Therapeutic use of granulocyte colony-stimulating factor (G-CSF) in patients with febrile neutropenia: a comprehensive systematic review for clinical practice guidelines for the use of G-CSF 2022 from the Japan Society of Clinical Oncology.

BACKGROUND: Febrile neutropenia represents a critical oncologic emergency, and its management is pivotal in cancer therapy. In several guidelines, the use of granulocyte colony-stimulating factor (G-CSF) in patients with chemotherapy-induced febrile neutropenia is not routinely recommended except in high-risk cases. The Japan Society of Clinical Oncology has updated its clinical practice guidelines for the use of G-CSF, incorporating a systematic review to address this clinical question. METHODS: The systematic review was conducted by performing a comprehensive literature search across PubMed, the Cochrane Library, and Ichushi-Web, focusing on publications from January 1990 to December 2019. Selected studies included randomized controlled trials (RCTs), non-RCTs, and cohort and case-control studies. Evaluated outcomes included overall survival, infection-related mortality, hospitalization duration, quality of life, and pain. RESULTS: The initial search yielded 332 records. Following two rounds of screening, two records were selected for both qualitative and quantitative synthesis including meta-analysis. Regarding infection-related mortality, the event to case ratio was 5:134 (3.73%) in the G-CSF group versus 6:129 (4.65%) in the non-G-CSF group, resulting in a relative risk of 0.83 (95% confidence interval, 0.27-2.58; p = 0.54), which was not statistically significant. Only median values for hospitalization duration were available from the two RCTs, precluding a meta-analysis. For overall survival, quality of life, and pain, no suitable studies were found for analysis, rendering their assessment unfeasible. CONCLUSION: A weak recommendation is made that G-CSF treatment not be administered to patients with febrile neutropenia during cancer chemotherapy. G-CSF treatment can be considered for patients at high risk.

Comparison between a single dose of PEG G-CSF and multiple doses of non-PEG G-CSF: a systematic review and meta-analysis from Clinical Practice Guidelines for the use of G-CSF 2022.

BACKGROUD: Granulocyte colony-stimulating factor (G-CSF) is widely used for the primary prophylaxis of febrile neutropenia (FN). Two types of G-CSF are available in Japan, namely G-CSF chemically bound to polyethylene glycol (PEG G-CSF), which provides long-lasting effects with a single dose, and non-polyethylene glycol-bound G-CSF (non-PEG G-CSF), which must be sequentially administrated for several days. METHODS: This current study investigated the utility of these treatments for the primary prophylaxis of FN through a systematic review of the literature. A detailed literature search for related studies was performed using PubMed, Ichushi-Web, and the Cochrane Library. Data were independently extracted and assessed by two reviewers. A qualitative analysis or meta-analysis was conducted to evaluate six outcomes. RESULTS: Through the first and second screenings, 23 and 18 articles were extracted for qualitative synthesis and meta-analysis, respectively. The incidence of FN was significantly lower in the PEG G-CSF group than in the non-PEG G-CSF group with a strong quality/certainty of evidence. The differences in other outcomes, such as overall survival, infection-related mortality, the duration of neutropenia (less than 500/µL), quality of life, and pain, were not apparent. CONCLUSIONS: A single dose of PEG G-CSF is strongly recommended over multiple-dose non-PEG G-CSF therapy for the primary prophylaxis of FN.

Effectiveness of G-CSF in chemotherapy for digestive system tumors: a systematic review of the Clinical Practice Guidelines for the Use of G-CSF 2022 delineated by the Japan Society of Clinical Oncology.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) reportedly reduces the risk of neutropenia and subsequent infections caused by cancer chemotherapy. Although several guidelines recommend using G-CSF in primary prophylaxis according to the incidence rate of chemotherapy-induced febrile neutropenia (FN), the effectiveness of G-CSF in digestive system tumor chemotherapy remains unclear. To address these clinical questions, we conducted a systematic review as part of revising the Clinical Practice Guidelines for the Use of G-CSF 2022 published by the Japan Society of Clinical Oncology. METHODS: This systematic review addressed two main clinical questions (CQ): CQ1: "Is primary prophylaxis with G-CSF effective in chemotherapy?", and CQ2: "Is increasing the intensity of chemotherapy with G-CSF effective?" We reviewed different types of digestive system tumors, including esophageal, gastric, pancreatic, biliary tract, colorectal, and neuroendocrine carcinomas. PubMed, Cochrane Library, and Ichushi-Web databases were searched for information sources. Independent systematic reviewers conducted two rounds of screening and selected relevant records for each CQ. Finally, the working group members synthesized the strength of evidence and recommendations. RESULTS: After two rounds of screening, 5/0/3/0/2/0 records were extracted for CQ1 of esophageal/gastric/pancreatic/biliary tract/colorectal/ and neuroendocrine carcinoma, respectively. Additionally, a total of 2/6/1 records were extracted for CQ2 of esophageal/pancreatic/colorectal cancer, respectively. The strength of evidence and recommendations were evaluated for CQ1 of colorectal cancer; however, we could not synthesize recommendations for other CQs owing to the lack of records. CONCLUSION: The use of G-CSF for primary prophylaxis in chemotherapy for colorectal cancer is inappropriate.

How should visual function monitoring be performed and interpreted in surgery for suprasellar tumors?

OBJECTIVE: Preservation of visual function is important in surgery for suprasellar tumors. Visual evoked potentials (VEPs) are expected to play an important role in monitoring visual function during surgery. Given the lack of information in this field, the authors aimed to investigate the effects of optic nerve compression caused by suprasellar tumors to understand the possible usefulness of VEP monitoring using off-response (OFR) VEP. METHODS: Eleven healthy volunteers who underwent surgery for standard record confirmation and 32 patients with optic chiasm lesions who underwent surgery were examined. Preoperative, postoperative, and intraoperative VEPs were recorded. Propofol anesthesia was administered during intraoperative VEP monitoring. Patients who underwent surgery were monitored using the same stimulation method during surgery. Light stimulation was given from a luminant pad on the eyelids, and low-intensity stimulation with continuous 500-msec emission and 500 msec off was performed. The luminescence intensity of the stimulation was at a maximum of 8000 lx with three attenuation steps, each of which was recorded repeatedly. RESULTS: The OFR potentials and delay latencies decreased as stimulus intensity decreased. In the patient with temporal hemianopia, monocular stimulation produced the highest OFR in the contralateral occipital lobe of the stimulated eye. The authors recorded preoperative, intraoperative, and postoperative VEP in 32 patients and observed intraoperative changes in 23 patients. In the cases where VEP declined during intraoperative recording, it recovered when surgery was discontinued. Furthermore, 3 patients eventually achieved a higher VEP than that achieved at the beginning of the surgery, and rapid recovery was confirmed with visual field examination immediately after surgery. Of the 5 patients in whom VEP did not recover during surgery, 3 showed decreased visual field and acuity after surgery. In 15 cases, potential dropped temporarily but returned to the original potential, and their visual field recovered after surgery. CONCLUSIONS: OFR has a diagnostic element in the visual field, in which the maximal potential was recorded on the opposite side of the stimulus with monocular stimulation. Unambiguous determination required stimulation of different intensities in both eyes or 1 eye and multiple recording electrodes placed in the occiput. Monitoring the OFR provides real-time alerts, making it a valuable tool for visual function evaluation in suprasellar surgery.

Effectiveness and safety of primary prophylaxis of granulocyte colony-stimulating factor during dose-dense chemotherapy for urothelial cancer: Clinical Practice Guidelines for the Use of G-CSF 2022.

Granulocyte colony-stimulating factor (G-CSF) decreases the incidence, duration, and severity of febrile neutropenia (FN); however, dose reduction or withdrawal is often preferred in the management of adverse events in the treatment of urothelial cancer. It is also important to maintain therapeutic intensity in order to control disease progression and thereby relieve symptoms, such as hematuria, infection, bleeding, and pain, as well as to prolong the survival. In this clinical question, we compared treatment with primary prophylactic administration of G-CSF to maintain therapeutic intensity with conventional standard therapy without G-CSF and examined the benefits and risks as major outcomes. A detailed literature search for relevant studies was performed using PubMed, Ichu-shi Web, and Cochrane Library. Data were extracted and evaluated independently by two reviewers. A qualitative analysis of the pooled data was performed, and the risk ratios with corresponding confidence intervals were calculated and summarized in a meta-analysis. Seven studies were included in the qualitative analysis, two of which were reviewed in the meta-analysis of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) therapy, and one randomized controlled study showed a reduction in the incidence of FN. Primary prophylactic administration of G-CSF may be beneficial, as shown in a randomized controlled study of dose-dense MVAC therapy. However, there are no studies on other regimens, and we made a "weak recommendation to perform" with an annotation of the relevant regimen (dose-dense MVAC).

Effectiveness and safety of primary prophylaxis with G-CSF after induction therapy for acute myeloid leukemia: a systematic review and meta-analysis of the clinical practice guidelines for the use of G-CSF 2022 from the Japan society of clinical oncology.

Although granulocyte colony-stimulating factor (G-CSF) reduces the incidence, duration, and severity of neutropenia, its prophylactic use for acute myeloid leukemia (AML) remains controversial due to a theoretically increased risk of relapse. The present study investigated the effects of G-CSF as primary prophylaxis for AML with remission induction therapy. A detailed literature search for related studies was performed using PubMed, Ichushi-Web, and the Cochrane Library. Data were independently extracted and assessed by two reviewers. A qualitative analysis of pooled data was conducted, and the risk ratio with corresponding confidence intervals was calculated in the meta-analysis and summarized. Sixteen studies were included in the qualitative analysis, nine of which were examined in the meta-analysis. Although G-CSF significantly shortened the duration of neutropenia, primary prophylaxis with G-CSF did not correlate with infection-related mortality. Moreover, primary prophylaxis with G-CSF did not affect disease progression/recurrence, overall survival, or adverse events, such as musculoskeletal pain. However, evidence to support or discourage the use of G-CSF as primary prophylaxis for adult AML patients with induction therapy remains limited. Therefore, the use of G-CSF as primary prophylaxis can be considered for adult AML patients with remission induction therapy who are at a high risk of infectious complications.

Landscape of driver mutations and their clinical effects on Down syndrome-related myeloid neoplasms.

Transient abnormal myelopoiesis (TAM) is a common complication in newborns with Down syndrome (DS). It commonly progresses to myeloid leukemia (ML-DS) after spontaneous regression. In contrast to the favorable prognosis of primary ML-DS, patients with refractory/relapsed ML-DS have poor outcomes. However, the molecular basis for refractoriness and relapse, and the full spectrum of driver mutations in ML-DS remain largely unknown. We conducted a genomic profiling study of 143 TAM, 204 ML-DS, and 34 non-DS acute megakaryoblastic leukemia cases, including 39 ML-DS cases analyzed by exome sequencing. Sixteen novel mutational targets were identified in ML-DS samples. Of these, inactivations of IRX1 (16.2%) and ZBTB7A (13.2%) were commonly implicated in the upregulation of the MYC pathway and were potential targets for ML-DS treatment with bromodomain-containing protein 4 inhibitors. Partial tandem duplications of RUNX1 on chromosome 21 were also found, specifically in ML-DS samples (13.7%), presenting its essential role in DS leukemia progression. Finally, in 177 patients with ML-DS treated following the same ML-DS protocol (the Japanese Pediatric Leukemia and Lymphoma Study Group AML-D05/D11), CDKN2A, TP53, ZBTB7A, and JAK2 alterations were associated with a poor prognosis. Patients with CDKN2A deletions (n = 7) or TP53 mutations (n = 4) had substantially lower 3-year event-free survival [28.6% vs. 90.5%, P < 0.001; 25.0% vs. 89.5%, P < 0.001] than those without these mutations. These findings considerably change the mutational landscape of ML-DS, provide new insights into the mechanisms of progression from TAM to ML-DS, and help identify new therapeutic targets and strategies for ML-DS.

Optimal timing of prophylactic pegylated G-CSF after chemotherapy administration for patients with cancer: a systematic review and meta-analysis from Clinical Practice Guidelines for the use of G-CSF 2022.

INTRODUCTION: The timing of prophylactic pegylated granulocyte colony-stimulating factor (G-CSF) administration during cancer chemotherapy varies, with Day 2 and Days 3-5 being the most common schedules. Optimal timing remains uncertain, affecting efficacy and adverse events. This systematic review sought to evaluate the available evidence on the timing of prophylactic pegylated G-CSF administration. METHODS: Based on the Minds Handbook for Clinical Practice Guideline Development, we searched the PubMed, Ichushi-Web, and Cochrane Library databases for literature published from January 1990 to December 2019. The inclusion criteria included studies among the adult population using pegfilgrastim. The search strategy focused on timing-related keywords. Two reviewers independently extracted and assessed the data. RESULTS: Among 300 initial search results, only four articles met the inclusion criteria. A meta-analysis for febrile neutropenia incidence suggested a potential higher incidence when pegylated G-CSF was administered on Days 3-5 than on Day 2 (odds ratio: 1.27, 95% CI 0.66-2.46, p = 0.47), with a moderate certainty of evidence. No significant difference in overall survival or mortality due to infections was observed. The trend of severe adverse events was lower on Days 3-5, without statistical significance (odds ratio: 0.72, 95% CI 0.14-3.67, p = 0.69) and with a moderate certainty of evidence. Data on pain were inconclusive. CONCLUSIONS: Both Day 2 and Days 3-5 were weakly recommended for pegylated G-CSF administration post-chemotherapy in patients with cancer. The limited evidence highlights the need for further research to refine recommendations.

Effectiveness and safety of primary prophylaxis of G-CSF during chemotherapy for prostate cancer, Japanese clinical guideline for appropriate use of G-CSF: clinical practice guidelines for the use of G-CSF 2022.

BACKGROUND: Docetaxel (DTX) is commonly used as a primary chemotherapy, and cabazitaxel (CBZ) has shown efficacy in patients who are DTX resistant. Primary prophylactic granulocyte colony stimulating factor (G-CSF) therapy is currently used with CBZ treatment in routine clinical care in Japan. METHODS: In this study, we performed a systematic review following the Minds guidelines to investigate the effectiveness and safety of primary prophylaxis with G-CSF during chemotherapy for prostate cancer and to construct G-CSF guidelines for primary prophylaxis use during chemotherapy. A comprehensive literature search of various electronic databases (PubMed, Cochrane Library, and Ichushi) was performed on January 10, 2020, to identify studies published between January 1990 and December 31, 2019 that investigate the impact of primary prophylaxis with G-CSF during CBZ administration on clinical outcomes. RESULTS: Ultimately, nine articles were included in the qualitative systematic review. Primary G-CSF prophylaxis during CBZ administration for metastatic castration-resistant prostate cancer was difficult to assess in terms of correlation with overall survival, mortality from infection, and patients' quality of life. These difficulties were owing to the lack of randomized controlled trials comparing patients with and without primary prophylaxis of G-CSF during CBZ administration. However, some retrospective studies have suggested that it may reduce the incidence of febrile neutropenia. CONCLUSION: G-CSF may be beneficial as primary prophylaxis during CBZ administration for metastatic castration resistant prostate cancer, and we made a "weak recommendation to perform" with an annotation of the relevant regimen.

Cytomorphological features of sebaceous carcinoma of the breast.

Sebaceous carcinoma of the breast is an extremely rare histological subtype of breast cancer, with fewer than 30 cases reported to date. Because of its extremely rare histological presentation, there are few case reports that highlight its cytological findings. In this case report, the cytomorphological features of a sebaceous carcinoma of the breast are described in detail. Cytomorphological analysis revealed atypical cells presenting predominantly as loose clusters. No tubular or papillary structures were evident in the clusters and no mucin production was observed. The diagnosis of sebaceous carcinoma of the breast requires prominent sebaceous differentiation of cells. In Papanicolaou-stained smears, the differentiated tumor cells were found within the yellowish clusters. When these yellowish clusters were observed at high magnification and shifted out of focus, the sebaceous differentiation of tumor cells could be recognized. This finding is an advantage of observing Papanicolaou-stained specimens. Like previous reports, some individual cells showing sebaceous differentiation were also observed. In cases where many yellowish clusters appear, close observation of the interior of the clusters can confirm the presence of sebaceous differentiation of tumor cells and serve as a diagnostic clue for the cytological diagnosis of sebaceous carcinoma of the breast.

Effectiveness and safety of primary prophylaxis with G-CSF for lung cancer: a systematic review and meta-analysis to develop clinical practice guidelines for the use of G-CSF 2022.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) is commonly administered to cancer patients undergoing myelosuppressive chemotherapy, especially when incidence rate of febrile neutropenia (FN) surpasses 20%. While primary prophylaxis with G-CSF has been proven effective in preventing FN in patients with cancer, there is limited evidence regarding its efficacy in specifically, lung cancer. Our systematic review focused on the efficacy of G-CSF primary prophylaxis in lung cancer. METHODS: We extracted studies on non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) using the PubMed, Ichushi Web, and Cochrane Library databases. Two reviewers assessed the extracted studies for each type of lung cancer and conducted quantitative and meta-analyses of preplanned outcomes, including overall survival, FN incidence, infection-related mortality, quality of life, and musculoskeletal pain. RESULTS: A limited number of studies were extracted: two on NSCLC and six on SCLC. A meta-analysis was not conducted owing to insufficient data on NSCLC. Two case-control studies explored the efficacy of primary prophylaxis with G-CSF in patients with NSCLC (on docetaxel and ramucirumab therapy) and indicated a lower FN frequency with G-CSF. For SCLC, meta-analysis of five studies showed no significant reduction in FN incidence, with an odds ratio of 0.38 (95% confidence interval 0.03-5.56, P = 0.48). Outcomes other than FN incidence could not be evaluated due to low data availability. CONCLUSION: Limited data are available on G-CSF prophylaxis in lung cancer. Primary prophylaxis with G-CSF may be weakly recommended in Japanese patients with NSCLC undergoing docetaxel and ramucirumab combination therapy.

The effect of center experience on allogeneic hematopoietic cell transplantation outcomes in acute myeloid leukemia.

This study aimed to address the prognostic impact of center experience based on the data of 7821 adults with acute myeloid leukemia who underwent allogeneic hematopoietic cell transplantation (HCT) from 2010 to 2019 in Japan, where medical care was provided within a uniform healthcare system. Center experience was defined based on the number of allogeneic HCTs performed for any indication during the study period, by which centers were divided into low-, intermediate-, and high-volume centers. After adjusting for known confounding factors, the risk of overall mortality was lowest for the high-volume centers and highest for the low-volume centers, with the difference between the center categories attributed primarily to the risk of relapse. Patients transplanted at high-volume centers had higher risks of acute and chronic graft-versus-host diseases but without an increased risk of non-relapse mortality (NRM). These findings reveal the presence of a center effect in allogeneic HCT conducted during the past decade in Japan, highlighting the difference in relapse based on center experience. The weaker effect on NRM compared with that on relapse suggests that the transplantation care quality is becoming equalized across the country.

Efficacy of adding levofloxacin to gemcitabine and nanoparticle-albumin-binding paclitaxel combination therapy in patients with advanced pancreatic cancer: study protocol for a multicenter, randomized phase 2 trial (T-CORE2201).

BACKGROUND: Advanced pancreatic cancer is one of the leading causes of cancer-related deaths. For patients with advanced pancreatic cancer, gemcitabine and nanoparticle albumin-binding paclitaxel (nabPTX) combination (GEM/nabPTX) therapy is one of the recommended first-line treatments. Several retrospective studies have suggested that the addition of levofloxacin improves the efficacy of GEM/nabPTX therapy in patients with advanced pancreatic cancer. This prospective study aims to evaluate whether the addition of antibiotics improves the treatment efficacy of GEM/nabPTX as a first-line chemotherapy in patients with advanced pancreatic cancer. METHODS: This multicenter, prospective, randomized, phase 2 trial will included 140 patients. Patients with advanced pancreatic cancer will be randomized in a 1:1 ratio to either the GEM/nabPTX therapy group or the GEM/nabPTX plus levofloxacin group. The primary endpoint for the two groups is median progression-free survival time (mPFS) for the full analysis set (FAS). The secondary endpoints for the two groups are median overall survival (mOS), response rate (RR), disease control rate (DCR), and adverse event (AE) for the FAS and mPFS, mOS, RR, DCR, and AE for the per-protocol set. This study will enroll patients treated with GEM/nabPTX as the first-line chemotherapy for stage IV pancreatic adenocarcinoma. DISCUSSION: GEM/nabPTX is a standard first-line chemotherapy regimen for patients with advanced pancreatic cancer. Recently, the superiority of 5-fluorouracil, liposomal irinotecan, and oxaliplatin combination therapy (NALIRIFOX) to GEM/nabPTX as first-line therapy for pancreatic cancer has been reported. However, the efficacy of NALIRIFOX is inadequate. Based on previous retrospective studies, it is hypothesized that treatment efficacy will improve when levofloxacin is added to GEM/nabPTX therapy. If the AEs (such as leukopenia, neutropenia, and peripheral neuropathy) that occur at an increased rate with levofloxacin and GEM/nabPTX combination therapy can be carefully monitored and properly managed, this simple intervention can be expected to improve the prognosis of patients with advanced pancreatic cancer. TRIAL REGISTRATION: This study was registered with the Japan Registry of Clinical Trials (jRCT; registry number: jRCTs021230005).

Impact of Center Volume on Chronic Graft Versus Host Disease in Patients With Allogeneic Stem Cell Transplantation.

Chronic graft-versus-host disease (cGVHD) is a complication of allogeneic hematopoietic stem cell transplantation (HSCT), negatively impacting quality of life (QoL) and increasing the risk of death. Complexity in cGVHD diagnosis and treatment causes significant variations in cGVHD management strategies across medical centers and physicians despite the existence of published guidelines. Thus, we hypothesized that center volume is associated with cGVHD incidence and outcomes after cGVHD develops. This study aimed to evaluate the effect of center volume on the incidence of cGVHD in patients who underwent HSCT and outcomes in patients with cGVHD. Our retrospective study included 28,786 patients who underwent their first HSCT (overall cohort) and 7664 who developed cGVHD (cGVHD cohort). We categorized institutions into quartiles (very low, low, high, and very high) using the number of HSCTs performed during the study period. We assessed cGVHD incidence in overall cohort and overall survival (OS) in cGVHD cohort. The very high-volume group showed significantly higher cGVHD incidence (adjusted hazard ratio [HR], 1.38; 95% confidence interval [CI]: 1.30 to 1.46) compared to the very low-volume group. However, the cGVHD incidence was similar among very low-, low- and high-volume groups. Low, high, and very high-volume groups showed significantly higher OS with adjusted HRs of 0.83 (95% CI: 0.73 to 0.94), 0.69 (95% CI: 0.61 to 0.79), and 0.68 (95% CI: 0.60 to 0.76), respectively, compared with the very low-volume group. In conclusion, we revealed a higher incidence of cGVHD in the very high-volume group and a poor survival outcome in the very low-volume group in patients with cGVHD.

TBI, etoposide, and cyclophosphamide conditioning for intermediate-risk relapsed childhood acute lymphoblastic leukemia.

BACKGROUND: In children with intermediate-risk relapsed acute lymphoblastic leukemia (ALL), allogeneic hematopoietic stem cell transplantation (allo-HSCT) has markedly improved the outcome of patients with an unsatisfactory minimal residual disease (MRD) response. Total body irradiation (TBI), etoposide (ETP), and cyclophosphamide (CY) have been shown to be equivalent to or better than TBI + ETP for conditioning, so we hypothesized that even greater survival could be achieved due to recent advances in HSCT and supportive care. PROCEDURE: We prospectively analyzed the efficacy and safety of allo-HSCT with a unified conditioning regimen of TBI + ETP + CY in children with intermediate-risk relapsed ALL, based on MRD in the bone marrow after induction, from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) ALL-R08-II nationwide cohort (UMIN000002025). RESULTS: Twenty patients with post-induction MRD ≥ 10-3 and two not evaluated for MRD underwent allo-HSCT. Engraftment was confirmed in all patients, and no transplantation-related mortality was observed. The 3-year event-free survival and overall survival rates after transplantation were 86.4% ± 7.3% and 95.5% ± 4.4%, respectively. CONCLUSION: Allo-HSCT based on post-induction MRD with TBI + ETP + CY conditioning was feasible in Japanese children with intermediate-risk relapsed ALL.

Sternocleidomastoid muscle-splitting method for high cervical carotid endarterectomy: illustrative cases.

BACKGROUND: The number of cervical carotid endarterectomies (CEAs) has decreased as carotid artery stenting (CAS) has increased. However, CEA and CAS both have advantages and disadvantages; therefore, appropriate procedures must be selected for individual patients. High-positioned carotid artery stenosis presents technical challenges for CEA and is occasionally managed by performing CAS. However, CAS is associated with a high risk of thrombosis in patients with soft plaques, suggesting a clinical need for a better procedure. Consequently, appropriate surgical treatment for patients requiring high-level CEAs is essential. OBSERVATIONS: In this study, a novel and straightforward method was devised. The primary concept underlying this technique is separation of the sternocleidomastoid muscle (SCM) from other anatomical structures to ensure a wider surgical field. By anatomically separating the SCM into the sternal and clavicular head groups, the objective of the wider surgical field can be met. Herein, we report technical innovations in high-positioned carotid artery stenosis and evaluate their efficacy in two patients. LESSONS: In conclusion, high CEA surgery using this new method is valuable and may eliminate barriers to more advanced approaches.

Intracellularly delivered human lactoferrin functions as an activator of Na+/H+ exchanger 7.

Here, we report that human lactoferrin (hLF), known for its anticancer properties, induced intracellular activation of the Na+/H+ exchanger (NHE) 7 in human lung cancer PC-9 cells. Compared to non-fused hLF, the fusion of human serum albumin (HSA) with hLF (hLF-HSA) facilitated its internalization into PC-9 cells in a caveolae-mediated manner, thereby exhibiting enhanced anti-proliferative effects. Although hLF alone did not exhibit any discernible effects, hLF-HSA resulted in organelle alkalization as detected using an acidotropic pH indicator. hLF-HSA-induced elevation of organelle pH and inhibition of cancer growth were abolished by NHE7 siRNA. hLF-HSA upregulated NHE7. Thus, upon cellular uptake, hLF-HSA triggers proton leakage through the upregulation of NHE7. This process led to organelle alkalization, probably in the trans-Golgi network (TGN) as suggested by the localization of NHE7 in PC-9 cells, thereby suppressing lung cancer cell growth. Forcing the cellular uptake of hLF alone using a caveolae-mediated endocytosis activator led to an increase in organelle pH. Furthermore, cell entry of hLF also activated proton-loading NHE7, leading to organelle acidification in the pancreatic cancer cell line MIA PaCa-2. Therefore, the intracellularly delivered hLF functions as an activator of NHE7.

Reduced-intensity allogenic transplantation for children and adolescents with Philadelphia chromosome-positive acute lymphoblastic leukemia.

Survival rates of patients with Philadelphia chromosome-positive ALL (Ph+ALL) have improved considerably with the introduction of tyrosine kinase inhibitors (TKI); however, hematopoietic stem cell transplantation (HSCT) continues to play an important role. Reduced-intensity conditioning (RIC) regimens have been widely applied particularly for older patients, but their validity for children and adolescents with Ph+ALL has not been investigated. In this study, data from patients receiving HSCT for de novo Ph+ALL in first or second remission at ages younger than 25 years and with a history of pre-HSCT TKI therapy were retrospectively collected through the nationwide registry in Japan. In 265 patients who received myeloablative conditioning (MAC) and 33 patients receiving RIC, 5-year leukemia-free survival (LFS) rates were 67.3% and 79.8%, respectively (p = 0.142). Multivariate analysis of LFS, focusing on patients with good performance status, identified RIC as a significant prognostic factor for LFS (hazard ratio 0.32, p = 0.032), as well as older age, higher leukocyte count at diagnosis, and disease with additional chromosomal abnormalities. These trends were similar when we focused on patients who received prophylactic post-HSCT TKI treatment, as 5-year LFS was 81.0% for MAC and 84.4% for RIC (p = 0.748). In summary, HSCT with RIC regimen showed at least comparable LFS to HSCT with MAC regimen, and RIC was an independent favorable prognostic factor on multivariate analysis adjusting potential prognostic factors. While patient numbers were limited, our data suggest that RIC may be safely applied in this group, particularly combined with prophylactic post-HSCT TKI maintenance therapy.

Topical therapy and skin care for transplant-associated atopic dermatitis in children and adolescents.

BACKGROUND: New-onset allergic diseases, such as food allergy or atopic dermatitis, can develop after allogeneic transplantation. There are limited reports of new-onset atopic dermatitis after allogeneic hematopoietic stem cell transplantation in children and adolescents, and its treatment is yet to be established. The pathogenesis may differ from typical atopic dermatitis in terms of alloimmunity including graft-versus-host disease. METHODS: We present five children and adolescents with new-onset atopic dermatitis after allogeneic hematopoietic stem cell transplantation. The characteristics and clinical profiles of skin treatment after hematopoietic stem cell transplantation are summarized. RESULTS: Graft-versus-host disease prophylaxis included systemic tacrolimus for all patients. After hematopoietic stem cell transplantation, all patients achieved complete donor chimerism of the bone marrow and had acute graft-versus-host disease of the skin. After engraftment, all patients had skin lesions that met the international consensus diagnostic criteria for atopic dermatitis. None of the patients met the diagnostic criteria for chronic graft-versus-host disease. Topical therapy and skin care based on atopic dermatitis guidelines improved skin condition and atopic dermatitis severity scores in all patients. In addition, type 2 inflammatory markers improved accordingly. CONCLUSION: Topical therapy and skin care may be effective for transplant-related atopic dermatitis after hematopoietic stem cell transplantation. When extensive dermatitis is observed after hematopoietic stem cell transplantation, this treatment may avoid excessive immunosuppressive therapy if it meets the diagnostic criteria for atopic dermatitis.

Jejunal gastrointestinal stromal tumor that developed in a patient with neurofibromatosis type 1: a case report.

BACKGROUND: Neurofibromatosis type 1 (NF1) is known to be associated with the frequent occurrence of unique gastrointestinal stromal tumors (GISTs), preferably occurring in the small intestine, with no mutations in the c-kit proto-oncogene or platelet-derived growth factor receptor-alpha (PDGFRA), with a high tendency for multifocal development, indolent nature, with low proliferation activity and favorable prognosis. CASE PRESENTATION: A woman in her forties visited her local doctor complaining of menstrual pain; a large mass was detected in her lower abdomen, and she was referred to our hospital. The patient had hundreds of skin warts and café au lait spots. The patient's mother had been diagnosed with type 1 neurofibromatosis. The patient met the diagnostic criteria for NF1 and was diagnosed with NF1. Ultrasonography showed a large heterogeneous cystic mass with various echo patterns, solid compartments and multiple septations. Magnetic resonance imaging showed a multilocular cystic mass with liquid content exhibiting various intensities, including that of blood. A small round solid mass was also observed close to the cystic tumor. Contrast-enhanced computed tomography showed that the round solid mass showed strong enhancement in the early phase, unlike the cystic tumor component. Open laparotomy revealed a multicystic exophytic tumor measuring 11.5 cm originating from the jejunal wall, 20 cm distal to the duodenojejunal flexure. A solid tumor measuring 2.1 cm was also found on the anal side of the large tumor. We resected the short segment of the jejunum, including the two lesions. Microscopic findings revealed that the cystic and solid tumors consisted of spindle-shaped tumor cells showing little atypia with a fascicular or bundle arrangement. Nuclear mitosis was scarce. Immunostaining of the tumor cells showed positive staining for KIT and DOG1 and negative staining for S100 and desmin. The NF1 patient was diagnosed with multiple GISTs accompanied by intratumoral hemorrhagic denaturation arising from the jejunum. The TNM staging was pT4N0M0, stage IIIA. CONCLUSION: We report a case of GISTs associated with NF1 that showed a jejunal origin, multifocal development and few mitotic figures. The recurrence risk, survival prognosis and need for adjuvant chemotherapy, particularly in cases where the initial GIST exhibits a very indolent pathology in NF1-related GISTs, remain to be elucidated.