Three-year progression-free survival of a patient with concomitant mucinous adenocarcinoma of the colon with peritoneal dissemination and multiple myeloma who received lenalidomide: a case report.

BACKGROUND: Concomitant multiple myeloma (MM) and other primary malignancies is rare. Therefore, the treatment outcomes of patients with these conditions have not been well discussed. Lenalidomide is an oral thalidomide analog drug used for MM. Recently, the antitumor effect of lenalidomide has been gaining attention, and lenalidomide has been applied for managing solid tumors. The current case showed the treatment course of a patient treated with lenalidomide for concomitant MM and colon cancer with peritoneal dissemination. CASE PRESENTATION: A 74-year-old female patient receiving treatment for MM was diagnosed with mucinous adenocarcinoma of the transverse colon. The patient was clinically diagnosed with stage IIIC T4aN2M0 disease. Subsequently, laparoscopic colectomy with lymph node dissection was planned. However, intraperitoneal observation revealed peritoneal dissemination that had sporadically and widely spread. Therefore, palliative partial colectomy was performed to prevent future hemorrhage or obstruction. The patient was discharged on the 10th postoperative day without postoperative complication. Based on the patient's preference, lenalidomide was continually administered for MM without systemic chemotherapy. The patient survived for > 36 months without any signs of tumor progression. CONCLUSION: The current case first showed the treatment course of concomitant MM and colon cancer. The antitumor effect of lenalidomide can possibly contribute to 3-year progression-free survival in patients with mucinous adenocarcinoma of the colon with peritoneal dissemination.

[Hemophagocytic lymphohistiocytosis following mRNA-1273 COVID-19 vaccination].

A 34-year-old man with no medical history presented with fever 4 days after receiving the first dose of mRNA-1273 coronavirus disease 2019 (COVID-19) vaccine. He had no prior clinical evidence of severe acute respiratory syndrome coronavirus 2 infection and was negative for serial polymerase chain reaction testing. Ten days after vaccination, he was referred to our hospital because of no response to antibiotics and the emergence of neutropenia, thrombocytopenia, and liver dysfunction. Blood tests also showed elevated serum ferritin and plasma soluble interleukin-2 receptors. Serological and PCR testing excluded active infections of cytomegalovirus, Epstein-Barr virus, and hepatitis viruses. Blood culture yielded no growth. Computed tomography revealed mild hepatosplenomegaly and porta hepatis lymphadenopathy but no focus on infection. Bone marrow aspiration demonstrated hemophagocytosis but no infiltrating lymphoma cells. Immediately, 2-mg/kg intravenous methylprednisolone was commenced based on the presumptive diagnosis of hemophagocytic lymphohistiocytosis (HLH), leading to the rapid and durable improvement of his symptoms and laboratory data. Later, without other causes triggering hemophagocytosis, and with the close link between vaccination and disease onset, the final diagnosis of vaccination-induced secondary HLH was made. HLH after COVID-19 vaccination, though extremely rare, can occur regardless of the vaccine type. Therefore, clinicians should recognize and deal with this occasionally fatal adverse event.

Lack of dose dependency for radiation pneumonitis after chemoradiotherapy with the use of tomotherapy for lung cancer.

A 71-year-old man with stage IIB (Union for International Cancer Control, 8th edition) non-small cell lung cancer underwent intensity-modulated radiation therapy with a dose of 66 Gy administered in 33 fractions concomitant with carboplatin and paclitaxel therapy. On computed tomography after completion of radiation therapy, ground-glass opacity, which was larger on the contralateral side, was observed, but it was not observed in the high-dose area on the ipsilateral side. Although the adverse event theoretically shows dose dependency, it was finally diagnosed as radiation pneumonitis. The presence of an atypical distribution of radiation pneumonitis should be recognized to improve the diagnosis, and it is suggested that the relative volume of the normal contralateral lung receiving a dose of ≥5 Gy is a possible risk factor for radiation pneumonitis.

[Chronic myeloid leukemia with an in-frame exon 4 deletion in ABL1 with acute abdomen due to an intrapelvic bulky mass as the initial symptom].

A 23-year-old woman was admitted to our hospital because of rapidly developing lower abdominal pain. Computed tomography revealed ascites, splenomegaly, and a huge mass that occupied the pouch of Douglas and surrounded her uterus. A markedly elevated white blood cell count of 495×109/l and the identification of the BCR-ABL1 fusion gene led to the diagnosis of chronic myeloid leukemia (CML). Although neither an increase in the blast percentage nor any additional chromosomal abnormality was observed in the patient, CML was considered in the blast phase because of extramedullary disease infiltration. Dasatinib was administered with the temporal use of hydroxyurea and VP-16, which resulted in rapid disappearance of her intrapelvic mass and complete hematologic response within 1 month. She refused to undergo allogeneic hematopoietic stem cell transplantation and continued to take dasatinib, achieving complete cytogenetic and major molecular responses within 5 and 11 months, respectively. CML cases initially presenting with extramedullary tumors are rare. Furthermore, in our case, a mutational analysis at diagnosis revealed an in-frame exon 4 deletion in ABL1, which is reported to decrease cell proliferation. This fact is intriguing because her clinical outcome was relatively favorable.

[A Case of Malignant Lymphoma Undergoing HAI Treatment for Multiple Liver Metastases of Carcinoid That Appeared about Nine Years after Resection of Rectal Carcinoid with Liver Metastases].

The present case pertained to a 70-year-old woman. The fecal occult blood test was positive. Colonoscopyrevealed rectal cancer. She underwent the first operation of low anterior resection. Pathological diagnosis was carcinoid, se, ly2, v0, n1. Approximately2 months later, multiple liver metastases were found. Because of strong enhancement at angiography, transarterial chemoembolization(TACE)was selected. After 3 rounds of TACE, we operated the residual liver metastasis approximately1 year and 7 months after the first operation. However, approximately8 years and 9 months after the first operation, multiple liver metastases were found again. Hepatic arterial infusion(HAI)was chosen because tumors showed weak en- hancement on CT. First, we tried high-dose HAI(5-FU 1 g/dayat 1-3 and 5-7, amount: 6 g/week), and liver metastases was almost in CR. However, extrahepatic metastasis was found on PET-CT. Because of rapid growth, we operated the growing lymph node. Pathological diagnosis was diffuse large-cell type B-cell malignant lymphoma. Thus, we extended the interval of HAI(weekly, biweekly, and monthly)and simultaneously4 courses of R-THP-COP(R: rituximab, THP: pirarubicin, C: cyclophosphamide, O: vincristine, P: prednisolone)therapyfor malignant lymphoma was administered. She is now an outpatient. Liver metastases continue to be in CR at approximately1 year and the IL-2R value is almost within normal range.

[Follicular lymphoma with nodular lesions mimicking gallbladder carcinoma].

A 68-year-old female was diagnosed with follicular lymphoma (FL) grade 2, based on the excisional biopsy of her enlarged left cervical lymph node. Positron-emission tomography/computed tomography (PET/CT) revealed the 18F-fluoro-deoxyglucose-avid lesions in the sigmoid colon and at the fundus of the gallbladder, besides those in the left neck. A sigmoid colon polyp, which was endoscopically resected, proved histologically to be a well- to moderately-differentiated tubular adenocarcinoma with deep invasion into the submucosa. In addition, nodular lesions of the gallbladder were enhanced on dynamic CT, markedly suggesting gallbladder carcinoma. Among FL, colorectal cancer, and presumed gallbladder adenocarcinoma, FL was considered having the lowest priority of treatment because of its indolent nature and low tumor burden. We performed laparoscopic-assisted sigmoid colectomy, followed by gallbladder bed resection on the same day. Unpredictably, gallbladder lesions were histologically revealed to be FL. Often, FL involves extranodal sites such as the gastrointestinal tracts. However, the gallbladder involvement is extremely rare, and preoperative distinction from gallbladder adenocarcinoma remains challenging to date; this report discusses its characteristics along with the literature review. Furthermore, our case, in which another malignant neoplasm coexisted, needed histological identification of the gallbladder lesions to ascertain the therapeutic strategy.

[Systemic lupus erythematosus with marked eosinophilia and clinical features mimicking TAFRO syndrome].

A 76-year-old woman was referred to our hospital because of fever, hemorrhagic skin lesion with pruritus, and severe thrombocytopenia. Anemia; marked eosinophilia; and elevated ALP, CRP, and soluble IL-2 receptor levels were observed on admission. Both anti-nuclear antibody and Coombs tests were positive. Computed tomography revealed bilateral pleural effusion, ascites, abdominal lymphadenopathy, and mild hepatosplenomegaly. A thorough examination for the initial differential diagnoses excluded the possibility of myeloid/lymphoid neoplasms with eosinophilia and gene rearrangement, infectious diseases, and eosinophilic granulomatosis with polyangiitis. Remaining possibilities included angioimmunoblastic T-cell lymphoma (AITL) and systemic inflammatory disorders. Although AITL was plausible, there was no histological evidence to support the diagnosis. The patient was then administered prednisolone alone, which led to a lasting resolution of her symptoms. The atypical AITL course raised the suspicion of a misdiagnosis; thus the possibility of an inflammatory disease was reconsidered. TAFRO syndrome was suspected owing to its characteristic clinical features (thrombocytopenia, anasarca, fever and organomegaly). Since a definitive diagnosis required the exclusion of systemic lupus erythematosus (SLE), anti-double-stranded DNA antibody was tested in the initial frozen serum sample. An unexpected positive result led to the final diagnosis of SLE. Here, we report a rare case of SLE lacking typical symptoms and exhibiting various hematological abnormalities, such as eosinophilia.

Variable SATB1 Levels Regulate Hematopoietic Stem Cell Heterogeneity with Distinct Lineage Fate.

Hematopoietic stem cells (HSCs) comprise a heterogeneous population exhibiting self-renewal and differentiation capabilities; however, the mechanisms involved in maintaining this heterogeneity remain unclear. Here, we show that SATB1 is involved in regulating HSC heterogeneity. Results in conditional Satb1-knockout mice revealed that SATB1 was important for the self-renewal and lymphopoiesis of adult HSCs. Additionally, HSCs from Satb1/Tomato-knockin reporter mice were classified based on SATB1/Tomato intensity, with transplantation experiments revealing stronger differentiation toward the lymphocytic lineage along with high SATB1 levels, whereas SATB1- HSCs followed the myeloid lineage in agreement with genome-wide transcription and cell culture studies. Importantly, SATB1- and SATB1+ HSC populations were interconvertible upon transplantation, with SATB1+ HSCs showing higher reconstituting and lymphopoietic potentials in primary recipients relative to SATB1- HSCs, whereas both HSCs exhibited equally efficient reconstituted lympho-hematopoiesis in secondary recipients. These results suggest that SATB1 levels regulate the maintenance of HSC multipotency, with variations contributing to HSC heterogeneity.

[Neutrophil recovery by eltrombopag treatment in a patient with adult-onset autoimmune neutropenia and immune thrombocytopenia].

Adult-onset autoimmune neutropenia (AIN) is rarely self-limiting, unlike infant-onset AIN. Although several therapeutic agents have been reported, including corticosteroids, more effective treatment options may exist. Here, we describe neutrophil recovery by eltrombopag in a 52-year-old male AIN patient with immune thrombocytopenia (ITP) who was referred to our hospital with severe neutropenia. Within a year of referral, he developed moderate thrombocytopenia. He was diagnosed with AIN and concurrent ITP, based on the detection of antineutrophil antibodies and bone marrow aspiration, respectively. Further platelet count reduction and the appearance of purpura prompted an initial treatment of 0.5 mg/kg prednisolone. Thrombocytopenia remission was prompt but transient, with platelet counts rapidly declining before initiating prednisolone tapering. Similarly, absolute neutrophil counts (ANCs), after a shorter recovery period, returned to the baseline level below 2×108/l. Further platelet reduction was prevented by eltrombopag administration. Intriguingly, the ANCs recovered following platelet recovery and remained above 5×108/l for > three months despite prednisolone dosage tapering. To our knowledge, this is the first report describing the effectiveness of eltrombopag in AIN.

Collection of homozygous mutant mouse embryonic stem cells arising from autodiploidization during haploid gene trap mutagenesis.

Haploid mouse embryonic stem cells (ESCs), in which a single hit mutation is sufficient to produce loss-of-function phenotypes, have provided a powerful tool for forward genetic screening. This strategy, however, can be hampered by undesired autodiploidization of haploid ESCs. To overcome this obstacle, we designed a new methodology that facilitates enrichment of homozygous mutant ESC clones arising from autodiploidization during haploid gene trap mutagenesis. Haploid mouse ESCs were purified by fluorescence-activated cell sorting to maintain their haploid property and then transfected with the Tol2 transposon-based biallelically polyA-trapping (BPATrap) vector that carries an invertible G418 plus puromycin double selection cassette. G418 plus puromycin double selection enriched biallelic mutant clones that had undergone autodiploidization following a single vector insertion into the haploid genome. Using this method, we successfully generated 222 homozygous mutant ESCs from 2208 clones by excluding heterozygous ESCs and ESCs with multiple vector insertions. This relatively low efficiency of generating homozygous mutant ESCs was partially overcome by cell sorting of haploid ESCs after Tol2 BPATrap transfection. These results demonstrate the feasibility of our approach to provide an efficient platform for mutagenesis of ESCs and functional analysis of the mammalian genome.

Use of hormone therapies in disseminated carcinomatosis of the bone marrow associated with hormone receptor-positive breast cancer.

Disseminated carcinomatosis of the bone marrow (DCBM) is diffusely invasive bone metastasis resulting from solid tumors. DCBM is often associated with disseminated intravascular coagulation (DIC) or hemolytic anemia. Generally, DCBM treatment includes cytotoxic chemotherapy for underlying solid tumors and management of hematological conditions if present. We report a case of DCBM accompanied with DIC in hormone receptor-positive breast cancer. Due to her life-threatening condition, we used hormone therapies, not cytotoxic chemotherapies, to treat her DCBM. With zoledronic acid, her DIC and general condition gradually improved and eventually she could return to her daily life. If DCBM occurs in hormone receptor-positive breast cancer, hormone therapy can be one of the treatment choices.

Pain Management of Malignant Psoas Syndrome Under Epidural Analgesia During Palliative Radiotherapy.

Malignant psoas syndrome is a rare malignant condition presenting as lumbosacral plexopathy and painful fixed flexion of the hip. Metastasis to the psoas muscle is observed, which damages the nerve bundles in the lumbosacral plexuses. The syndrome presents as refractory lower back pain with several other neurological symptoms. The pain is difficult to control because it is a mixture of nociceptive and neuropathic pain, which indicates that treatment requires a versatile approach. The authors report a case of severe back pain caused by metastasis to the psoas muscle of advanced gastric cancer in a patient who underwent palliative radiotherapy under epidural analgesia. Despite conventional analgesics and subcutaneous oxycodone, he had difficulties in maintaining supine position because of the back pain and had a problem to receive radiotherapy, which required him to stay still in the same position during the treatment. By epidural analgesia, he could remain in supine position and complete radiotherapy without increasing opioid administration. His back pain was improved after the radiotherapy. Epidural analgesia is an effective treatment choice for a patient who is unable to keep the position during palliative radiotherapy.

Structure-Activity Relationship of Oligomeric Flavan-3-ols: Importance of the Upper-Unit B-ring Hydroxyl Groups in the Dimeric Structure for Strong Activities.

Proanthocyanidins, which are composed of oligomeric flavan-3-ol units, are contained in various foodstuffs (e.g., fruits, vegetables, and drinks) and are strongly biologically active compounds. We investigated which element of the proanthocyanidin structure is primarily responsible for this functionality. In this study, we elucidate the importance of the upper-unit of 4-8 condensed dimeric flavan-3-ols for antimicrobial activity against Saccharomyces cerevisiae (S. cerevisiae) and cervical epithelioid carcinoma cell line HeLa S3 proliferation inhibitory activity. To clarify the important constituent unit of proanthocyanidin, we synthesized four dimeric compounds, (-)-epigallocatechin-[4,8]-(+)-catechin, (-)-epigallocatechin-[4,8]-(-)-epigallocatechin, (-)-epigallocatechin-[4,8]-(-)-epigallocatechin-3-O-gallate, and (+)-catechin-[4,8]-(-)-epigallocatechin and performed structure-activity relationship (SAR) studies. In addition to antimicrobial activity against S. cerevisiae and proliferation inhibitory activity on HeLa S3 cells, the correlation of 2,2-diphenyl-l-picrylhydrazyl radical scavenging activity with the number of phenolic hydroxyl groups was low. On the basis of the results of our SAR studies, we concluded that B-ring hydroxyl groups of the upper-unit of the dimer are crucially important for strong and effective activity.

Anti-Resorptive Functions of Poly(ethylene sodium phosphate) on Human Osteoclasts.

Osteoporosis involves hyperactive osteoclasts. A large number of current drugs result in side effects affecting their efficacy in the clinic. Polyphosphoesters are unique polymeric biomaterials because of their biocompatibility, biodegradability, and bone affinity. We studied the viability and ability of human osteoclasts to resorb bone when dosed with poly(ethylene sodium phosphate) (PEP·Na). This did not trigger any change in osteoblast cell viability, however the polymer diminished human osteoclasts and their ability to resorb bone at concentrations as low as 10(-4) m · mL(-1). This is the first report to validate the possibility of using polyphosphoesters for selective inhibition of human osteoclast functions, indicating its potential to be used as an effective polymer prodrug for treatment of osteoporosis.

Simulation and estimation of gene number in a biological pathway using almost complete saturation mutagenesis screening of haploid mouse cells.

BACKGROUND: Genome-wide saturation mutagenesis and subsequent phenotype-driven screening has been central to a comprehensive understanding of complex biological processes in classical model organisms such as flies, nematodes, and plants. The degree of "saturation" (i.e., the fraction of possible target genes identified) has been shown to be a critical parameter in determining all relevant genes involved in a biological function, without prior knowledge of their products. In mammalian model systems, however, the relatively large scale and labor intensity of experiments have hampered the achievement of actual saturation mutagenesis, especially for recessive traits that require biallelic mutations to manifest detectable phenotypes. RESULTS: By exploiting the recently established haploid mouse embryonic stem cells (ESCs), we present an implementation of almost complete saturation mutagenesis in a mammalian system. The haploid ESCs were mutagenized with the chemical mutagen N-ethyl-N-nitrosourea (ENU) and processed for the screening of mutants defective in various steps of the glycosylphosphatidylinositol-anchor biosynthetic pathway. The resulting 114 independent mutant clones were characterized by a functional complementation assay, and were shown to be defective in any of 20 genes among all 22 known genes essential for this well-characterized pathway. Ten mutants were further validated by whole-exome sequencing. The predominant generation of single-nucleotide substitutions by ENU resulted in a gene mutation rate proportional to the length of the coding sequence, which facilitated the experimental design of saturation mutagenesis screening with the aid of computational simulation. CONCLUSIONS: Our study enables mammalian saturation mutagenesis to become a realistic proposition. Computational simulation, combined with a pilot mutagenesis experiment, could serve as a tool for the estimation of the number of genes essential for biological processes such as drug target pathways when a positive selection of mutants is available.

Risk factors for rebleeding and prognostic factors for postoperative survival in patients with balloon-occluded retrograde transvenous obliteration of acute gastric variceal rupture.

PURPOSE: Balloon-occluded retrograde transvenous obliteration (B-RTO) has shown great potential in controlling acute gastric variceal hemorrhage, although rebleeding related to the procedure may occur in a small percentage of patients. The purpose of this study was to identify risk factors of perioperative rebleeding and prognostic factors of postoperative survival in B-RTO performed for acute episodes of gastric variceal hemorrhage. METHODS: We retrospectively analyzed 39 consecutive patients who underwent B-RTO for gastric variceal rupture at our hospital between June 2003 and May 2011. Uni- and multi-variate analyses were performed to assess risk factors for perioperative rebleeding and prognostic factors for postoperative survival. RESULTS: Surgical success and complete eradication of varices were achieved in 36 cases (92.3 %) and 35 cases (89.7 %), respectively. Six patients experienced rebleeding either intraoperatively (n = 3) or within 1 h after B-RTO (n = 3). Child-Pugh class C was identified as a risk factor for rebleeding on univariate (P = 0.018) and multivariate analyses (odds ratio, 6.003; P = 0.014). With a median follow-up of 23 months (range 0-106.6 months), overall survival rates at 1, 3, and 5 years were 91.7, 74.7, and 67.2 %, respectively. Multivariate analyses revealed Child-Pugh class C as a prognostic factor for survival (relative risk, 4.014; P = 0.023). CONCLUSION: Although B-RTO is generally effective in the treatment of acute gastric variceal rupture, patients classified as Child-Pugh class C have a higher risk of perioperative rebleeding and shorter survival.

Lung cancer: a 6-field technique using lateral beams in conformal radiotherapy for bilateral supraclavicular lymph node metastases.

A 6-field technique using lateral beams in conformal radiotherapy was developed for patients with bilateral supraclavicular lymph node metastasis of lung cancer. The possibility of using this technique in practice was evaluated. Six fields with the same isocenter point (IP) were arranged. Two fields using anterior-posterior opposed beams involved all of the planning target volume (PTV). The next 2 fields using off-cord oblique beams involved the PTV inferior to the IP. The remaining 2 fields using lateral opposed beams, that shielded the spinal cord, involved the PTV superior to the IP. The oblique 2 fields and lateral 2 fields were connected using a half-beam technique. In 6 patients with non-small-cell lung cancer (NSCLC, n = 4) or small-cell lung cancer (SCLC, n = 2), treatment re-planning based on this technique was performed. This technique was applicable in 4 patients with NSCLC, in whom the general criteria of radiotherapy for lung cancer were met. In 2 patients with SCLC, the cumulative volume of lung that received more than 20 Gy exceeded 37% of the total lung volume. This technique was usable in 67% of the patients and was not necessarily contraindicated in the other 33%.

Enhancement of microhomology-mediated genomic rearrangements by transient loss of mouse Bloom syndrome helicase.

Bloom syndrome, an autosomal recessive disorder of the BLM gene, confers predisposition to a broad spectrum of early-onset cancers in multiple tissue types. Loss of genomic integrity is a primary hallmark of such human malignancies, but many studies using disease-affected specimens are limited in that they are retrospective and devoid of an appropriate experimental control. To overcome this, we devised an experimental system to recapitulate the early molecular events in genetically engineered mouse embryonic stem cells, in which cells undergoing loss of heterozygosity (LOH) can be enriched after inducible down-regulation of Blm expression, with or without site-directed DNA double-strand break (DSB) induction. Transient loss of BLM increased the rate of LOH, whose breakpoints were distributed along the chromosome. Combined with site-directed DSB induction, loss of BLM synergistically increased the rate of LOH and concentrated the breakpoints around the targeted chromosomal region. We characterized the LOH events using specifically tailored genomic tools, such as high-resolution array comparative genomic hybridization and high-density single nucleotide polymorphism genotyping, revealing that the combination of BLM suppression and DSB induction enhanced genomic rearrangements, including deletions and insertions, whose breakpoints were clustered in genomic inverted repeats and associated with junctional microhomologies. Our experimental approach successfully uncovered the detailed molecular mechanisms of as-yet-uncharacterized loss of heterozygosities and reveals the significant contribution of microhomology-mediated genomic rearrangements, which could be widely applicable to the early steps of cancer formation in general.

NAD-dependent histone deacetylase, SIRT1, plays essential roles in the maintenance of hematopoietic stem cells.

Sir2 has been shown to be essential for transcriptional silencing and longevity provided by calorie restriction in Saccharomyces cerevisiae and Caenorhabditis elegans. In this study, we investigated the role for its mammalian homologue, SIRT1, in hematopoietic cells. SIRT1 inhibitor, nicotinamide (NA), promoted and its activator, resveratrol, inhibited the differentiation of murine bone marrow c-Kit(high)Sca-1(+)Lineage(-) (KSL) cells during the culture system ex vivo. To further clarify the roles of SIRT1 in hematopoietic cells, we isolated KSL cells from fetal liver of SIRT1 knockout (KO) mice and cultured them for 5days, because SIRT1 KO mice die shortly after the delivery. In agreement with the results from the experiments using NA and resveratrol, KSL cells isolated from SIRT1 KO mice more apparently differentiated and lost the KSL phenotype than those from wild-type (WT) mice. Furthermore, in each of colony assay, replating assay, or serial transplantation assay, SIRT1 KO KSL cells lost earlier the characteristics of stem cells than WT KSL cells. In addition, we found that SIRT1 maintains prematurity of hematopoietic cells through ROS elimination, FOXO activation, and p53 inhibition. These results suggest that SIRT1 suppresses differentiation of hematopoietic stem/progenitor cells and contributes to the maintenance of stem cell pool.