Myeloma bone disease: pathogenesis and management in the era of new anti-myeloma agents.

INTRODUCTION: Multiple myeloma (MM) is a malignancy of plasma cells with characteristic bone disease. Despite recent great strides achieved in MM treatment owing to the implementation of new anti-MM agents, MM is still incurable and bone destruction remains a serious unmet issue in patients with MM. APPROACH: In this review, we will summarize and discuss the mechanisms of the formation of bone disease in MM and the available preclinical and clinical evidence on the treatment for MM bone disease. CONCLUSIONS: MM cells produce a variety of cytokines to stimulate receptor activator of nuclear factor-κB ligand-mediated osteoclastogenesis and suppress osteoblastic differentiation from bone marrow stromal cells, leading to extensive bone destruction with rapid loss of bone. MM cells alter the microenvironment through bone destruction where they colonize, which in turn favors tumor growth and survival, thereby forming a vicious cycle between tumor progression and bone destruction. Denosumab or zoledronic acid is currently recommended to be administered at the start of treatment in newly diagnosed patients with MM with bone disease. Proteasome inhibitors and the anti-CD38 monoclonal antibody daratumumab have been demonstrated to exert bone-modifying activity in responders. Besides their anti-tumor activity, the effects of new anti-MM agents on bone metabolism should be more precisely analyzed in patients with MM. Because prognosis in patients with MM has been significantly improved owing to the implementation of new agents, the therapeutic impact of bone-modifying agents should be re-estimated in the era of these new agents.

A machine learning model using SNPs obtained from a genome-wide association study predicts the onset of vincristine-induced peripheral neuropathy.

Vincristine treatment may cause peripheral neuropathy. In this study, we identified the genes associated with the development of peripheral neuropathy due to vincristine therapy using a genome-wide association study (GWAS) and constructed a predictive model for the development of peripheral neuropathy using genetic information-based machine learning. The study included 72 patients admitted to the Department of Hematology, Tokushima University Hospital, who received vincristine. Of these, 56 were genotyped using the Illumina Asian Screening Array-24 Kit, and a GWAS for the onset of peripheral neuropathy caused by vincristine was conducted. Using Sanger sequencing for 16 validation samples, the top three single nucleotide polymorphisms (SNPs) associated with the onset of peripheral neuropathy were determined. Machine learning was performed using the statistical software R package "caret". The 56 GWAS and 16 validation samples were used as the training and test sets, respectively. Predictive models were constructed using random forest, support vector machine, naive Bayes, and neural network algorithms. According to the GWAS, rs2110179, rs7126100, and rs2076549 were associated with the development of peripheral neuropathy on vincristine administration. Machine learning was performed using these three SNPs to construct a prediction model. A high accuracy of 93.8% was obtained with the support vector machine and neural network using rs2110179 and rs2076549. Thus, peripheral neuropathy development due to vincristine therapy can be effectively predicted by a machine learning prediction model using SNPs associated with it.

A Genome-Wide Association Study Predicts the Onset of Dysgeusia Due to Anti-cancer Drug Treatment.

Dysgeusia is a major side effect of anti-cancer drug treatment. Since dysgeusia significantly lowers the patient's QOL, predicting and avoiding its onset in advance is desirable. Accordingly, aims of the present study were to use a genome-wide association study (GWAS) to identify genes associated with the development of dysgeusia in patients taking anti-cancer drugs and to predict the development of dysgeusia using associated single nucleotide polymorphisms (SNPs). GWAS was conducted on 76 patients admitted to the Department of Hematology, Tokushima University Hospital. Using Sanger sequencing for 23 separately collected validation samples, the top two SNPs associated with the development of dysgeusia were determined. GWAS identified rs73049478 and rs41396146 SNPs on the retinoic acid receptor beta (RARB) gene associated with dysgeusia development due to the administration of anti-cancer drugs. Evaluation of the two SNPs using 23 validation samples indicated that the accuracy rate of rs73049478 was relatively high (87.0%). Thus, the findings of the present study suggest that the rs73049478 SNP of RARB can be used to predict the onset of dysgeusia caused by the administration of anti-cancer drugs.

[Primary cutaneous anaplastic large cell lymphoma with systemic progression responding to low-dose methotrexate therapy].

The standard therapies for primary cutaneous anaplastic large cell lymphoma (pcALCL) in an advanced stage remain undefined. A 71-year-old man presented with multiple erythema and nodules. He was diagnosed with lymphomatoid papulosis (LyP) through a skin biopsy from the left postauricular area. All skin lesions achieved complete response by electron beam irradiation. However, nodular lesions appeared in both inner canthi 5 months later. Histopathological evaluation of the lesional biopsy revealed dominant infiltration of CD30-positive large cells. Positron emission tomography/computed tomography revealed fluorodeoxyglucose-positive cervical and inguinal lymph node swelling and right tonsillitis, followed by the diagnosis of pcALCL and TNM classification T3bN3M0. Since the patient had severe chronic obstructive pulmonary disease and recurrent pneumonia, he received low-dose methotrexate (MTX) (15 mg/week) therapy. Low-dose MTX effectively debulked the lymphadenopathies over time without particular adverse effects. Although the standard therapies for pcALCL are not established, low-dose MTX was effective and considered safe for patients with frailty and compromised respiratory function. Further study is warranted on the pathophysiology of pcALCL after the development of LyP and mechanisms of action of low-dose MTX against LyP and pcALCL.

TAK1 is a pivotal therapeutic target for tumor progression and bone destruction in myeloma.

Along with the tumor progression, the bone marrow microenvironment is skewed in multiple myeloma (MM), which underlies the unique pathophysiology of MM and confers aggressiveness and drug resistance in MM cells. TGF-ß-activated kinase-1 (TAK1) mediates a wide range of intracellular signaling pathways. We demonstrate here that TAK1 is constitutively overexpressed and phosphorylated in MM cells, and that TAK1 inhibition suppresses the activation of NF-κB, p38MAPK, ERK and STAT3 to decrease the expression of critical mediators for MM growth and survival, including PIM2, MYC, Mcl-1, IRF4, and Sp1, along with a substantial reduction in the angiogenic factor VEGF in MM cells. Intriguingly, TAK1 phosphorylation was also induced along with upregulation of vascular cell adhesion molecule-1 (VCAM-1) in bone marrow stromal cells (BMSCs) in cocultures with MM cells, which facilitated MM cell-BMSC adhesion while inducing IL-6 production and receptor activator of nuclear factor κ-Β ligand (RANKL) expression by BMSCs. TAK1 inhibition effectively impaired MM cell adhesion to BMSCs to disrupt the support of MM cell growth and survival by BMSCs. Furthermore, TAK1 inhibition suppressed osteoclastogenesis enhanced by RANKL in cocultures of bone marrow cells with MM cells, and restored osteoblastic differentiation suppressed by MM cells or inhibitory factors for osteoblastogenesis overproduced in MM. Finally, treatment with the TAK1 inhibitor LLZ1640-2 markedly suppressed MM tumor growth and prevented bone destruction and loss in mouse MM models. Therefore, TAK1 inhibition may be a promising therapeutic option targeting not only MM cells but also the skewed bone marrow microenvironment in MM.

[Diagnosis of Serous Adenocarcinoma following Pneumatosis Intestinalis Development during Bevacizumab Therapy for Cancer of Unknown Primary-A Case Report].

A 75-year-old woman was treated with TC plus Bev for cancer of unknown primary. During treatment, she presented to the clinic with chief complaints of general malaise and anorexia. On presentation, abdominal distention and upper abdominal tenderness were noted, and sepsis was suspected. A thoracoabdominal CT scan revealed prominent intramural emphysema and mesenteric gas in the ascending colon. An emergency laparotomy was performed for suspected pneumatosis intestinalis non-obstructive intestinal ischemia. However, no intra-abdominal contamination or ischemic changes were observed intraoperatively. Histological examination revealed a small adenocarcinoma on the serous surface of the ascending colon, and immunochemical staining confirmed the diagnosis of serous adenocarcinoma as the patient's primary cancer. This report describes a case in which the patient achieved long-term survival after diagnosis. It also emphasizes the importance of identifying the subset of patients with cancer of unknown primary who have a good prognosis in order to provide appropriate treatment.

Active Hexose Correlated Compound Has Protective Effects in Ischemia-Reperfusion Injury of the Rat Small Intestine.

BACKGROUND: Ischemia-reperfusion (IR) injury of the small intestine is a serious problem in abdominal aortic aneurysm surgery or small intestine transplantation. Active hexose correlated compound (AHCC) is a popular anti-inflammatory drug in complementary and alternative medicine. The aim of this study was to examine whether pretreatment with AHCC reduces intestinal IR injury. METHODS: Rats were given a normal diet (IR group) or normal diet supplemented with 2% AHCC (IR + AHCC group) ad libitum for 10 d. After 1 d of fasting, the superior mesenteric artery was occluded by clipping for 45 min. Intestinal and blood samples were collected for 1-6 h after reperfusion. The messenger RNA (mRNA) and protein levels of inflammatory factors were analyzed. RESULTS: The IR + AHCC group had reduced mucosal abrasion and significantly increased mucosal thickness of the intestinal tissues 6 h after reperfusion, compared with the IR group. AHCC decreased mRNA expression of inducible nitric oxide synthase (iNOS), cytokine-induced neutrophil chemoattractant 1 and interleukin 6 in the mucosa of the small intestine. AHCC also decreased expression of iNOS protein. Serum levels of cytokine-induced neutrophil chemoattractant 1 and tumor necrosis factor α were decreased in the IR + AHCC group compared with the IR group. Electrophoretic mobility shift assay of mucosal nuclear extracts revealed that AHCC inhibited the activation of nuclear factor kappa B. AHCC also inhibited the expression of iNOS antisense transcript, which stabilizes iNOS mRNA. CONCLUSIONS: Our findings suggest that AHCC reduces expression of inflammatory mediators, in part, by inhibiting nuclear factor kappa B activation. AHCC may have anti-inflammatory effect in patients with intestinal IR injury.

Effect of serum concentration and concomitant drugs on vancomycin-induced acute kidney injury in haematologic patients: a single-centre retrospective study.

PURPOSE: Appropriate use of vancomycin (VCM) is important in preventing acute kidney injury (AKI). Because of the high frequency of VCM use for febrile neutropenia and concomitant use of other nephrotoxic drugs, haematologic patients have a different nephrotoxic background compared with patients with other diseases. Therefore, it is unclear whether the risk factors of VCM-induced AKI identified in other patient groups are also applicable to haematologic patients. Herein, we performed a single-centre retrospective analysis to identify the factors associated with VCM-induced AKI in haematologic patients. METHODS: We retrospectively analysed 150 haematologic patients to whom VCM was administered between April 2010 and March 2018 at Tokushima University Hospital. VCM-induced AKI was defined according to Kidney Disease Improving Global Outcomes (KDIGO) criteria. Multivariate logistic regression analyses were performed to identify risk factors for VCM-induced AKI. RESULTS: Seventeen patients had VCM-induced AKI. Multivariate analysis revealed that the risk factors of VCM-induced AKI were an initial VCM trough concentration of > 15 mg/L and concomitant use of tazobactam/piperacillin (TAZ/PIPC) and liposomal amphotericin B (L-AMB). Patients with an initial VCM trough concentration of < 10 mg/L showed significantly lower efficacy in febrile neutropenia. Interestingly, concomitant L-AMB use increased the incidence of VCM-induced AKI in a VCM concentration-dependent manner, whereas concomitant TAZ/PIPC increased the incidence in a VCM concentration-independent manner. CONCLUSIONS: The optimal initial VCM trough concentration was 10-15 mg/L in haematologic patients, considering safety and effectiveness. There were differences in the effect of VCM-induced AKI between nephrotoxic drugs.

Unique anti-myeloma activity by thiazolidine-2,4-dione compounds with Pim inhibiting activity.

Proviral Integrations of Moloney virus 2 (PIM2) is overexpressed in multiple myeloma (MM) cells, and regarded as an important therapeutic target. Here, we aimed to validate the therapeutic efficacy of different types of PIM inhibitors against MM cells for their possible clinical application. Intriguingly, the thiazolidine-2,4-dione-family compounds SMI-16a and SMI-4a reduced PIM2 protein levels and impaired MM cell survival preferentially in acidic conditions, in contrast to other types of PIM inhibitors, including AZD1208, CX-6258 and PIM447. SMI-16a also suppressed the drug efflux function of breast cancer resistance protein, minimized the sizes of side populations and reduced in vitro colony-forming capacity and in vivo tumourigenic activity in MM cells, suggesting impairment of their clonogenic capacity. PIM2 is known to be subject to ubiquitination-independent proteasomal degradation. Consistent with this, the proteasome inhibitors bortezomib and carfilzomib increased PIM2 protein levels in MM cells without affecting its mRNA levels. However, SMI-16a mitigated the PIM2 protein increase and cooperatively enhanced anti-MM effects in combination with carfilzomib. Collectively, the thiazolidine-2,4-dione-family compounds SMI-16a and SMI-4a uniquely reduce PIM2 protein in MM cells, which may contribute to their profound efficacy in addition to their immediate kinase inhibition. Their combination with proteasome inhibitors is envisioned.

Cryptosporidiosis in a transplant recipient with severe intractable diarrhea: Detection of Cryptosporidium oocysts by intestinal biopsies.

Disseminated Cryptosporidium infection results in manifestations similar to those of graft-versus-host disease (GVHD), which hampers the detection of Cryptosporidium infection after allogeneic hematopoietic stem cell transplantation. Surveillance of oocysts on the surface of intestinal epithelial cells is needed for early and appropriate detection of Cryptosporidium infection in transplant recipients on immunosuppressants with severe intractable diarrhea. We present the first case of Cryptosporidium meleagridis infection in Japan after allogeneic cord blood transplantation.

Steroid pulse therapy in patients with encephalopathy associated with severe fever with thrombocytopenia syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne infectious disease caused by the SFTS virus (SFTSV). Clinical symptoms of SFTS often involve encephalopathy and other central neurological symptoms, particularly in seriously ill patients; however, pathogenesis of encephalopathy by SFTSV is largely unknown. Herein, we present case reports of three patients with SFTS, complicated by encephalopathy, admitted to Tokushima University hospital: one patient was a 63-year-old man, while the other two were 83- and 86-year-old women. All of them developed disturbance of consciousness around the 7th day post onset of fever. After methylprednisolone pulse therapy of 500 mg/day, all of them recovered without any neurological sequelae. SFTSV genome was not detected in the cerebrospinal fluid of 2 out of the 3 patients that were available for examination. In these patients, disturbance of consciousness seemed to be an indirect effect of the cytokine storm triggered by SFTSV infection. We propose that short-term glucocorticoid therapy might be beneficial in the treatment of encephalopathy during early phase of SFTSV infection.

[A Case of Aggressive Angiomyxoma in a 75-Year-Old Man].

Aggressive angiomyxoma is an uncommon mesenchymal tumor that mostly involves the pelvic and perineal regions in young women.We herein report an extremely rare case of aggressive angiomyxoma in a 75-year-old man. The patient had undergone follow-up for an intraductal papillary mucinous neoplasm.In September 2015, CT detected a tumor measuring 33 mm in diameter around the pelvis, and the tumor showed gradual increase in size.MRI revealed a relatively sharply marginated tumor with low signal intensity on T1-weighted images and high signal intensity on T2-weighted images.For treatment and diagnosis, we laparoscopically resected the tumor. Histopathologically, the specimen showed spindle tumor cells within a myxoid background and vascular structures.The tumor was diagnosed as aggressive angiomyxoma, and surgical margins were negative for tumor cells. The patient is currently doing well without any signs of recurrence as of 18 months postoperatively.

[Analysis of long-term survivors with cardiac AL amyloidosis].

Cardiac AL amyloidosis (CA) is generally known as a severe disease with very poor prognosis. Here we retrospectively examined seven patients with CA in our cohort who achieved long-term survival. All six patients who underwent high-dose melphalan and autologous stem cell transplantation (ASCT) survived for >3 years, whereas four patients survived for >5 years. Patients who underwent ASCT had prompt hematological responses, and five patients showed organ responses. ASCT helps to achieve a quick and deep hematological response required for long-term survival in patients with CA. New agents have been implemented for the treatment of CA. However, the risks and benefits of each treatment modality should be considered according to patient condition, thus making the best use of ASCT in combination with new agents for the treatment of CA.

[Two Successful Cases of Surgical Treatment of Reconstructed Gastric Tube-Bronchial Fistula after Esophagectomy for Esophageal Cancer by Pedunculated Latissimus Dorsi Flap].

We herein report 2 cases of successful surgical treatment of reconstructed gastric tube-bronchial fistulas caused by leakage after esophagectomy for esophageal cancer. One patient was a 56-year-old man who developed a reconstructed gastric tube-bronchial fistula, and the fistula was closed by conservative treatment. However, he developed pneumonia on postoperative day 117, and the reconstructed gastric tube-bronchial fistula was found to have recurred. Fibrin glue was endoscopically injected into the fistula, but this treatment was unsuccessful. The other patient was a 60-year-old man who developed a reconstructed gastric tube-bronchial fistula and severe pneumonia, and his condition did not improve by conservative treatment. We performed a reoperation for both patients using a pedunculated latissimus dorsi flap, and both patients recovered well.

[Multiple myeloma].

Owing to the positive clinical benefits obtained with new agents, complete remission (CR) can be used as a surrogate for overall survival, and should be achieved. Although multiple myeloma is a heterogeneous disease in terms of myeloma cell- and patient-related risk factors, patients should receive the most effective combination therapy based on proteasome inhibitors and/or immunomodulatory drugs (IMiDs) as backbone medication irrespective of the risks encountered in the setting of induction therapy ("one-size-fits-all" therapy), followed by consolidation/maintenance therapy to achieve CR with the ultimate goal of extended survival. Myeloma-defining biomarkers have been established to identify high-risk smoldering myeloma requiring treatment. The development of salvage treatments yielding better outcomes for relapsed/refractory myeloma is urgently needed. Upcoming novel molecular targeting agents with different modes of action and immunotherapeutic agents will be integrated into myeloma treatment regimens with a great therapeutic impact, and further evolution of the treatment paradigm for multiple myeloma is eagerly anticipated.

[A Case of Intra-Abdominal Desmoid Tumor with Abacterial Peritonitis].

A woman in her 50s visited our hospital in February 2015 with a complaint of dull abdominal pain in the right lower quadrant. She had a medical history of appendectomy for appendicitis in her 20s. Computed tomography(CT)revealed a tumor 90 mm in diameter near the ileocecum. Elective surgery was planned under the suspicion of gastrointestinal tumor, malignant lymphoma, or ileal cancer. She was emergently hospitalized 1 day earlier than scheduled because of high fever and severe abdominal pain. CT revealed that the tumor had increased to 120 mm in diameter without free air. Her white blood cell count was not elevated, and her symptoms improved readily with medical treatment. Thus, we performed the operation as scheduled. A tumor with a dark red recess on the surface had invaded the transverse colon intraoperatively, and a small amount of purulent ascites was present at the pouch of Douglas. We performed ileocecal resection with partial transverse colectomy. Histopathological examination led to the diagnosis of desmoid tumor in the mesentery of the terminal ileum. The surgical margins were negative for tumor cells. The tumor surface around the recess showed peritonitis, and the ascites showed no bacteria or tumor cells. The patient had been doing well without recurrence after discharge. Some cases of desmoid tumor with peritonitis have been reported, but most were caused by tumor penetration into the intestinal tract. We report herein a rare case of intra-abdominal desmoid tumor with abacterial peritonitis.

pyroGlu-Leu inhibits the induction of inducible nitric oxide synthase in interleukin-1ß-stimulated primary cultured rat hepatocytes.

Pyroglutamyl leucine (pyroGlu-Leu), which is a peptide isolated from wheat gluten hydrolysate, has been reported to be a hepatoprotective compound in acute liver failure. In inflamed liver, proinflammatory cytokines including interleukin (IL)-1ß and tumor necrosis factor (TNF)-α stimulate the induction of inducible nitric oxide synthase (iNOS). Excess production of nitric oxide (NO) by iNOS is an inflammatory biomarker in liver injury. We examined proinflammatory cytokine-stimulated hepatocytes as a simple "in vitro inflammation model" to determine liver protective effects of pyroGlu-Leu and its mechanisms of action. We hypothesized that pyroGlu-Leu inhibits the induction of iNOS gene expression, resulting in the attenuation of hepatic inflammation. Hepatocytes were isolated from rats by collagenase perfusion and cultured. Primary cultured cells were treated with IL-1ß in the presence or absence of pyroGlu-Leu. The induction of iNOS and its signaling pathway were analyzed. IL-1ß stimulated the enhancement of NO production in hepatocytes and this effect was inhibited by pyroGlu-Leu. pyroGlu-Leu decreased the expression of iNOS protein and its mRNA. Transfection experiments with iNOS-luciferase constructs revealed that pyroGlu-Leu inhibited both of iNOS promoter transactivation and its mRNA stabilization. pyroGlu-Leu also decreased the expression of an iNOS gene antisense transcript, which is involved in iNOS mRNA stability. However, pyroGlu-Leu had no effects on IκB degradation and NF-κB activation. Results demonstrate that pyroGlu-Leu inhibited the induction of iNOS gene expression at transcriptional and post-transcriptional steps through IκB/NF-κB-independent pathway, leading to the prevention of NO production. pyroGlu-Leu may have therapeutic potential for liver injury through the suppression of iNOS.

Alpha-lipoic acid exerts a liver-protective effect in acute liver injury rats.

BACKGROUND: Recent evidence indicates that alpha-lipoic acid (α-LA) has a variety of liver-protective effects through the suppression of inflammatory mediators including tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (iNOS). However, there are few reports that α-LA markedly enhanced the survival rate in animal models of liver injury with more than 90% death. The aim of this study was to investigate the beneficial effects of α-LA in a rat model of acute liver injury and to clarify the mechanisms of α-LA action. METHODS: Rats were treated with d-galactosamine and lipopolysaccharide (GalN and LPS) to induce acute liver injury. α-LA (100 mg/kg) was administered intraperitoneally 1 h before GalN and LPS injection. Inflammatory mediators including TNF-α and iNOS were analyzed. RESULTS: A single injection of α-LA improved the survival rate by more than 80%. α-LA prevented serum transaminase increases, histopathologic changes, and apoptosis in the liver. In the serum, α-LA decreased TNF-α production and increased interleukin (IL)-10 production. In the liver, α-LA reduced TNF-α and IL-6 messenger RNA (mRNA) but enhanced IL-10 mRNA. α-LA decreased the expression of iNOS mRNA and its antisense transcript, leading to the reduction of iNOS protein expression and resulting in the inhibition of nitric oxide production. An electrophoretic mobility shift assay revealed that α-LA reduced the activation of nuclear factor-kappa B induced by GalN and LPS. CONCLUSIONS: α-LA inhibited the induction of inflammatory mediators, such as TNF-α and iNOS, in part through the inhibition of nuclear factor-kappa B activation and enhanced the induction of IL-10. α-LA may have therapeutic potential for use in the prevention of acute liver injury.

Influence of Rictor and Raptor Expression of mTOR Signaling on Long-Term Outcomes of Patients with Hepatocellular Carcinoma.

BACKGROUND: Aberrant signaling mediated by the mammalian target of rapamycin (mTOR) occurs at high frequency in hepatocellular carcinoma (HCC), indicating that mTOR is a candidate for targeted therapy. mTOR forms two complexes called mTORC1 (mTOR complexed with raptor) and mTORC2 (mTOR complexed with rictor). There are minor studies of the expression kinetics of mTORC1 and mTORC2 in HCC. METHODS: We studied 62 patients with HCC who underwent curative resection. We used univariate and multivariate analyses to identify factors that potentially influence disease and overall survival after hepatectomy. The mRNA and protein levels of mTOR, rictor and raptor in cancer and non-cancer tissues were analyzed using quantitative RT-PCR, immunohistochemistry and Western blotting. RESULTS/CONCLUSION: High ratio of the levels of rictor and raptor mRNAs in tumors was identified as independent prognostic indicators for disease-free survival. Low and high levels of preoperative serum albumin and mTOR mRNA in the tumor, respectively, were identified as independent indicators of overall survival. HCC is likely to recur early after hepatic resection in patients with high levels of mTOR and rictor mRNAs and high rictor/raptor ratios in cancer tissues. We conclude that analysis of mTOR expression in cancer tissues represents an essential strategy to predict HCC recurrence after curative treatment.