Differences in discharge letter content: oncologists' vs. home care physicians' needs.

PURPOSE: To compare the details, oncologists include in discharge letters with what home care physicians need. Although discharge letters are important to share patients' information for home palliative care, few studies have compared the details, especially patients' emotions, regarding what oncologists include in discharge letters and home care physicians' needs. METHODS: This cross-sectional study was conducted by sending anonymous, self-administered questionnaires to 500 certified oncologists (OCs) and 500 directors of home care supporting clinics (HCs) in Japan between March and May 2023. The survey considered 20 potential items found in discharge letters, and compared rates of OCs including these items and HCs needs. RESULTS: Of 310 valid responses, 186 were from OCs (average age: 47.7; 29 females) and 124 from HCs (average age: 55.4; 9 females). Major items with lower inclusion rates for OCs included patients' emotions regarding medical conditions (58.4% in OCs vs. 92.6% in HCs, p < 0.001), families' emotions regarding medical conditions (60.0 vs. 92.6%, respectively, p < 0.001), patients' perceptions regarding medical conditions (84.9 vs. 94.3%, respectively, p = 0.011), families' perceptions regarding medical conditions (84.3 vs. 95.1%, respectively, p = 0.004), and potential late-onset treatment-related adverse events (79.3 vs. 92.6%, respectively, p = 0.002). Conversely, OCs included patients' activities of daily living more frequently (96.2 vs. 90.2%, respectively, p = 0.031). CONCLUSION: Transitioning to home-based palliative care may necessitate accurate information and consideration of patients' and families' perceptions and emotions regarding medical conditions in discharge letters for continuous provision of high-quality care.

Cancer Pain Management in Patients Receiving Inpatient Specialized Palliative Care Services.

CONTEXT: Cancer pain is a common complication that is frequently undertreated in patients with cancer. OBJECTIVES: This study is aimed at assessing the time needed to achieve cancer pain management goals through specialized palliative care (SPC). METHODS: This was a multicenter, prospective, longitudinal study of inpatients with cancer pain who received SPC. Patients were continuously followed up until they considered cancer pain management successful, and we estimated this duration using the Kaplan-Meier method. We investigated the effectiveness of pain management using multiple patient-reported outcomes (PROs) and quantitative measures, including pain intensity change in the Brief Pain Inventory. A paired-sample t-test was used to compare the pain intensity at the beginning and end of the observation period. RESULTS: Cancer pain management based on the PROs was achieved in 87.9% (385/438) of all cases. In 94.5% (364/385) of these cases, cancer pain management was achieved within 1 week, and the median time to pain management was 3 days (95% confidence interval [CI], 2-3). The mean worst pain intensity in the last 24 h at the start and end of observation were 6.9 ± 2.2 and 4.0 ± 2.3, respectively, with a difference of -2.9 (95% CI, -3.2 to -2.6; p < 0.01). Overall, 81.6% of the patients reported satisfaction with cancer pain management, and 62 adverse events occurred. CONCLUSION: SPC achieved cancer pain management over a short period with a high level of patient satisfaction resulting in significant pain reduction and few documented adverse events.

Prevalence of opioid-induced adverse events across opioids commonly used for analgesic treatment in Japan: a multicenter prospective longitudinal study.

PURPOSE: Although opioids have been shown to be effective for cancer pain, opioid-induced adverse events (AEs) are common. To date, little is known about the differences in risks of AEs by opioid type. This study was performed to compare the prevalence of AEs across opioids commonly used for analgesic treatment in Japan. METHODS: This study was conducted as a preplanned secondary analysis of a multicenter prospective longitudinal study of inpatients with cancer pain who received specialized palliative care for cancer pain relief. We assessed daily AEs until termination of follow-up. We rated the severity of AEs based on the Common Terminology Criteria for Adverse Events version 5.0. We computed adjusted odds ratios for each AE (constipation, nausea and vomiting, delirium, and drowsiness) with the following variables: opioid, age, sex, renal dysfunction, and primary cancer site. RESULTS: In total, 465 patients were analyzed. Based on the descriptive analysis, the top four most commonly used opioids were included in the analysis: oxycodone, hydromorphone, fentanyl, and tramadol. With respect to the prevalence of AEs among all analyzed patients, delirium (n = 25, 6.3%) was the most frequent, followed by drowsiness (n = 21, 5.3%), nausea and vomiting (n = 19, 4.8%), and constipation (n = 28, 4.6%). The multivariate logistic analysis showed that no single opioid was identified as a statistically significant independent predictor of any AE. CONCLUSION: There was no significant difference in the prevalence of AEs among oxycodone, fentanyl, hydromorphone, and tramadol, which are commonly used for analgesic treatment in Japan.

A quantification method of somatic mutations in normal tissues and their accumulation in pediatric patients with chemotherapy.

Somatic mutations are accumulated in normal human tissues with aging and exposure to carcinogens. If we can accurately count any passenger mutations in any single DNA molecule, since their quantity is much larger than driver mutations, we can sensitively detect mutation accumulation in polyclonal normal tissues. Duplex sequencing, which tags both DNA strands in one DNA molecule, enables accurate count of such mutations, but requires a very large number of sequencing reads for each single sample of human-genome size. Here, we reduced the genome size to 1/90 using the BamHI restriction enzyme and established a cost-effective pipeline. The enzymatically cleaved and optimal sequencing (EcoSeq) method was able to count somatic mutations in a single DNA molecule with a sensitivity of as low as 3 × 10-8 per base pair (bp), as assessed by measuring artificially prepared mutations. Taking advantages of EcoSeq, we analyzed normal peripheral blood cells of pediatric sarcoma patients who received chemotherapy (n = 10) and those who did not (n = 10). The former had a mutation frequency of 31.2 ± 13.4 × 10-8 per base pair while the latter had 9.0 ± 4.5 × 10-8 per base pair (P < 0.001). The increase in mutation frequency was confirmed by analysis of the same patients before and after chemotherapy, and increased mutation frequencies persisted 46 to 64 mo after chemotherapy, indicating that the mutation accumulation constitutes a risk of secondary leukemia. EcoSeq has the potential to reveal accumulation of somatic mutations and exposure to environmental factors in any DNA samples and will contribute to cancer risk estimation.

Clinical role and safety of tapentadol in patients with cancer: A single-center experience.

OBJECTIVE: To evaluate real-world data on the use of tapentadol (TAP) in cancer patients. DESIGN: Single-center retrospective study. SETTING: Curative/palliative. PATIENTS, PARTICIPANTS: Patients who started TAP between October 2014 and December 2018 at our institution. MAIN OUTCOME MEASURE(S): The primary outcome was the reason for TAP initiation. Secondary outcomes included prescription duration, TAP cessation rate, reason for cessation, and adverse events (AEs). Since the palliative care team (PCT) tended to prescribe to cancer patients with intractable pain more often than patients in usual care, and also tended to prescribe opioids based on their characteristics, we decided to compare patients with and without PCT intervention. RESULTS: There were 175 patients who first received TAP during the study period, of whom 81 patients (46.3 percent) were male. The median age was 60 years. TAP was prescribed for opioid-naive patients in 45 (26 percent) cases and opioid switch in 130 (74 percent) cases. When comparing the PCT group (n = 121) and the non-PCT group (n = 54) using univariate analysis, the PCT group had a higher opioid switch rate (81.8 percent vs 57.4 percent, p < .001), higher proportion of patients with neuropathic pain (NP) (65.3 percent vs 16.7 percent, p < .001), and a higher proportion of patients with a history of nausea (41.3 percent vs 18.5 percent, p < .01). The cessation rate due to AEs was 8 percent overall. CONCLUSIONS: Palliative care physicians prescribed TAP for patients with NP or a history of nausea. Opioid-naive patients were preferred by oncologists. TAP has good tolerability in both groups, with a low dropout rate due to AEs.

Effectiveness and safety of opioids for dyspnea in patients with lung cancer: secondary analysis of multicenter prospective observational study.

Background: Patients with lung cancer are more likely to have comorbidities [e.g., interstitial lung disease (ILD)], chronic obstructive pulmonary disease) and metastases that may affect dyspnea and the effectiveness and safety of opioids for dyspnea than other cancer types. Therefore, this study examined the effectiveness and safety of opioids for dyspnea, among the patients with lung cancer. Methods: The present study is a secondary analysis of a multicenter prospective observational study examining the effectiveness and safety of opioids for dyspnea in patients with cancer in Japan. For this secondary analysis, patients with lung cancer with a documented dyspnea Numerical Rating Scale (NRS) at baseline were included. The primary outcome was dyspnea NRS, and Integrated Palliative care Outcome Scale/Support Team Assessment Schedule (IPOS/STAS) scores change between baseline and 24 hours after baseline. As secondary outcomes, we investigated the predictors of opioid effectiveness for dyspnea improvement and adverse events (nausea, somnolence, and delirium). Results: This study analyzed 124 patients with lung cancer with known dyspnea NRS at baseline. The median age was 74, and the Eastern Cooperative Oncology Group performance status of 107 patients were 3-4. Both NRS and IPOS/STAS score of dyspnea significantly improved 24 hours after opioid initiation [-1.64, 95% confidence interval (CI): -2.12 to -1.17, P<0.001; -1.03; 95% CI: -1.21 to -0.85, P<0.001; respectively]. Moreover, the improvement of NRS score was greater than the minimal clinically important difference of 1 point. In the multivariate logistic regression analysis, ILD was significantly associated with a better improvement [(hazard ratio (HR): 3.39, 95% CI: 1.34-11.09, P=0.043]. Somnolence was the most common grade 3-4 adverse event (n=16), followed by delirium (n=9). Conclusions: Opioids were effective and safe for treating dyspnea in patients with lung cancer. Furthermore, lung cancer patients with ILD may benefit more from opioids.

Whole-exome Sequencing Reveals New Potential Susceptibility Genes for Japanese Familial Pancreatic Cancer.

OBJECTIVE: The primary objective of this study was to identify novel genes that predispose people in the Japanese population to FPC. SUMMARY OF BACKGROUND DATA: Familial history of pancreatic cancer is an important risk factor but, to date, few genes predisposing individuals to increased risk of developing FPC have been identified. METHODS: We performed whole-exome sequencing of germline DNA from 81 Japanese FPC patients. We also investigated somatic gene alterations in 21 matched tumor tissues through whole-exome sequencing and copy number analysis. RESULTS: Our germline variants identified previously known FPC susceptibility genes such as ATM and BRCA2, and several novel tumor suppressor genes with potentially deleterious variants for FPC. Interestingly, somatic whole-exome analysis demonstrated that most tumor samples with suspicious loss of heterozygosity of candidate genes were KRAS wild-types, implying that these cases may not have required KRAS activation as a driver event for carcinogenesis. CONCLUSIONS: Our findings indicate that FPC patients harbor potentially deleterious causative germline variants in tumor suppressor genes, which are known to acquire somatic mutations in pancreatic cancer, and that somatic loss of heterozygosity of some FPC susceptibility genes may contribute to the development of FPC in the absence of somatic KRAS-activating mutation. Genetic testing for a wider variety of FPC-predisposition genes could provide better screening approach for high-risk groups of pancreatic cancer.

Identification of a metastatic lung adenocarcinoma of the palate mucosa through genetic and histopathological analysis: a rare case report and literature review.

BACKGROUND: Cancers of unknown primary origin (CUPs) are reported to be the 3-4th most common causes of cancer death. Recent years have seen advances in mutational analysis and genomics profiling. These advances could improve accuracy of diagnosis of CUPs and might improve the prognosis of patients with CUPs. CASE PRESENTATION: A 76-year old male with an adenocarcinoma of unknown primary origin in the lung presented with another tumor of the palate mucosa. The tumor cells in the pleural effusion were all negative for immunohistochemical markers (TTF-1 and Napsin A) and lung-specific oncogenic driver alterations (EGFR mutation and ALK translocation). The tumor of the palate mucosa was likewise identified as an adenocarcinoma, and the cells showed cytological similarities with the tumor cells in the pleural effusion; TTF-1, Napsin A, EGFR mutation and ALK translocation were all negative. This result suggested that origins of the tumors of the palate mucosa and in the lung were the same, even though the origin had not yet been determined. Next, we addressed whether the tumor of the palate mucosa was a primary tumor or not. Secretory carcinoma (SC), which is a common type of minor salivary gland tumor (MSGT), was suspected; however, mammaglobin was negative and ETV6-NTRK3 (EN) fusion was not observed. Other MSGTs were excluded based on histological and immunohistochemical findings. Furthermore, an additional examination demonstrated an oncogenic KRAS mutation at codon 12 (p.G12D) in both palate tumor and in pleural effusion. KRAS mutation is known to exist in one-third of lung adenocarcinomas (LUADs), but quite rare in MSGTs. The possibility of metastasis from other organs was considered unlikely from the results of endoscopic and imaging studies. This result indicated that the primary site of the CUP was indeed the lung, and that the tumor of the palate mucosa was a metastasis of the LUAD. CONCLUSIONS: A tumor of the palate mucosa that showed diagnostic difficulties was determined to be a metastatic LUAD by genomic alterations and histopathological findings.

Germline variants in pancreatic cancer patients with a personal or family history of cancer fulfilling the revised Bethesda guidelines.

BACKGROUND: Pancreatic cancer (PC) is categorized as a neoplasm associated with Lynch syndrome; however, the precise proportion of PC patients harboring DNA mismatch repair genes (MMR genes) remains unclear, especially in the Asian population. METHODS: Among 304 Japanese patients with pathologically proven pancreatic ductal adenocarcinoma, we selected 20 (6.6%) patients with a personal or family history involving first- or second-degree relatives fulfilling the revised Bethesda guidelines (RBG), defined as RBG-compatible cases. We analyzed germline variants in 21 genes related to a hereditary predisposition for cancer as well as clinical features in all 20 cases. RESULTS: The RBG-compatible cases did not show any unique clinicopathological features. Targeted sequencing data revealed three patients carrying deleterious or likely deleterious variants. Specifically, these three patients harbored a nonsense variant in ATM, a frameshift variant in ATM, and a concurrent nonsense variant in PMS2 and missense variant in CHEK2 (double-mutation carrier), respectively. Although an MMR gene mutation was identified in only one of the 20 patients, up to 15% of the RBG-compatible PC cases were associated with germline deleterious or likely deleterious variants. CONCLUSIONS: These findings showed that these guidelines could be useful for identifying PC patients with DNA damage repair genes as well as MMR genes.

Randomized phase II study of sequential carboplatin plus paclitaxel and gefitinib in chemotherapy-naïve patients with advanced or metastatic non-small-cell lung cancer: Long-term follow-up results.

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib was initially approved in Japan in 2002 for the treatment of advanced or metastatic non-small-cell lung cancer (NSCLC); however, the optimal order of conventional cytotoxic chemotherapy (carboplatin and paclitaxel) and gefitinib administration has not been determined. We conducted a randomized phase II study of carboplatin and paclitaxel followed by gefitinib vs. gefitinib followed by carboplatin and paclitaxel to select a candidate for further development in a phase III study of chemotherapy-naïve patients with advanced or metastatic NSCLC, regardless of their EGFR mutation status. A total of 97 patients meeting this description were randomly assigned to arm A (carboplatin and paclitaxel followed by gefitinib; n=49) or B (gefitinib followed by carboplatin and paclitaxel; n=48) from June, 2003 to October, 2005. Carboplatin and paclitaxel were administered in 4 cycles every 3 weeks; gefitinib was continued until disease progression or development of unacceptable toxicity. The primary endpoint was overall survival; the secondary endpoints were response rate and adverse event prevalence. The median overall follow-up was 65.1 months (range, 28.7-75.1 months). The major toxicities were hematological (carboplatin and paclitaxel) or skin rash, diarrhea and hepatic dysfunction (gefitinib). Interstitial lung disease was observed in 1 patient from each arm. In arms A and B, the carboplatin and paclitaxel response rate, gefitinib response rate, and median survival durations were 34.8 and 26.5%, 33.3 and 35.7%, and 18.8 and 17.2 months, respectively. Arm A was selected for a subsequent phase III study.

Germline mutations in Japanese familial pancreatic cancer patients.

Clinicopathologic and genetic features of familial pancreatic cancer (FPC) in Asian countries remain largely unknown. The main purpose of this study was to determine the prevalence of FPC and to define causative FPC-predisposition genes in a Japanese cohort with pancreatic ductal adenocarcinoma (PDAC).We reviewed 1,197 patients with a pathologically proven PDAC and found that 88 (7.3%) were FPC patients who had at least one first-degree relative with PDAC. There were no significant differences between the FPC cases and sporadic cases in terms of gender, age, tumor location, stage, family history of any cancer except PDAC, and personal history of smoking, other cancers, diabetes mellitus and chronic pancreatitis. In the FPC patients, we then investigated the prevalence of germline mutations in 21 genes associated with hereditary predispositions for pancreatic, breast and ovarian cancers by means of the next-generation sequencing using a custom multiple-gene panel. We found that eight (14.5%) of the 54 FPC patients with available germline DNA carried deleterious mutations in BRCA2, PALB2, ATM, or MLH1. These results indicate that a significant fraction of patients with PDAC in Japan have a family history of pancreatic cancer, and some of them harbor deleterious causative mutations in known FPC predisposition genes.

Early-Stage Induction of SWI/SNF Mutations during Esophageal Squamous Cell Carcinogenesis.

The SWI/SNF chromatin remodeling complex is frequently inactivated by somatic mutations of its various components in various types of cancers, and also by aberrant DNA methylation. However, its somatic mutations and aberrant methylation in esophageal squamous cell carcinomas (ESCCs) have not been fully analyzed. In this study, we aimed to clarify in ESCC, what components of the SWI/SNF complex have somatic mutations and aberrant methylation, and when somatic mutations of the SWI/SNF complex occur. Deep sequencing of components of the SWI/SNF complex using a bench-top next generation sequencer revealed that eight of 92 ESCCs (8.7%) had 11 somatic mutations of 7 genes, ARID1A, ARID2, ATRX, PBRM1, SMARCA4, SMARCAL1, and SMARCC1. The SMARCA4 mutations were located in the Forkhead (85Ser>Leu) and SNF2 family N-terminal (882Glu>Lys) domains. The PBRM1 mutations were located in a bromodomain (80Asn>Ser) and an HMG-box domain (1,377Glu>Lys). For most mutations, their mutant allele frequency was 31-77% (mean 61%) of the fraction of cancer cells in the same samples, indicating that most of the cancer cells in individual ESCC samples had the SWI/SNF mutations on one allele, when present. In addition, a BeadChip array analysis revealed that a component of the SWI/SNF complex, ACTL6B, had aberrant methylation at its promoter CpG island in 18 of 52 ESCCs (34.6%). These results showed that genetic and epigenetic alterations of the SWI/SNF complex are present in ESCCs, and suggested that genetic alterations are induced at an early stage of esophageal squamous cell carcinogenesis.

Clinicopathologic Features and Germline Sequence Variants in Young Patients (≤40 Years Old) With Pancreatic Ductal Adenocarcinoma.

OBJECTIVES: The median age of patients with pancreatic ductal adenocarcinoma (PDAC) is approximately 70 years, and PDAC rarely affects individuals younger than 40 years. Here, we investigated clinicopathologic features and genetic background of PDAC occurring in young patients (age ≤ 40 years) to determine whether any difference exists in comparison with those of older patients (>40 years). METHODS: We reviewed 908 patients with pathologically proven PDAC for clinicopathologic characteristics. In addition, we performed targeted sequencing of germline variants for 49 genes that are associated with a hereditary predisposition for cancer in 9 young patients with available DNA. RESULTS: Among the 908 patients, a total of 17 were diagnosed at age younger than 40 years. There were no significant differences between young and old groups in terms of sex, smoking history, tumor location, Union for International Cancer Control stage, family histories of any cancer and PDAC in first-degree relatives, and medical history of other cancer. Targeted sequencing analysis demonstrated no definite "pathogenic" variants. CONCLUSIONS: The clinicopathologic features in young patients were generally similar to those in older patients. The rarity of family history of PDAC and the sequencing analysis for germline variants suggest that hereditary factors might have a weak, if any, relationship with early-onset PDAC.

Retrospective analysis of the efficacy of chemotherapy and molecular targeted therapy for advanced pulmonary pleomorphic carcinoma.

BACKGROUND: Pulmonary pleomorphic carcinoma (PPC) follows an aggressive clinical course and outcomes are disappointing. Due to its rarity, however, the clinicopathological and molecular characteristics of this disease remain unclear. METHODS: We retrospectively evaluated the efficacy of chemotherapy and molecular targeted therapy in 16 patients with PPC who received chemotherapy or EGFR-TKI. We also investigated the status of EGFR mutation, KRAS mutation and ALK expression. RESULTS: On histologic review of the malignant epithelial component, adenocarcinoma was identified in seven cases (43.8%), large cell carcinoma in four (25.0%), and squamous cell carcinoma in two (12.5%). For the sarcomatoid component, 14 cases (87.5%) had both spindle cell tumor and giant cell and 2 (12.5%) had giant cell. Eleven patients received cytotoxic chemotherapy as first-line but did not achieve an objective response, although one patient who received docetaxel as second-line achieved a partial response. We also found that one patient achieved long stable disease of about 9 years without progression after receiving cisplatin and gemcitabine treatment. EGFR mutation, KRAS mutation and ALK expression were investigated in 14 patients whose tumor specimens were available. EGFR mutation was observed in 2 (14.3%) and KRAS mutation in 3 (21.4%), while no patient was positive for ALK expression. One patient harboring EGFR exon 19 deletion was treated with gefitinib after postoperative recurrence and achieved a complete response of about 35 months. CONCLUSIONS: Although advanced PPC showed a poor response to chemotherapy, one patient with EGFR mutation achieved an extended complete response. We therefore recommend the evaluation of driver gene alteration such as EGFR in the treatment of advanced PPC.

[Perioperative management and postoperative complication rates of patients on dual antiplatelet therapies after coronary drug eluting stent implantation].

BACKGROUND: Few studies have examined the perioperative status of dual antiplatelet therapy and postoperative thrombotic or bleeding complication rates of patients undergoing non-cardiac surgery with recent history of coronary stent implantation. METHODS: Eight patients underwent surgery with antiplatelet therapy discontinued on both pre- and post-operative period (pre/postop group); 7 patients with only post-operative discontinuation (postop group); and 2 patients with therapy maintained (maintained group). All patients had history of coronary drug eluting stent implantation within 12 months of surgery. RESULTS: Antiplatelets were discontinued 7 days before surgery and restarted on postoperative day 7 for the pre/postop group, and on postoperative day 5 for postop group. Re-exploration due to bleeding complication was required in 1 patient in the postop group. Two or more units of red cell concentrate transfusion were required in 2 pre/postop, 3 postop, and 1 maintained group patients intraoperatively. No cardiac thrombotic complications including in-hospital stent thrombosis were observed, in line with previous reports of low stent thrombosis rates in Asian patients. CONCLUSIONS: In the present study, bleeding complications requiring transfusion were frequently observed in patients with dual antiplatelet therapy undergoing non-cardiac surgery, whereas perioperative therapy discontinuation did not trigger thrombotic complications including stent thrombosis.

ATF6beta is a host cellular target of the Toxoplasma gondii virulence factor ROP18.

The ROP18 kinase has been identified as a key virulence determinant conferring a high mortality phenotype characteristic of type I Toxoplasma gondii strains. This major effector molecule is secreted by the rhoptries into the host cells during invasion; however, the molecular mechanisms by which this kinase exerts its pathogenic action remain poorly understood. In this study, we show that ROP18 targets the host endoplasmic reticulum-bound transcription factor ATF6ß. Disruption of the ROP18 gene severely impairs acute toxoplasmosis by the type I RH strain. Because another virulence factor ROP16 kinase modulates immune responses through its N-terminal portion, we focus on the role of the N terminus of ROP18 in the subversion of host cellular functions. The N-terminal extension of ROP18 contributes to ATF6ß-dependent pathogenicity by interacting with ATF6ß and destabilizing it. The kinase activity of ROP18 is essential for proteasome-dependent degradation of ATF6ß and for parasite virulence. Consistent with a key role for ATF6ß in resistance against this intracellular pathogen, ATF6ß-deficient mice exhibit a high susceptibility to infection by ROP18-deficient parasites. The results reveal that interference with ATF6ß-dependent immune responses is a novel pathogenic mechanism induced by ROP18.