoracic esophagus at a health check, and was initially diagnosed as an undifferentiated carcinoma of the esophagus by the esophago-gastric endoscope. Although curative chemoradiotherapy was scheduled after the diagnosis, the interim evaluation revealed that the tumor was malignant melanoma of the esophagus with right renal metastasis. Since then, CVD (cisplatin, vindesine and dacarbazine) therapy, palliative radiotherapy and DAC-Tam (dacarbazine, nimustine, cisplatin and tamoxifen) therapy were carried out, but all of them proved ineffective, and multiple newly metastatic lesions appeared in liver and lymph nodes. Oral intake was impossible because of progressing stricture of the esophagus. As a fourth-line therapy, weekly paclitaxel therapy was started, and his oral intake was improved after the second course. He received the therapy as an outpatient for four months. After the third course, tumor lesions were evaluated as a partial response by CT. Consequently, five courses of the therapy were performed with modest adverse effects. Weekly paclitaxel therapy was reasonably safe as reported in other reports and considered to be a promising regimen for malignant melanoma of the esophagus.

AFP-producing hepatoid adenocarcinoma in association with Barrett's esophagus with multiple liver metastasis responding to paclitaxel/CDDP: a case report.

A case of alpha-fetoprotein (AFP)-producing hepatoid adenocarcinoma in association with Barrett's esophagus with multiple liver metastases, responding to chemotherapy, is reported. A 47-year-old man was admitted to our hospital with abdominal pain after subtotal esophagectomy for an esophageal adenocarcinoma in association with Barrett's esophagus, and was diagnosed as having multiple liver tumors. Most tumor markers were normal, but the serum AFP level was markedly elevated. Dynamic computed tomography and ferumoxide enhanced magnetic resonance imaging did not provide evidence of any primary hepatocellular carcinoma. Since microscopic examination of the resected tumor showed a poorly-differentiated adenocarcinoma with hepatoid features displaying AFP-immunoreactivity, the liver tumors were thus considered to be metastatic deposits. Surgery was not feasible so chemotherapeutic agents were tried, and the combination of paclitaxel (TXL) and cisplatin (CDDP) gave a partial response and good control for a period. This is the first report, to our knowledge, of effective chemotherapy for liver metastases from an AFP-producing hepatoid adenocarcinoma of the esophagus.

[The state of the art of hereditary cancer studies].

During the last two decades, many genes responsible for hereditary cancer syndromes have been isolated. Based on the accumulating genetic information, genetic testing for both patients and the relatives is carried out in hospitals and clinics, and the clinical significance has been investigated. In addition to the genetic analyses of known genes and the functional analyses of the gene products, the recent research trends in hereditary cancer studies tend to move into the second era of research strategies including the isolation of novel genes responsible for remaining hereditary cancers, associated studies for finding cancer-susceptibility variants and the comprehensive analyses of expression profiles in tumors. Such new strategies are not only important to elucidate the pathophysiological mechanism of each hereditary cancer but may provide a potential application of tailor-made cancer therapy depending on the mutation status because many of the gene products seem to participate in the chemosensitivity of cancer cells. Furthermore, the research efforts have been expected to develop novel strategies for cancer prevention, diagnostics and therapeutics. In this paper, we have outlined the state of the art of studies on hereditary cancer syndrome, focusing on familial breast cancer and hereditary non-polyposis colorectal cancer.

[Retrospective analysis on efficacy and toxicity of 5-fluorouracil (5-FU) and l-leucovorin (l-LV) in advanced or recurrent colorectal cancer].

The aim of this study was to evaluate the efficacy and toxicity of 5-fluorouracil (5-FU) and l-leucovorin (I-LV) in 50 patients with advanced or recurrent colorectal cancer in our institute. The dose of 5-FU was 600 mg/m2 and the dose of l-LV was 250 mg/m2. Objective response were 36.8% of patients who had administration of full-dose and 14.8% of patients who had the administration of reduced dose or prolonged interval. No significant difference was observed in clinical benefit rates between patients administrated in full-dose and patients in reduced dose or prolonged interval. Median survival time (MST) of patients in reduced dose or prolonged interval is longer than patients in full-dose. These data suggest that 5-FU/l-LV can be given in the outpatient and yields improved prognosis and minimal adverse reactions even in patients in reduced dose or prolonged interval.

A novel germline mutation of the LKB1 gene in a patient with Peutz-Jeghers syndrome with early-onset gastric cancer.

The gene responsible for Peutz-Jeghers syndrome (PJS), LKB1 (also called STK11) was mapped to chromosome 19p13.3 and was found to encode a putative serine/threonine protein kinase, LKB1. As only a limited number (approximately 100) of germline mutations of the gene have been reported, and because the protein function is still unclear, information about LKB1 mutations and their expression should be accumulated to understand the phenotype-genotype correlation of this disease. Here we report a patient with sporadic PJS with early-onset gastric cancer. We found a novel germline frameshift mutation (757-758insT) in the LKB1 gene and a marked reduction in LKB1 protein expression in the carcinoma cells, suggesting that the loss of LKB1 function may have led to the carcinogenesis of the gastric cancer.

Identification and evaluation of 55 genetic variations in the BRCA1 and the BRCA2 genes of patients from 50 Japanese breast cancer families.

We sequenced approximately 23 kb genomic regions containing all the coding exons and their franking introns of two breast cancer susceptibility genes, BRCA1 and BRCA2, of 55 individuals from 50 unrelated Japanese breast cancer families. We identified 55 single-nucleotide polymorphisms (SNPs) (21 in BRCA1 and 34 in BRCA2) containing nine pathogenic protein-truncating mutations (four in BRCA1 and five in BRCA2 from ten patients). Among the remaining 46 SNPs, allele frequencies of 40 were examined in both the breast cancer patients and 28 healthy volunteers with no breast cancer family history by PCR-RFLP or by direct DNA sequencing. Twenty-eight SNPs were common and were also found in the healthy volunteers and/or a SNP database. The remaining 18 were rare (allele frequency <0.05) and were not found in the healthy volunteers and/or the database. The pathogenic significance of these coding SNPs (cSNPs) remains to be clarified. The SNP information from this study will be useful in the future genetic testing of both BRCA1 and BRCA2 genes in the Japanese population.

Collaboration of breast cancer clinic and genetic counseling division for BRCA1 and BRCA2 mutation family in Japan.

BACKGROUND: BRCA1 and BRCA2 mutations cause high breast cancer incidence rates as high as 80% Although prophylactic therapy is still controversial, several prophylactic therapies have been proposed and tried for BRCA1 and BRCA2 mutation carriers. Prophylactic surgery, chemo-prevention and precise screening have been proposed as prophylactic therapy. All BRCA1 and BRCA2 mutation carriers need knowledge about their disease and the countermeasures that are used to protect against onset of disease. Counseling plays an important role in this regard for people with genetic diseases. Therefore, collaboration between breast cancer clinics and genetic counseling services is the most important issue in clinical practice. Our group consists of three national universities and a general hospital. In this article we describe our trial to construct a clinical system against hereditary breast cancer as an interim report for the Japanese Ministry of Health, Labour and Welfare. PATIENTS AND METHODS: Twenty familial breast cancer patients were registered in this study. The whole sequence of BRCA1 and BRCA2 were analyzed. If pathological mutations were detected, their first degree families were introduced to the counseling division at each institute when candidates visited counseling divisions. RESULTS AND DISCUSSION: Four cases of a deleterious mutation in BRCA1 or BRCA2 were detected among 20 cases. Their first degree relatives are now under consideration for visiting counseling divisions. The clinical system described in this study should play a role to protect BRCA1 or BRCA2 mutation carriers in Japan.

Isolation of temperature-sensitive p53 mutations from a comprehensive missense mutation library.

Temperature-sensitive (ts) mutations have been used as a genetic and molecular tool to study the functions of many gene products. Each ts mutant protein may contain a temperature-dependent intramolecular mechanism such as ts conformational change. To identify key ts structural elements controlling the protein function, we screened ts p53 mutants from a comprehensive mutation library consisting of 2,314 p53 missense mutations for their sequence-specific transactivity through p53-binding sequences in Saccharomyces cerevisiae. We isolated 142 ts p53 mutants, including 131 unreported ts mutants. These mutants clustered in beta-strands in the DNA-binding domain, particularly in one of the two beta-sheets of the protein, and 15 residues (Thr155, Arg158, Met160, Ala161, Val172, His214, Ser215, Pro223, Thr231, Thr253, Ile254, Thr256, Ser269, Glu271, and Glu285) were ts hot spots. Among the 142 mutants, 54 were examined further in human osteosarcoma Saos-2 cells, and it was confirmed that 89% of the mutants were also ts in mammalian cells. The ts mutants represented distinct ts transactivities for the p53 binding sequences and a distinct epitope expression pattern for conformation-specific anti-p53 antibodies. These results indicated that the intramolecular beta-sheet in the core DNA-binding domain of p53 was a key structural element controlling the protein function and provided a clue for finding a molecular mechanism that enables the rescue of the mutant p53 function.

Evaluation of the diagnostic accuracy of the stop codon (SC) assay for identifying protein-truncating mutations in the BRCA1and BRCA2genes in familial breast cancer.

Screening for protein-truncating mutations of the BRCA1 and BRCA2 genes is useful in genetic testing for familial breast cancer because, first, the methods are usually simple and not expensive, and second, the detected mutations indicate pathogenic mutations in general. We evaluated the diagnostic accuracy of the stop codon (SC) assay for detecting protein-truncating mutations in the BRCA1 and BRCA2 genes by comparing the results with DNA sequencing in samples from 29 patients with breast cancer from 24 Japanese families with a history of breast cancer. Protein-truncating mutations were detected in 5 of the 24 families (20.8%; two in the BRCA1 gene and three in the BRCA2 gene). Among the 176 DNA fragments examined using the SC assay, the existence of three protein-truncating mutations (one in the BRCA1 gene and two in the BRCA2gene) was predicted correctly by the assay. Only one reverse transcriptase-polymerase chain reaction fragment was positive for the SC assay but was negative using DNA sequencing. Our study showed clearly that the SC assay is sensitive (3 of 3, 100%) and specific (172 of 173, 99%) for detecting pathogenic protein-truncating mutations in the BRCA1 and BRCA2 genes, and that it could be useful for screening larger populations.

Analysis of the human APC mutation spectrum in a saccharomyces cerevisiae strain with a mismatch repair defect.

Somatic APC mutations in colorectal tumors with an RER phenotype reflect excessive frameshift mutations, especially in simple repetition tracts within the coding sequence. Because this type of mutation is characteristic of cells with a deficient DNA MMR system, the APC mutation signature of RER tumors may be attributable to a defect in the MMR system. However, there is little experimental evidence to prove that the spectrum of mutations and the APC gene distribution are directly influenced by MMR system defects. We therefore examined the mutation spectrum of the MCR of the APC gene after transfection into both MMR-proficient and MMR-deficient yeast strains and compared it with a previously reported human APC mutation database. Small insertions or deletions in mono- or dinucleotide repeats were more common in the MMR-deficient than in the MMR-proficient strain (91.2% vs. 38.1%, Fisher's exact test p < 0.0001). Furthermore, the 2 mutation hot spots, 4385-4394(AG)(5) and 4661-4666(A)(6), found in the yeast system corresponded with those in human tumors. Combining our data with those from human tumors, there appears to be hypermutable mutations in specific simple repetitive sequences within the MCR, which are more prevalent in MMR-deficient cells and RER tumors than in MMR-proficient cells and non-RER tumors. We therefore consider that the differences in the spectra of RER and non-RER tumors are attributable at least in part to the MMR system of the host cells.