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SAMD9 and SAMD9L germline mutations have recently emerged as a new class of predispositions to pediatric myeloid neoplasms. Patients commonly have impaired hematopoiesis, hypocellular marrows, and a greater risk of developing clonal chromosome 7 deletions leading to MDS and AML. We recently demonstrated that expressing SAMD9 or SAMD9L mutations in hematopoietic cells suppresses their proliferation and induces cell death. Here, we generated a mouse model that conditionally expresses mutant Samd9l to assess the in vivo impact on hematopoiesis. Using a range of in vivo and ex vivo assays, we showed that cells with heterozygous Samd9l mutations have impaired stemness relative to wild-type counterparts, which was exacerbated by inflammatory stimuli, and ultimately led to bone marrow hypocellularity. Genomic and phenotypic analyses recapitulated many of the hematopoietic cellular phenotypes observed in patients with SAMD9 or SAMD9L mutations, including lymphopenia, and pinpointed TGF-β as a potential targetable pathway. Further, we observed nonrandom genetic deletion of the mutant Samd9l locus on mouse chromosome 6, mimicking chromosome 7 deletions observed in patients. Collectively, our study has enhanced our understanding of mutant Samd9l hematopoietic phenotypes, emphasized the synergistic role of inflammation in exaggerating the associated hematopoietic defects, and provided insights into potential therapeutic options for patients.

Purpose: To retrospectively investigate whether apical lesion, alveolar bone loss, probing pocket depth, or local infectious symptoms were associated with the onset of medication-related osteonecrosis of the jaw (MRONJ) in patients treated with high-dose antiresorptive agents who did not undergo tooth extraction., Methods: The study included 92 patients receiving high-dose antiresorptive agent therapy who had teeth with apical lesion ≧ 3 mm, alveolar bone loss ≧ 1/2, probing pocket depth ≧ 4 mm, or local infection symptoms such as swelling, pain, and pus discharge, but did not undergo tooth extraction. Univariate and multivariate Cox regression analyses were performed to determine the relationship between each variable and MRONJ onset., Results: MRONJ developed in 15 of 92 patients (35 of 404 teeth) from 74 to 1883 days (median, 383 days) after the first visit. Multiple Cox regression analysis revealed that a lower number of teeth, diabetes, increased leukocyte count, administration of antiresorptive agents for 180 days or more, local infection symptoms, apical lesion ≧ 3 mm, and probing pocket depth ≧ 4 mm were significantly correlated with the development of MRONJ., Conclusion: It is recommended that teeth with apical lesion ≧ 3 mm, probing pocket depth ≧ 4 mm, or local infection symptoms are extracted before or as early as possible after beginning of medication in cancer patients receiving high-dose antiresorptive agent therapy to prevent the development of MRONJ., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

It is controversial as to whether the withdrawal of antiresorptive (AR) agents is necessary while treating medication-related osteonecrosis of the jaw (MRONJ). In this study, we investigated whether a drug holiday promoted sequestrum separation and improved the surgical outcomes of MRONJ patients with malignant tumors, who were undergoing high-dose AR therapy. In total, we included 103 MRONJ patients with malignant tumors as their primary disease who underwent surgery at Nagasaki University Hospital or Kansai Medical University Hospital from January 2009 to December 2020. We recorded the patients' age, sex, primary disease, MRONJ stage, type and administration period of the AR agent, presence of diabetes, corticosteroid use, drug holiday period, white blood cell count, serum albumin, serum creatinine, outcomes, and computed tomography findings. The relationships between a drug holiday and sequestrum separation, and between a drug holiday and outcome, were analyzed. Drug holidays of 60, 90, and 120 days were not significant factors of sequestrum separation and did not influence patients' surgical outcomes as per the univariate and multivariate analyses. MRONJ patients with cancer as their primary disease should be operated upon immediately and without drug holidays if their general condition permits surgery.

Tooth extraction has been avoided since it has been considered a major risk factor for medication-related osteonecrosis of the jaw (MRONJ). However, MRONJ may also develop from tooth that is an infection source. This study aimed to clarify whether tooth extraction is a risk factor for the development of MRONJ in cancer patients receiving bone-modifying agents (BMAs). This retrospective observational study included 189 patients (361 jaws) from two hospitals. The risk factors of MRONJ were identified by comparing patient characteristics between those who did and did not develop MRONJ. Furthermore, the effect of tooth extraction during BMA therapy was analyzed after adjusting for confounding factors using the propensity score matching method. MRONJ occurred in 33 patients jaws. A longer duration of BMA administration, fewer number of teeth, presence of symptoms of local infection, and infected teeth were independent risk factors of MRONJ. However, tooth extraction during BMA therapy did not increase the risk. Propensity score matching analysis showed that tooth extraction significantly lowered the risk of MRONJ development. Teeth that can be an infection source increases the risk of MRONJ, and thus, they need to be extracted even during BMA administration., (© 2021. The Author(s).)

Patients develop a number of oral complications during cancer treatments. Oral bacteria are associated with the onset of dental focal infections and the progression of oral mucositis. Dental focal infections are frequently associated with the systemic onset of bacteremia, sepsis, and pneumonia. The degeneration of oral function with these complications may become an obstacle to cancer treatments. Although comprehensive oral management, including oral care, the removal of dental focal infections, and improvements in oral function with dentures, is conducted for cancer patients in Japan, few studies have assessed its efficacy.The aim of the present study was to investigate the incidence of dental/oral complications in cancer patients with perioperative oral managements (POMs) based on a large number of case series with a multicenter retrospective analysis.The medical records of cancer patients with POMs were retrospectively reviewed and the incidence of oral complications and efficacy of oral management were investigated.A total of 2744 cancer patients with POMs (1684 males and 1080 females, mean age 65.9 ± 13.0 years) were included and investigated in the present study. Among these patients, 2097 (76.4%) started POM before the initiation of cancer treatments, with 2130 (77.6%) receiving oral care only and 391 (14.2%) being subjected to invasive treatments, such as tooth extraction. The incidence of dental focal infections during the period of cancer treatments was 8.2%. The most frequent infection was acute periodontitis, including alveolar abscesses (112 patients, 4.1%). The incidence of grade 2 and 3 oral mucositis was 2.8%. Prolonged fever was observed in 113 patients (4.1%), with 7 having dental focal infections (6.2%). These incidence rates were lower than those reported previously.Based on analyses of a large number of patients, the present results support the efficacy of oral management in cancer patients. However, further studies are needed to establish adequate oral management guidelines for cancer patients.

Root amputation, immunosuppressive therapy, mandibular tooth extraction, pre-existing inflammation, and longer duration of treatment with bone-modifying agents were significantly associated with an increased risk of medication-related osteonecrosis of the jaw. Hopeless teeth should be extracted without drug holiday before the development of inflammation in cancer patients receiving high-dose bone-modifying agents., Introduction: No studies have comprehensively analyzed the influence of pre-existing inflammation, surgical procedure-related factors such as primary wound closure, demographic factors, and drug holiday on the incidence of medication-related osteonecrosis of the jaw (MRONJ). The purpose of this study was to retrospectively investigate the relationships between these various factors and the development of MRONJ after tooth extraction in cancer patients receiving high-dose bone-modifying agents (BMAs) such as bisphosphonates or denosumab., Methods: Risk factors for MRONJ after tooth extraction were evaluated with univariate and multivariate analyses. The following parameters were investigated in all patients: demographics, type and duration of BMA use, whether BMA use was discontinued before tooth extraction (drug holiday), the duration of such discontinuation, the presence of pre-existing inflammation, and whether additional surgical procedures (e.g., incision, removal of bone edges, root amputation) were performed., Results: We found that root amputation (OR = 22.62), immunosuppressive therapy (OR = 16.61), extraction of mandibular teeth (OR = 12.14), extraction of teeth with pre-existing inflammation, and longer duration (≥ 8 months) of high-dose BMA (OR = 7.85) were all significantly associated with MRONJ., Conclusions: Tooth extraction should not necessarily be postponed in cancer patients receiving high-dose BMA. The effectiveness of a short-term drug holiday was not confirmed, as drug holidays had no significant impact on MRONJ incidence. Tooth extraction may be acceptable during high-dose BMA therapy until 8 months after initiation.

Skin reactions to nivolumab are typical immune-related adverse events. We investigated the relation between patient background and test values before nivolumab administration and skin reactions. From February 2016 to February 2017, we evaluated the clinical outcomes of 21 patients who were administered nivolumab. Patients were divided into 2 groups: 3 cases of skin reactions to nivolumab(skin reaction group)and 18 cases without skin reactions to nivolumab(non-skin reaction group). In the skin reaction group, the numbers of eosinophils and basophils before nivolumab administration were significantly higher than those in the non-skin reaction group(p=0.0015 and p=0.0075, respectively). It was suggested that the numbers of eosinophils or basophils before nivolumab administration might be associated with the appearance of skin reactions.

Methods for preventing medication-related osteonecrosis of the jaw (MRONJ) in cancer patients who have received high-dose bisphosphonate (BP) or denosumab (Dmab) have not yet been established. Tooth extraction after starting medication has been believed to be a major risk factor for MRONJ, and therefore this procedure tends to be avoided. This study investigated the risk factors for MRONJ, with a special reference to the correlation between tooth extraction and development of MRONJ. One hundred and thirty-five cancer patients who were administrated high-dose BP or Dmab were enrolled in the study. Demographic factors, general condition, treatment factors, and dental findings were examined retrospectively using medical records and panoramic X-ray findings. The cumulative occurrence rate of MRONJ was calculated using the Kaplan-Meier method, and the correlation between these variables and development of MRONJ was analyzed by univariate and multivariate Cox regression analysis. MRONJ developed in 18 of 135 patients. The 1-, 2-, and 3-year cumulative occurrence rates were 8.6%, 21.5%, and 29.2%, respectively. The duration of medication before first visit to the dental unit and the presence of a tooth with clinical symptoms were significantly correlated with the development of MRONJ. The rate of MRONJ occurrence in patients who had teeth with clinical symptoms, but who did not undergo tooth extraction, became higher 2 years later than that in patients who underwent extraction of teeth with symptoms, although not significant. Early dental examination and effective preventative care to avoid infection/inflammation are important for preventing MRONJ., Competing Interests: The authors have declared that no competing interests exist.

Risk factors for hypokalemia were analyzed in patients who received anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR MoAbs) at Gifu Municipal Hospital between February 2010 and March 2013. Subjects were 51 patients (27 men and 24 women) with the median age (interquartile range) of 66 (63-72) years. The study period started from the initiation of anti-EGFR MoAbs administration and ended 4 weeks after administration was completed. Patients were categorized into the side effect group if both minimum serum potassium (Min S-K) grade and b grade (pre-treatment S-K grade-Min S-K grade) were B1; otherwise, they were placed into the no side effect group. Univariate analysis for factors to prevent the side effect identified the "concomitant use of hyperkalemia-inducing drugs" to be statistically significant (p=0.010). Multivariate analysis was conducted on factors with a p value of <0.25 in the univariate analysis and on "concomitant use of hyperkalemia-inducing drugs," which was likely to clinically affect S-K decrease, although its p value was >0.25. It showed that "concomitant use of hyperkalemia-inducing drugs" was a significant risk-prevention factor (odds ratio: 0.138, 95% confidence interval[CI]: 0.033-0.581, p=0.007). In conclusion, "concomitant use of hyperkalemia-inducing drugs" is a factor associated with preventing hypokalemia accompanying anti-EGFR MoAbs administration.

Stomatitis is a characteristic adverse event of everolimus and other mTOR inhibitors, and occurs at a high incidence and impairs QOL owing to pain. Most cases of stomatitis are mild to moderate. However, when stomatitis becomes serious, it can interfere with the continuation of medication. Therefore, it is important to place more emphasis on the prevention as well as early detection and treatment. In addition, patient education is also important. The possible occurrence of stomatitis, its signs and symptoms, as well as the importance of oral care need to be thoroughly explained prior to starting treatment. In order to smoothly carry out these measures, it will also be essential that cancer-treating physicians coordinate and collaborate with dentists, nurses, and pharmacists. It is desirable to establish appropriate prevention and management methods on the basis of the results of the Phase III prospective study, Oral Care-BC, currently ongoing in Japan.

Context: A recent mixed-methods study to evaluate the effects of a comprehensive regional palliative care program, the Japan Outreach Palliative Care Trial of the Integrated Model study, achieved broad positive outcomes at a regional level. This is a secondary analysis of patient outcomes., Objectives: The primary aims were to explore: 1) the changes in domains of patient-reported quality of care and quality of life after interventions, and 2) the changes in quality of care and quality of life of patients with different characteristics (i.e., performance status, age, and anticancer treatment)., Methods: A region-representative sample of metastatic/locally advanced cancer patients in outpatient settings participated in questionnaire surveys before and after regional intervention. Responses were obtained from 859 of 1880 and 857 of 2123 in the pre- and postintervention surveys, respectively., Results: All subdomain scores of the quality of care, except for help with decision making, significantly improved in the postintervention survey. The percentages of the patients who reported that improvement was necessary decreased from 13% to 5.0%. Although there were no or only a marginally significant difference in total and subdomain scores of quality of life between preintervention and postintervention surveys, the subgroups of patients with a poor performance status and those receiving no anticancer treatment achieved a significant improvement in the quality of life., Conclusion: Although average changes in patient-reported outcomes were relatively small in the total sample of patients, the intervention seemed to provide tangible benefits for the patients with poor general conditions. A future regional intervention trial should include patient outcomes in those with a poor general condition to evaluate the net effects of the program., (Copyright © 2014 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: We investigated palliative care knowledge, difficulty and self-reported practice among a region-wide sample of nurses who cared for cancer patients in Japan., Methods: A cross-sectional questionnaire survey was distributed to 9 designated cancer centers, 17 community hospitals and 73 district nurse services across 4 regions in 2008. We used the Palliative Care Knowledge Test, the Palliative Care Difficulty Scale (five-point Likert scale) and the Palliative Care Self-Reported Practices Scale (five-point Likert scale)., Results: In total, 2378 out of 3008 nurses (79%) responded. The knowledge, difficulty and self-reported practice scores were 51 ± 20%, 3.2 ± 0.7 and 3.7 ± 0.6, respectively. In the knowledge test, philosophy scored highest (88 ± 26%) and psychiatric problems scored lowest (37 ± 29%). In the difficulty test, alleviating symptoms scored most difficult (3.5 ± 0.8) and providing expert support scored least difficult (2.9 ± 1.3). In the self-reported practice questionnaire, pain and delirium relief were most frequently (4.0 ± 0.8) and least frequently (3.1 ± 0.9) provided, respectively. Knowledge was significantly poorer in community hospitals (P = 0.035); difficulty scores were significantly higher in community hospitals (P < 0.001) and district nurse services (P = 0.013); and self-reported practice scores were significantly poorer in community hospitals (P < 0.001) but superior in district nurse services (P < 0.001) than in designated cancer centers., Conclusions: Knowledge, difficulty and self-reported practice for symptom management, particularly psychological symptoms, were insufficient, particularly in community hospitals. Education, expert support and adequate clinical experiences would help provide quality palliative care., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

It appears that cancer care has been shifting on a large scale because of the Cancer Control Program Organic Act. In the wave of cancer care reform, an active part of a Oncology Clinical Nurse Specialist is indispensable in order to raise a quality of Cancer nursing. There have been 79 Oncology Clinical Nurse Specialist working in the Japanese hospitals. The Oncology Clinical Nurse Specialist' roles are of "practice", "consultation", "coordination", "ethical coordination", "education", and "study". They work and cooperate with the general staff at hospitals, and that they strive for a medical (nursing) care reform on the hospital scene. Regarding activities of Oncology Clinical Nurse Specialist with palliative care team and consulting support center that are expanding in Basic Plan to Promote the Cancer Control Program, they have been moving forward through cases in the local cooperation and continuous medical (nursing) care.

Activity of transforming growth factor (TGF) in urine was examined by the use of cloned BALB/3T3 A31-1-1 indicator cells. When urine was extracted by an acid-ethanol method, fractionated on a Bio-Gel P-100 column, and analyzed for TGF activity, samples from healthy persons showed no activity, but 80% of the samples from advanced cancer patients had the activity. Activity observed in tumor-bearing patients was eliminated after therapy. Further analysis was carried out in a much simpler way by the fractionation of urine samples after only dialysis and lyophilization. An extensive survey of TGF activity in urine using BALB/3T3 indicator cells revealed weak or intermediate (19%) activity in healthy persons and high (56%) or intermediate (31%) activity in advanced cancer patients. When urine samples were analyzed and compared using both BALB/3T3 cells and NRK 49F cells, the BALB/3T3 cells were shown to form colonies in response to beta-type TGF but not to alpha-type TGF. The present results are the first demonstration of an elevated level of beta-type TGF in urine from cancer patients.

Tests were performed to study the transforming growth factor (TGF) activity in samples of pleural fluid and ascites in patients with solid tumors and non-neoplastic diseases such as congestive heart failure and liver cirrhosis. The measurement of the activity was carried out in terms of colony formation in soft agar with NRK cells as indicator cells. When the fluid samples were directly assayed, 24% (4/17) of the cancer cases and 1 of the 4 control cases were positive. The eluate of Bio-Gel P-60 gel filtration was positive in all cases. beta-Type as well as alpha-type TGF activity was found in pleural and peritoneal effusions not only from cancer patients, but also from patients with non-malignant diseases.