Symptoms and health-related quality of life in patients with newly diagnosed multiple myeloma: a multicenter prospective cohort study.

OBJECTIVE: Existing cross-sectional observational studies indicate that patients with multiple myeloma experience negative physical and psychological symptoms and low health-related quality of life. The study aim was to determine symptom prevalence, health-related quality of life and symptoms associated with health-related quality of life in patients with newly diagnosed multiple myeloma. METHODS: This multicenter longitudinal cohort study was conducted in four hospitals in Japan. Patients with newly diagnosed multiple myeloma were asked to report their symptom intensity and health-related quality of life using validated questionnaires at three points: at diagnosis (T1), 1 month (T2) and 12 months after diagnosis (T3). Symptoms associated with health-related quality of life were explored using a mixed-effects model. RESULTS: A total of 106 patients completed the assessment at T1. The symptoms more than 30% of patients reported were pain, disturbed sleep and distress at T1, pain, dry mouth, disturbed sleep and fatigue at T2, fatigue, numbness of tingling and pain and numbness or tingling at T3. Pain and depression were significantly associated with health-related quality of life negatively. CONCLUSIONS: The finding suggests that more than 30% of multiple myeloma patients suffered from pain and various symptoms and they received suboptimal palliative care within a year after starting initial chemotherapy. Pain and depression should be the main targets of interventions to improve health-related quality of life in this population.

Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone combined with high-dose methotrexate plus intrathecal chemotherapy for newly diagnosed intravascular large B-cell lymphoma (PRIMEUR-IVL): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a rare disease for which there is no available standard treatment. We aimed to ascertain the safety and activity of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) with high-dose methotrexate and intrathecal chemotherapy as CNS-oriented therapy for patients with previously untreated IVLBCL. METHODS: PRIMEUR-IVL is a multicentre, single-arm, phase 2 trial at 22 hospitals in Japan. Eligible patients had untreated histologically confirmed IVLBCL, were aged 20-79 years, had an Eastern Cooperative Group performance status of 0-3, and had no apparent CNS involvement at diagnosis. Patients received three cycles of R-CHOP (rituximab 375 mg/m2 intravenously on day 1 [except cycle one, which was on day 8]; cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2·0 mg] intravenously on day 1 of cycle one and day 2 of cycles two and three; and prednisolone 100 mg/day orally on days 1-5 of cycle one and days 2-6 of cycles two and three) followed by two cycles of rituximab with high-dose methotrexate (3·5 g/m2 intravenously on day 2 of cycles four and five) every 2 weeks and three additional cycles of R-CHOP. Intrathecal chemotherapy (methotrexate 15 mg, cytarabine 40 mg, and prednisolone 10 mg) was administered four times during the R-CHOP phase. The primary endpoint was 2-year progression-free survival. Efficacy analyses were done in all enrolled patients; safety analyses were done in all enrolled and treated patients. The trial is registered in the UMIN Clinical Trials Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165); the trial is ongoing for long-term follow-up. FINDINGS: Between June 16, 2011, and July 21, 2016, 38 patients were enrolled, of whom 37 were eligible; one patient was excluded because of a history of testicular lymphoma. Median follow-up was 3·9 years (IQR 2·5-5·5). 2-year progression-free survival was 76% (95% CI 58-87). The most frequent adverse events of grade 3-4 were neutropenia and leucocytopenia, which were reported in all 38 (100%) patients. Serious adverse events were hypokalaemia, febrile neutropenia with hypotension, hypertension, and intracerebral haemorrhage (reported in one [3%] patient each). No treatment-related deaths occurred during protocol treatment. INTERPRETATION: R-CHOP combined with rituximab and high-dose methotrexate plus intrathecal chemotherapy is a safe and active treatment for patients with IVLBCL without apparent CNS involvement at diagnosis, and this regimen warrants future investigation. FUNDING: The Japan Agency for Medical Research and Development, the Center for Supporting Hematology-Oncology Trials, and the National Cancer Center.

[Cooperation between a Hospital without Dentists and Local Dental Associations in Oral Management of Cancer Patients].

Severe oral mucositis induced by cancer chemotherapy can cause intolerable pain and increase the risk of systemic infections, necessitating dose reduction and discontinuation of antineoplastic agents. Moreover, this adverse effect may have an impact on patient nutrition and quality of life. An effective and prophylactic intervention should be useful for alleviating this complication. Because Nagoya Memorial Hospital has neither a dentistry nor an oral surgery department, we collaborated with dental associations near the hospital. First, we performed a questionnaire survey on the present status of the members of the local dental associations. The survey showed that 86% of the community dentists were interested in communicating with our hospital. In addition, they agreed to provide us with information on their specialty and status of amenities. In discussion with the community dentists, we decided on fax-based communication for collaboration to improve the quality of oral management in cancer patients. Three seminar series were conducted to share updated information on cancer treatment and enhance communication between the medical doctors and the dentists. Our hospital has registered 129 community dentists and enrolled 81 cancer patients in this medical and dental cooperation initiative.

[Sustained remission with allogeneic peripheral blood stem cell transplantation and subsequent maintenance therapy with dasatinib in a patient with myeloblastic crisis of imatinib-resistant CML].

A 45-year-old man with chronic myelogenous leukemia (CML) in the chronic phase was treated with imatinib mesylate (IM). Although partial cytogenetic response (CyR) was obtained in 3 months, the patient exhibited back pain after treatment with IM for 5 months. He was diagnosed with myeloblastic crisis of CML with 30% blasts in the bone marrow. An extramedullary tumor with a diameter of 5-cm was found adjacent to the pancreatic head. Mutation analysis of the bcr/abl chimeric gene was negative. After the treatment with dasatinib (140 mg/day) for 40 days, complete CyR was obtained by bone marrow examination and the extramedullary tumor shrunk resulting in partial response on computed tomography. Allogeneic peripheral blood stem cell transplantation (allo-PBSCT) was performed from his HLA-DR one locus-mismatched sister. He has been in molecular remission for 24 months after allo-PBSCT and maintenance therapy with dasatinib has been administered. Dasatinib was tolerable without severe adverse events before and after allo-PBSCT in this case.

Diagnosis of a SMARCA4-deficient undifferentiated tumor using multigene panel testing: A case report.

Key Clinical Message: SMARCA4-deficient thoracic carcinoma is a malignant tumor that may present as cancer of unknown primary. This tumor is refractory and requires a novel approach. In addition to identifying therapeutic targets, multigene panel testing can reveal novel genetic mutations, leading to more pathologically relevant diagnoses and appropriate tumor care. Abstract: SMARCA4-deficient undifferentiated tumors are characterized by SMARCA4 inactivation. We present a case of a 74-year-old man with an undifferentiated tumor and a novel SMARCA4 mutation detected using multigene panel testing. The tumor was multiagent and refractory to three chemotherapy lines. The test results helped guide appropriate medical management.

Serological response 5 months after the BNT162b2 COVID-19 vaccination in patients with various hematological disorders in Japan.

Purpose: Patients with hematological malignancies are at an increased risk of severe infection with coronavirus disease 2019 (COVID-19). However, developing an adequate immune response after vaccination is difficult, especially in patients with lymphoid neoplasms. Since the long-term effects of the BNT162b2 vaccine are unclear, the humoral immune response 5 months after the two vaccinations in patients with hematological disorders was analyzed. Materials and Methods: Samples were collected from 96 patients vaccinated twice with BNT162b2 and treated with at least one line of an antitumor or immunosuppressive drug in our hospital from November 2021 to February 2022. Serum anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) spike (S) antibody titers were analyzed. Patients were age- and sex-matched using propensity matching and compared with a healthy control group. Patients with serum anti-SARS-CoV-2 S antibodies were defined as 'responder' if >50 U/mL. The patients had B-cell non-Hodgkin lymphoma (B-NHL), multiple myeloma, chronic myeloid leukemia, etc. Results: Patients had significantly low antibody levels (median, 55.3 U/mL vs. 809.8 U/mL; p<0.001) and a significantly low response rate (p<0.001). Multivariate analysis showed that patients with B-NHL, aged >72 years, were associated with a low response to vaccination. There were no significant differences between patients with chronic myeloid leukemia and healthy controls. Conclusion: Our study shows that patients with hematological disorders are at risk of developing severe COVID-19 infections because of low responsiveness to vaccination. Moreover, the rate of antibody positivity differed between the disease groups. Further studies are warranted to determine an appropriate preventive method for these patients, especially those with B-NHL.

[Pilot study on clinical effects of rebamipide gargle against oral mucositis induced by fluoropyrimidines].

Rebamipide, a cytoprotective agent, has been suspected to attenuate oral mucositis through anti-inflammatory potentials and induction of endogenous prostaglandin synthesis. This prospective study was designed to assess the clinical efficacy of rebamipide gargle against oral mucositis, which is induced by fluoropyrimidines in patients with stomach and colorectal cancer. We first conducted a pilot study on gargle flavors, because the solution in this agent has a strong and bitter after taste. Nine kinds of flavors were prepared, and six characteristics were evaluated by ten volunteers: sourness, bitterness, sweetness, remain, after taste, and hard to drink. We determined the contents of rebamipide using HPLC, which showed stability in an acidic condition. Finally, we decided that 100% Pokka Lemon should be used as the flavor of the rebamipide solution. A clinical study was then started to compare the preventive effects rebamipide gargle and placebo have on stomatitis, quality of life (QOL), and the therapeutic effects of chemotherapy.

[Combination therapy of S-1 and 24-h infusion of cisplatin after palliative gastrectomy for stage IV gastric cancer].

We prospectively analyzed the adverse effects and outcomes of 15 patients with stage IV gastric cancer who underwent palliative gastrectomy from December, 2002 to May, 2008 and subsequently received combination therapy of S-1 and 4-h infusion of cisplatin. The National Cancer Institute common toxicity criteria (version 3. 0) were applied to evaluate the adverse effects of this therapy, and the Kaplan-Meier method was used to plot the survival curve. The side effects most frequently observed were anorexia (grade 3; 33%), although one case of grade 4 who was easily fatigued was noted during the first course and could not receive further courses of this therapy. The 2-year survival rate was 33% and median survival time was 31 months. It has been suggested that 24-h infusion of cisplatin combined with oral S-1 after reduction surgery might improve survival in patients with stage IV gastric cancer.

Bidirectional information sharing between Nagoya Memorial Hospital and health insurance pharmacies using a communication sheet for pharmaceutical cooperation.

BACKGROUND: We collaborated with the regional pharmaceutical associations near Nagoya Memorial Hospital and created a communication sheet for pharmaceutical cooperation between the hospital and health insurance pharmacies. METHODS: The communication sheet for pharmaceutical cooperation was issued in October 2014. We conducted a questionnaire survey of both cancer patients and community pharmacists 1 year after the implementation of the use of this sheet. Based on the results of the survey, we modified our communication sheet and added a unified reply form in October 2016. We examined the number of replies from community pharmacists from October 2014 to April 2019. We then analyzed how community pharmacists instructed and communicated with cancer patients using the results of both the questionnaire survey and the reply form, which were compared before and after introducing the modified version of the communication sheet. RESULTS: During the 5 years of observation, 743 communication sheets were sent from Nagoya Memorial Hospital to community pharmacists. As a result of pharmaceutical cooperation in using the communication sheet, 96.4% of prescribed medication were immediately prepared in health insurance pharmacies on that day. The communication sheet also enhanced the conversations between cancer patients and pharmacists. The introduction of the unified reply form increased the response rate of community pharmacists from 1.7 to 69.5% (p < 0.001). The communication between community pharmacists and cancer patients was significantly hindered by prescriptions without an oral cancer drug and patient age < 65 years old (p < 0.05). However, this hindrance was reduced by the use of the modified form. CONCLUSIONS: The communication sheet for pharmaceutical cooperation is useful for bidirectional information sharing between hospitals and health insurance pharmacies, which may enable pharmacists to provide cancer patients with medication instructions in coordination with hospitals and increase the quality of outpatient pharmacy services.

[Two advanced gastric cancer cases with peritoneal metastases successfully treated by s-1/paclitaxel combination therapy].

Two unresectable advanced gastric cancer cases with peritoneal metastases were successfully treated by the combination therapy of S-1 and paclitaxel. S-1 (1.25m(2): 80 mg/day, 1.25m(2)-1.50m(2)<:120 mg/day) was administered orally for 14 consecutive days followed by 14 days rest and a 2-hour infusion of paclitaxel (50 mg/m(2)) was administered on day 1 and 15 of each course. Treatment was repeated every 4 weeks unless disease progression or severe adverse effects were observed. Case 1: 65-year-old male (performance status: PS 3) with type 1 gastric cancer with malignant ascites. Case 2: 66-year-old male (PS3) with peritoneal metastases whose primary gastric lesion was surgically resected. Partial response was obtained in the former and complete response in the latter. Combination therapy of S-1 and paclitaxel can be highly recommended for patients with inoperable gastric cancer with poor PS.

Overexpression of carboxylesterase-2 results in enhanced efficacy of topoisomerase I inhibitor, irinotecan (CPT-11), for multiple myeloma.

Multiple myeloma (MM) remains an incurable disease and further development of novel agents is needed. Because constitutive expression of topoisomerase I (TopoI) in MM cells and the efficacy of SN-38, an active metabolite of irinotecan (CPT-11), have been reported, we investigated the therapeutic potential of CPT-11. Of the eight MM cell lines analyzed, four showed 50% inhibitory concentration values of less than 2 microg/mL for CPT-11 and less than 2 ng/mL for SN-38. This efficacy was partly explained by the high expression level of human carboxylesterase-2 (hCE-2) in MM cells. Interestingly, high expression of hCE-2 represented the nature of normal plasma cells, suggesting that hCE-2 could efficiently generate SN-38 within the plasma cells. As expected, higher sensitivity to CPT-11 was observed in hCE-2-overexpressing U266 cells than mock U266 cells. On the other hand, the expression levels of hCE-1, TopoI, UGT1A and ABCG2 did not seem to be associated with the sensitivity of MM cells to CPT-11. In a murine xenograft model inoculated s.c. with RPMI8226 cells, administration of CPT-11 alone significantly reduced the tumor volume. When a combination of CPT-11 and bortezomib was administered, the subcutaneous tumors completely disappeared. Thus, clinical trials on CPT-11 in patients with relapsed or refractory MM are warranted.

Pathological complete response induced by the combination therapy of S-1 and 24-h infusion of cisplatin in two cases initially diagnosed as inoperable advanced gastric cancer.

We report on two patients, successfully treated by the combination therapy of S-1 and 24-h infusion of cisplatin (CDDP), who were initially diagnosed with unresectable stage 4 advanced gastric cancer. Each patient had a very good clinical response and underwent curative gastrectomy after completion of 14 and 10 courses of S-1/CDDP chemotherapy, respectively. A microscopically detailed examination of surgically obtained specimens showed the complete disappearance of malignant cells in the two cases. S-1/CDDP combination therapy can, therefore, be highly active in incurable advanced gastric carcinoma.

[A case of recurrent rectal cancer with lymphangiosis carcinomatosa successfully treated with modified FOLFOX6 therapy].

A 56-year-old woman with multiple lung metastases and lymphangiosis carcinomatosa due to recurrent rectal cancer was treated with chemotherapy of modified FOLFOX6 (mFOLFOX6) regimen: l-leucovorin (l-LV 200 mg/m(2)) and oxaliplatin (L-OHP 85 mg/m(2)) were given as a 2-hour infusion followed by bolus injection of 5-FU 400 mg/m(2) and a 46- hour infusion 5-FU 2,400 mg/m(2) every two weeks. Since partial response was achieved and dyspnea was remarkably improved, she was discharged without oxygen therapy after 5 courses.

[A case of interstitial pneumonia induced by S-1/irinotecan combination therapy].

A 67-year-old man with multiple liver metastases of colonic cancer was treated with combination therapy of S-1 and irinotecan (CPT-11): S-1 (120 mg/day) administered orally for 14 consecutive days followed by 14 days rest. CPT-11 (100 mg/m(2)) was given as a 2-hour infusion on day 1 and 15. The patient complained of high fever and subsequent exertional dyspnea in the middle of the second course of S-1/CPT-11 therapy. He was hospitalized with severe hypoxemia. CT scan showed extensive ground glass and consolidative changes in bilateral lungs. Steroid pulse therapy with oxygen therapy remarkably improved his symptoms, and abnormal findings on CT scan also resolved. Drug-induced pneumonia needs to be considered in the differential diagnosis when patients treated with S-1/CPT-11 combination therapy present high fever and dyspnea.

Bladder squamous cell cancer accompanied by Trousseau's syndrome: a case report.

The association between thrombosis and cancer has been recognized since Trousseau's report in 1865. We present a case of bladder squamous cell carcinoma associated with multiple cerebral infarctions. This patient was diagnosed as having Trousseau's syndrome and received radiotherapy for bladder cancer treatment, along with anticoagulation therapy.

Induction of class II major histocompatibility complex expression in human multiple myeloma cells by retinoid.

Class II major histocompatibility complex (MHC II) is normally silenced in plasma/multiple myeloma (MM) cells at the transcriptional level through downregulation of class II transactivator (CIITA), allowing MM cells to escape from immunological responses. Here we demonstrate that a retinoic acid receptor-alpha/beta-selective retinoid Am80 (tamibarotene) could induce the expression of functional MHC II molecules in human MM cell lines. Am80 upregulated expression of the interferon regulatory factor-1 gene, followed by enhancement of CIITA expression. This is the first report demonstrating that retinoid can induce the expression of MHC II in terminally-differentiated plasma/MM cells.

Chemo-Immunotherapy Using Lentinan for the Treatment of Gastric Cancer with Liver Metastases.

Gastric cancer is the third leading cause of cancer-related mortality worldwide. Systemic chemotherapy is the main treatment option for advanced gastric cancer when the tumor is inoperable. Despite recent advances in chemotherapeutic agents, the prognosis of unresectable or recurrent gastric cancer remains extremely poor. In Japan, combination therapy including S-1 and cisplatin is the standard first-line treatment for advanced gastric cancer; however, the five-year survival rate remains very low. Lentinan, the backbone of beta-(1,3)-glucan with beta-(1,6) branches, an active ingredient purified from Shiitake mushrooms, has been approved as a biological response modifier for the treatment of gastric cancer. This agent has been used in combination with oral fluoropyrimidines to improve the overall survival of gastric cancer patients. A retrospective chart review on 138 metastatic gastric cancer patients receiving chemotherapy was performed in Nagoya Memorial Hospital from 1 September 2010 to 31 August 2015. 12 patients with liver metastases were treated by lentinan in combination with S-1-based chemotherapy. The rate of objective response was 42% (5/12) and the disease control rate was 83% (10/12) in response to chemo-immunotherapy using lentinan, with a median overall survival of 407 days (95% CI: 207-700 days).

Global real-time quantitative reverse transcription-polymerase chain reaction detecting proto-oncogenes associated with 14q32 chromosomal translocation as a valuable marker for predicting survival in multiple myeloma.

CCND1, FGFR3 and c-MAF mRNA expression of tumor samples from 123 multiple myeloma patients were analyzed by global RQ/RT-PCR. CCND1, FGFR3 and c-MAF were positive in 44 (36%), 28 (23%) and 16 (13%) of patients, respectively. In 7 patients, both FGFR3 and c-MAF were positive. The expression of c-MAF was independent unfavorable prognostic factors for overall survival (OS). Autologous stem cell transplantation improved progression-free survival of CCND1-positive patients. Bortezomib, thalidomide or lenalidomide extended OS of FGFR3 and/or c-MAF-positive patients. Thus, CCND1, FGFR3 and c-MAF mRNA expression can predict survival and is useful for planning stratified treatment strategies for myeloma patients.