Search

A 49-year-old man underwent an open cholecystectomy for advanced gallbladder cancer in 2021. Three months after surgery, the patient underwent an additional resection, which showed no malignant findings, but 12 months after surgery, contrast-enhanced CT and MRI showed a new mass lesion in segment 8 of the liver, and the patient was diagnosed with postoperative hepatic metastatic recurrence of gallbladder cancer. After referral to our institution, he received 1 course of gemcitabine+cisplatin(GC)therapy and 8 courses of gemcitabine+cisplatin+durvalumab(GCD)therapy. Contrast- enhanced CT and MRI showed that the metastases had shrunk, and PET scan showed no FDG accumulation. Two months after completion of chemotherapy, there was no evidence of metastatic enlargement and new metastasis including distant metastasis, and the patient was referred to our department. Since curative resection was expected, a laparoscopic partial hepatectomy of segment 8 of the liver was performed. Pathological diagnosis revealed no residual tumor. If the metastases could be well controlled by systemic chemotherapy, hepatectomy for hepatic metastases of biliary tract cancer could be a treatment option.

A 70-year-old man who developed recurrent Stage ⅣA1 Sézary syndrome after first-line treatment received 6 cycles of mogamulizumab treatment. After mogamulizumab treatment completion, persistent effects on peripheral blood lesions were observed. Although Sézary syndrome is a relatively uncommon cutaneous lymphoma, it is important to recognize that the effects of mogamulizumab may not be limited to the treatment course and might be sustained even after treatment completion.

A 43-year-old man was admitted to our department due to fever and headache. The cerebrospinal fluid analysis confirmed bacterial meningitis. Campylobacter species were isolated from blood cultures on the third day of admission. The patient was treated with meropenem (MEPM) and discharged on the 17th day. However, he experienced a recurrence of meningitis and was readmitted on the 68th day, initiating MEPM therapy. Campylobacter fetus was isolated from cerebrospinal fluid cultures on the 74th day. MEPM was continued until the 81st day, followed by one month of minocycline (MINO) therapy. The patient had an uneventful recovery without further recurrence. This case highlights the potential for recurrence of Campylobacter fetus meningitis approximately two months after the resolution of the initial infection. In addition to carbapenem therapy for at least two weeks, the adjunctive administration of MINO may be beneficial.

Malignant forms of meningioma, such as atypical and anaplastic meningiomas, commonly relapse. Recently, there have been many reports elucidating the molecular biological mechanisms underlying meningioma recurrence. Tumors with loss of CDKN(cyclin dependent kinase)2A and 2B or lack of the tri-methylation of lysine 27 on histone H3 protein have a particularly high recurrence rate. In general, primary treatment for recurrent meningiomas comprises stereotactic radiosurgery(SRS)or stereotactic radiotherapy(SRT). However, re-operation is recommended for SRS-, SRT-refractory tumors. One of the benefits of reoperation is that it allows tumor control while decompressing the normal tissue, and changing the tumor microenvironment. Another is that it facilitates the acquisition of pathological and molecular genetic information, which can enable clinicians to recommend precision medicine. However, during reoperation, it is often difficult to detach the tumor from the surrounding brain tissue and cranial nerves because of severe adhesion. In cases of malignant meningiomas with multiple relapses, it is important to share the purpose and goal of the surgery with the patients and their families. In other words, which is being prioritized more, a high resection rate or functional outcomes? Furthermore, salvage surgery should also be a consideration.

Pseudocirrhosis, which is radiologically and clinically similar to liver cirrhosis, may develop following chemotherapy for breast cancer with liver metastasis. There are few reports of eribulin treatment. We report 5 patients with metastatic or recurrent breast cancer who developed pseudocirrhosis during eribulin treatment. All patients had diffuse liver metastasis, and the liver metastases significantly reduced in size during the early phase of eribulin treatment, when they developed pseudocirrhosis. Subsequently, the patients had poor prognoses.

Subsequent to a medical examination, a 61-year-old male was referred to our hospital with jaundice. He was diagnosed with intrahepatic cholangiocarcinoma involving the hepatic hilum and was referred to our department to undergo a left trisectionectomy of the liver, extrahepatic bile duct resection, and regional lymphadenectomy. He was discharged on postoperative day 39 without liver failure. Two months postoperatively, positron-emission tomography/computed tomography(PET/ CT)indicated recurrences in the bone, and paraaortic lymph node. Gemcitabine and cisplatin combination first-line therapy was administered. Disease progression occurred after 4 courses of therapy. Gene panel testing was performed and the patient was switched to pembrolizumab owing to high microsatellite instability. After 2 courses of pembrolizumab, notable shrinkage of the paraaortic lymph node recurrence was confirmed on computed tomography as well as a partial response. PET-CT revealed disappearance of abnormal accumulation in all lesions at 20 months postoperatively. This has been sustained for 24 months following surgery without remarkable immune-related side-effects.

The patient, an 83-year-old woman, was diagnosed with ER- and PgR-positive left breast cancer(T2N0M0, Stage ⅡA) at the age of 68. At the time, she underwent preoperative chemotherapy followed by Bp+Ax and postoperative radiotherapy to the conserved breast. She also received endocrine therapy as adjuvant therapy. At the age of 73, she underwent radiotherapy for multiple bone metastases and left axillary lymphadenectomy due to left axillary lymph node recurrence. After surgery, she received 4 regimens of endocrine therapy over a period of 5 years and 1 month for bone metastases. At the age of 79, S-1 was administered for pulmonary metastasis which continued for the next 2 years and 8 months. At the age of 81, palbociclib+letrozole were administered for 1 year and 8 months owing to the progression of bone metastases. At the age of 83, she developed liver metastases and was administered ethinyl estradiol, starting at 1.5 mg/day and continued at a reduced dose of 0.5 mg/day for 9 months. The reduction in tumor markers after treatment initiation was rapid, and there were no serious adverse events. Ethinyl estradiol was useful for maintaining QOL in this elderly patient with recurrent breast cancer.

We conducted an online questionnaire survey to investigate changes in well-being and anxiety in patients with hepatocellular carcinoma requiring repeated locoregional therapy(hepatectomy/ablation)and the differences between patients' and treating physicians' perceptions of what is important to patients when selecting treatment. Between December 2022 and January 2023, we collected responses from 162 patients and 115 physicians in Japan. Results showed no clinically significant changes in well-being over time. Patients experiencing recurrences and repeated locoregional therapy reported increased anxiety regarding"effectiveness of treatment"and"how to handle the disease."As"factors that patients consider important when receiving locoregional therapy,"many patients and physicians selected suppression of recurrence, prolonged survival, and safety; however, patients placed more importance on"reducing the number of locoregional therapies"as they repeatedly experienced recurrence and therapy. Regarding"information that patients consider important when selecting adjuvant therapy,""effectiveness of treatment"and"adverse effects of treatment"were important to both patients and physicians, while"maintaining a normal daily life"was more important in patients and"length of treatment"was more important in physicians. In conclusion, some factors are perceived by both physicians and patients as important when selecting treatment, but there is a gap in perception for other factors. Physicians and patients should discuss their opinions on what is important in treatment before deciding on a treatment strategy.

An 80-year-old male patient presented with a 2.5 cm-sized submucosal tumor on the greater curvature side of the upper gastric body during an endoscopic examination in 200X. We diagnosed gastric GIST by biopsy and performed laparoscopic- assisted partial gastrectomy. Imatinib was started as postoperative adjuvant therapy, but was discontinued after 1 month due to eyelid edema. The patient was followed up with a contrast-enhanced CT scan and a PET-CT scan. A 7 cm-sized mass in the gastrosplenic region was discovered on a 200X+7 years CT scan; this mass was thought to be possible recurrence of peritoneal dissemination. The patient did not want to undergo surgery or drug treatment, and was followed up. Five months later he complained of abdominal pain. The CT scan showed that the mass had shrunk slightly, but a small amount of ascites was observed, and tumor rupture was suspected. Therefore, we performed resection of the tumor in the office. Numerous disseminated nodules were found in the intra-abdominal cavity. Pathological examination revealed recurrence of GIST, and the patient was started on imatinib 200 mg/day. The dose was temporarily increased to 300 mg/day, but was reduced again to 200 mg/day 1 month later due to eyelid edema. Thereafter, the dose was temporarily discontinued due to stomatitis, and from 200X+8 years, 200 mg/day was administered for 2 weeks and then discontinued for 2 weeks. At present, 14 years after the first surgery and 6 years after recurrence, he remains alive thanks to imatinib continuation.

Pulmonary lymphangitis carcinomatosis is generally characterized by resistance to chemotherapy and is associated with a poor prognosis. Herein, we present a case of pulmonary lymphangitic carcinomatosis from recurrent breast cancer that responded well to trastuzumab deruxtecan(T-DXd). The patient was a 40-year-old woman with hormone receptor-positive, HER2-positive breast cancer. At the age of 31, she had undergone a left mastectomy with axillary lymph node dissection. She received adjuvant chemotherapy(5-fluorouracil-epirubicin-cyclophosphamide, docetaxel, and trastuzumab)followed by endocrine therapy(tamoxifen and LH-RHa). Three years after the surgery, pulmonary and bone metastases were detected and she was treated with trastuzumab, pertuzumab, and capecitabine. Liver metastases were detected, and she was treated with trastuzumab emtansine. Nine years after surgery, the patient developed dyspnea and was diagnosed with lymphangitis carcinomatosis. After initiating T-DXd, dyspnea rapidly improved, and ground glass opacity on CT scan disappeared. She responded well to the treatment, with prolonged, stable disease for 1 year and 2 months. Thus, T-DXd may be effective against pulmonary lymphangitis carcinomatosis, which is generally characterized by resistance to chemotherapy.

A 73-year-old woman underwent a descending colectomy for descending colon cancer. The tumor was graded as pStage Ⅲb(pT3[SS], pN1b, pM0, Cur A), according to the 9th edition of the Japanese Classification of Colorectal, Appendiceal, and Anal Carcinoma. Postoperative treatment of adjuvant chemotherapy comprised oral tegafur/uracil and Leucovorin for 6 months with no evident recurrence. However, contrast-enhanced CT and FDG-PET/CT examination 8 years and 7 months after surgery revealed a 30 mm irregular recurrent tumor in the left iliac fossa. Since the tumor was adjacent to the left psoas muscle, it was considered that RM0(no tumor identified at the radial margin)could not be achieved in that region. Owing to the patient's good general condition, systemic chemotherapy with CAPOX+bevacizumab was administered. Although adverse events prompted discontinuation of the treatment during the first course, the recurrent tumor had significantly regressed. Systemic chemotherapy with mFOLFOX6+bevacizumab as selected subsequent treatment achieved a significant tumor shrinkage to date. Although a recurrence more than 5 years after curative resection of colorectal cancer is extremely rare, the possibility of late recurrence must be considered in patients with well-differentiated tumors who received adjuvant chemotherapy and had negative vascular invasion.

A 55-year-old man developed ischemic stroke in the bilateral cerebellar hemispheres and bilateral occipital lobes. He was admitted to our hospital 17 months later with recurrent ischemic stroke in the posterior circulation. The left vertebral artery (VA) was occluded on brain magnetic resonance angiography but was visualized with a delay on continuous three-phase CT angiography (CTA). Conventional angiography confirmed a to-and-fro blood flow pattern at the distal end of the left VA, therefore the patient was diagnosed with VA stump syndrome (VASS). VASS is a recurrent posterior circulation ischemic stroke caused by thrombi in an occluded unilateral VA. VASS should be suspected in patients with unilateral VA occlusion and repeated posterior-circulation ischemic stroke. The diagnostic criteria for VASS include confirmation of VA occlusion and the presence of an antegrade flow component at the distal end. In this case, the presence of collateral circulation in the VA was suspected based on CTA findings, leading to the diagnosis of VASS. It was thus suggested that devising the imaging method of CTA may help diagnose VASS.

The patient was a 54-year-old male at the time of initial examination. He was aware of numbness and weakness in the left hemisphere of his body and came to see the hospital. He was diagnosed with brain metastasis of lung cancer and started treatment(cT2N0M1[Brain]). He underwent gamma knife for the head lesion and nivolumab for the lung lesion. The patient's lesions shrank with the success of the medical treatment, but recurred with small intestinal metastasis. He underwent a partial resection of the small intestine and was treated again with nivolumab, which resulted in a complete response. He is currently alive without recurrence. We have experienced a very rare case of recurrence-free survival after treatment for brain metastasis and small intestinal metastasis of lung cancer.

The patient is a 76-year-old man. His chief complaint of chest pain led to a diagnosis of pericardial effusion of unknown cause, and pericardial drainage was performed. On the 30th day, chest pain appeared again. Echocardiography revealed a pericardial fluid reaccumulation and a substantial mass in the pericardial space. Surgical drainage was performed to find the cause. A hematoma/mass was present on the epicardium. The pericardial sac was filled with hematoma. The hematoma was removed, but part of the mass infiltrated close to the anterior descending branch of the left coronary artery, and removal of that part was abandoned. The intrapericardial hematoma and epicardium were submitted to pathology leading to the diagnosis of synovial sarcoma. The patient was discharged home 14 days after surgery.

A 67-year-old man visited our hospital for epigastric pain. Esophagogastroduodenoscopy(EGD)revealed type 2 gastric cancer from the cardia to the gastric angle, and histopathological examination revealed papillary adenocarcinoma(pap), HER2-positive. Contrast-enhanced CT showed wall thickening mainly in the posterior wall of the gastric body, enlarged lymph nodes that were lumped together with the main lesion, and 8 low-absorption areas with ring shaped contrast effects in both lobes of the liver. The patient was diagnosed as gastric cancer cT4aN(+)M1[HEP], clinical Stage ⅣB. Six courses of capecitabine plus cisplatin plus trastuzumab(XP plus Tmab)therapy and 17 courses of capecitabine plus trastuzumab(X plus Tmab)therapy were performed. After chemotherapy, liver and lymph node metastases disappeared on CT and MRI. EGD showed residual gastric cancer, and the policy was to resect the primary tumor. Laparoscopic total gastrectomy with D2 lymph node dissection was performed. Pathological results showed T1b(SM)depth, no lymph node metastasis, and histologic response was Grade 2a. Six courses of X plus Tmab were administered as postoperative adjuvant chemotherapy, but were discontinued at the patient's request. Currently, 5 years have passed since the first chemotherapy and 3.5 years have passed since the surgery, and the patient is alive without recurrence, suggesting that the conversion surgery may have contributed to the prolonged survival.

A 72-year-old woman with relapsed FLT3-ITD-positive acute myeloid leukemia was treated with gilteritinib and achieved complete remission with incomplete hematological recovery. However, two months later, she developed optic nerve infiltration and lost vision in her right eye while maintaining hematological remission on gilteritinib. Intrathecal injection of cytotoxic drugs reduced the number of blasts in the cerebrospinal fluid (CSF), but her vision did not recover. At the onset of optic nerve infiltration, at a dose of 80 mg/day gilteritinib, the plasma trough and CSF levels of gilteritinib were 151.9 ng/ml and 1.9 ng/ml, respectively, with a central nervous system (CNS) penetration rate of 1.3%. Hematologic progressive disease (PD) was detected after 40 days, and the patient died one month later. Target sequencing at the time of hematologic PD revealed the FLT3 F691L mutation, which is known to confer resistance to gilteritinib. In this patient, pharmacokinetic (low CNS penetration of gilteritinib) and pharmacodynamic (acquisition of a drug resistance mutation) mechanisms were thought to be responsible for the CNS relapse and hematologic PD, respectively. We believe this is a valuable case to report considering the scarcity of data on CNS penetration of FLT3 inhibitors and their effects on CNS disease in the literature.

The severe acute respiratory syndrome coronavirus 2 vaccine has contributed to infection control and the prevention of complications due to coronavirus disease 2019 (COVID-19). Conversely, the COVID-19 vaccine has been associated with adverse effects due to liver injury caused by autoimmunity or drugs. To date, Japanese journals have only published five reports of autoimmune liver damage associated with the COVID-19 vaccination. Although the pathogenic mechanism has not yet been fully elucidated, corticosteroids or azathioprine have shown effectiveness in certain patients. However, there have been cases of liver injury resulting in deaths. Here, we encountered three patients who developed autoimmune hepatitis (AIH) within 10 days following vaccination. All three patients were treated with prednisolone (PSL) and achieved remission. However, the serum alanine aminotransferase levels in all cases were observed to either increase or cease to improve during the therapeutic course before PSL administration. It is therefore imperative to closely monitor liver injury after the COVID-19 vaccination. In cases where AIH is suspected and a recurrence of liver dysfunction occurs, PSL may be administered. Future considerations should not only encompass the underlying mechanism by which autoimmunity contributes to the development of liver injury following COVID-19 vaccination but also the optimal treatment period for PSL and the long-term prognosis of AIH after COVID-19 vaccination.

Many effective new agents for relapsed childhood acute lymphoblastic leukemia (ALL) are now becoming available, and international standard chemotherapy should be developed to optimize use of these agents. Randomized controlled trials (RCTs) are needed to establish a standard treatment, but few have been conducted for relapsed childhood ALL in Japan due to the small patient population. Participation in international RCTs is necessary to access sufficient patients for informative study results, but differences in approved drugs and healthcare systems between countries make this challenging. In 2014, the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) participated in an international study on standard-risk relapsed childhood ALL (IntReALL SR 2010) involving two RCTs and multiple drugs not approved in Japan, which was addressed by replacing the unapproved drugs with alternative approved drugs with the same or similar efficacy. This article discusses the historical background of treatment development for relapsed childhood ALL, our experience in participating in the IntReALL SR 2010 trial, and prospects for treating relapsed childhood ALL.

Relapsed and/or refractory (R/R) primary central nervous system lymphoma (PCNSL) has a poor prognosis. A 57-year-old man diagnosed with PCNSL achieved a complete response by high-dose methotrexate-based chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT). The disease was not cured, so he was treated with the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel after the third relapse. However, the disease relapsed again 28 days after CAR T-cell therapy. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was attempted as curative therapy after bridging with second ASCT and tirabrutinib monotherapy. Although a temporary response was achieved, the disease relapsed 98 days after allo-HSCT. While receiving tirabrutinib for relapse after allo-HSCT, the patient developed acute respiratory failure due to transplant-related toxicity and post-transplant thrombotic microangiopathy. He died 175 days after allo-HSCT. Although various treatments for PCNSL have been investigated in recent years, the treatment strategy for R/R PCNSL has not been established. Further studies are warranted to improve the outcomes of patients with R/R PCNSL.

A 62-year-old woman with adult T-cell leukemia/lymphoma (ATL) received umbilical cord blood transplantation (CBT) in first complete remission. However, relapse of ATL was detected on day 74 post-transplantation, as evidenced by the rapid growth of lymphoma cells in peripheral blood and an increase in soluble interleukin-2 receptor (sIL2R) levels. Discontinuation of immunosuppressant therapy alone did not improve ATL findings, but treatment with lenalidomide caused lymphoma cells to disappear from the peripheral blood and sIL2R levels to return to normal. Pancytopenia was observed as a lenalidomide-associated adverse effect, but lymphocyte counts were not reduced. The patient was judged to be in complete remission based on results of Southern blot analysis and human T-cell leukemia virus 1 (HTLV-1)-infected cell analysis using flow cytometry (HAS-Flow). Flow cytometric analysis of peripheral blood and FISH analysis of X and Y chromosomes revealed that the therapeutic effect of lenalidomide was associated with an increase in the number of donor-derived peripheral natural killer cells. ATL relapse was not observed at 13 months into lenalidomide treatment. Our results suggest that lenalidomide is an effective option for the treatment of post-transplant relapsed ATL.

Aggressive types of adult T-cell leukemia-lymphoma (ATL), namely, the acute type, lymphoma type, and chronic type with poor prognostic factors, have a poor prognosis. Although allogeneic hematopoietic stem cell transplantation (HSCT) may improve prognosis, relapse is common. In June 2021, tucidinostat was approved for relapsed or refractory ATL in Japan. We report a case of a 62-year-old man with relapsed ATL after allogeneic HSCT. In March 2017, he was diagnosed with ATL (acute type) and received two courses of mLSG-15 therapy. ATL cells reappeared in his peripheral blood, so he underwent allogeneic bone marrow transplantation in September 2017. In June 2021, his soluble interleukin-2 receptor (sIL-2R) level increased, and he began experiencing sensory abnormalities in his face and legs. In September, he developed respiratory failure and was diagnosed with relapse of ATL. He was again treated with mLSG-15. His sIL-2R normalized and the sensory abnormalities decreased, but sIL-2R rose again in February 2022. After tucidinostat treatment was initiated, sIL-2R normalized and the patient's general condition improved. Tucidinostat shows promise as an effective treatment for ATL that has relapsed after allogeneic HSCT.

Background: Maze surgery is often performed for atrial fibrillation during cardiac surgery, and a certain number of therapeutic effects are observed. However, the effectiveness of pulmonary vein isolation (PVI) remains unclear., Methods: 329 arrhythmia surgeries was performed between 2012 and 2021. The patients were divided into three groups:paroxysmal atrial fibrillation (PAf) group, persistent atrial fibrillation group (PerAf), and long persistent atrial fibrillation( LongPerAf) group. In the PVI and maze groups, postoperative sinus rhythm rate and the rate of freedom from Af recurrence were compared., Results: In PAf, PerAf cases, there was no difference between PVI and maze groups in the rate of freedom from recurrent Af and postoperative sinus rhythm rate. In LongPerAf cases, the rates of freedom from recurrent Af and postoperative sinus rhythm were significantly lower in the PVI group., Conclusion: PVI was considered effective in patients with atrial fibrillation of less than one year duration due to the simplicity of the procedure and low complications.

A 76-year-old male patient underwent a distal gastrectomy for advanced gastric cancer. As the postoperative serum CA19-9 level was elevated, chemotherapy was initiated. Computed tomography(CT)detected a solitary peritoneal recurrence in the left subhepatic space 17 months later. Consequently, chemoradiotherapy(CRT)at a total dose of 60 Gy, combined with S-1 therapy, was administered for local tumor control. After CRT, CT scans revealed a remarkable reduction in the peritoneal recurrence. Presently, 8 months after CRT, the patient remains alive with no indications of regrowth. CRT could prove efficacious as a treatment for gastric cancer patients with localized peritoneal recurrences.

A 74-year-old man was admitted to our hospital with complaints of weakness in the lower extremities, urinary retention for 10 days, and generalized vesicular rash for 7 days. Spinal magnetic resonance imaging showed contrast enhancement at the Th12-L1 level of the spinal cord and cauda equina. Serum and cerebrospinal fluid varicella-zoster virus (VZV)-immunoglobulin (Ig) G antibody titers were markedly elevated, and VZV-IgM was detected in cerebrospinal fluid. The patient was diagnosed with VZV transverse myelitis and cauda equina syndrome with subsequent varicella and was treated with acyclovir and prednisolone. Two months later, muscle weakness, and dysuria had almost completely resolved. We hypothesize that latent VZV in the ganglia reactivated and caused transverse myelitis, which subsequently spread to the body via the bloodstream, resulting in the development of varicella.

Eclipsed mitral regurgitation is a relatively new disease concept reported in recent years, of which is not fully elucidated. A 73-year-old female had repeated episodes of heart failure of unknown cause. During cardiac catheterization and echocardiography performed, mitral regurgitation suddenly worsened and improved in a few minutes. The patient was diagnosed as having eclipsed mitral regurgitation with multiple episodes of acute exacerbation and remission. Although mechanism of exacerbation remains unclear, morphological change of the left ventricle is likely to be a major cause, and mitral valve replacement seems better than plasty for prevention of recurrent heart failure. The patient underwent valve replacement using a bioprothesis and was discharged from the hospital on her own 24 days after surgery. Six months after the operation, she has been doing well without recurrence of heart failure.

A 61-year-old male was diagnosed with unresectable advanced gastric cancer(cT4b[SI; panc], N+, M0, cStage ⅣA). However he was administered S-1 plus oxaliplatin as a primary treatment and ramucirumab plus paclitaxel as a secondary treatment, the primary tumor and lymph nodes were enlarged. We judged PD and switched to the third-line treatment with nivolumab. After starting nivolumab, both the primary tumor and the lymph nodes shrank, and the PET-CT scan after 24 courses showed no FDG accumulation in the primary tumor or lymph nodes, so we judged the response as CR. The patient requested discontinuation of nivolumab, and nivolumab administration was stopped. Twenty months later after nivolumab administration was discontinued, CT scan showed re-growth of the primary tumor, and nivolumab administration was resumed. After resumption, he received 22 courses of nivolumab for 10 months with maintenance of SD.

FMS-like tyrosine kinase 3 (FLT3) mutation is present in 25% of acute myeloid leukemia (AML) cases. It is associated with poor prognosis due to a high relapse rate and short remission duration. Consequently, various FLT3 inhibitors were developed. Two second-generation FLT3 inhibitors, including gilteritinib and quizartinib, are used for treating relapsed/refractory FLT3-mutated AML. Additionally, in May 2023, quizartinib was approved for newly-diagnosed FLT3-mutated AML, in combination with standard remission induction, consolidation, and maintenance therapies based on a phase 3 trial. Furthermore, high relapse rates were observed even in patients who underwent allogeneic hematopoietic cell transplantation while in their first complete remission, and post-transplant maintenance therapy using oral FLT3 inhibitors has been tried. This review summarizes breakthroughs in treatments of FLT3-mutated AML aiming for a better prognosis.

Chimeric antigen receptor transgenic T cell (CAR-T) therapy targeting the CD19 antigen was approved for relapsed/refractory acute lymphocytic leukemia in the United States in 2017 and in Japan in 2019. Despite the excellent efficacy of CAR-T therapy, the relapse rate is about 50%. To reduce this rate, it will be important to examine predictive factors for relapse and which patients should receive hematopoietic cell transplantation. In addition, as the high cost of CAR-T cells has become a financial toxicity that threatens the health insurance system in many countries, development of less expensive CAR-T products using non-viral vectors is also underway.

The number of cases of chimeric antigen receptor T (CAR-T) cell therapy has been rapidly increasing in Japan since Tisagenlecleucel was approved in March 2019, and clinical experience with CAR-T therapy for CD19 has demonstrated that the therapy can be performed safely than initially expected. The current challenge for CAR-T therapy is insufficient response, as about 50% of patients who receive CD19 CAR-T therapy eventually relapse or become refractory. The causes can be generally classified as CAR-T cell exhaustion and lack of sufficient effector function, loss of the target antigen, and extremely rapid tumor growth, and countermeasures are being investigated and developed for each of these causes. Additionally, the development of novel CAR-T therapies is also desired. In this article, we discuss the current status and future prospects of these issues, including our own efforts.

Cancer genomic medicine or cancer immunotherapy has led to a paradigm shift in cancer treatment. When the first treatment does not work, patients may be able to have second-line therapy or additional rounds of treatment after that, however, most advanced cancers eventually acquire resistance to those treatments. To stop this perpetual cycle, a deeper understanding of cancer evolutionary trajectories during the acquisition of therapeutic resistance is needed. We and others have recently provided evidence that non-genetic drug resistance is due to dormant persister cells, yet little is known about how persister cancer cells promote tumor relapse. To study the non-genetic evolution of cancer cells, a single-cell analysis will enable us to trace the phenotypic plasticity of cancer cells. As persister cancer cells are considered to act as a reservoir for drug-resistant mutants, we may be able to overcome cancer relapse or metastasis if we can better understand their evolutionary trajectories.

A tyrosine kinase inhibitor (TKI) was used to treat the patient, a 35-year-old woman who was diagnosed with chronic myeloid leukemia at the age of 22 years. Since a four-year deep molecular response (DMR) was obtained, spontaneous pregnancy was planned under TKI withdrawal. Even though her disease had advanced to MR2.0 at the time of pregnancy confirmation, 2 months from TKI cessation, interferon α therapy was initiated in light of the patient's history. Later, the patient reached MR3.0, gave birth to a healthy baby, and maintained MR3.0-4.0. TKI was resumed after about 6 months of breastfeeding. Treatment-free remission (TFR) is required for natural conception despite the teratogenicity and miscarriage risks associated with BCR::ABL1 TKIs. When planning a pregnancy, it is also necessary to take the patients' backgrounds, disease states, and medical history into account.

Immune cell therapies targeting B-cell maturation antigen (BCMA) have been developed for relapsed and refractory multiple myeloma (RR-MM). Chimeric antigen receptor (CAR)-T cell therapies appear promising for RR-MM, and two BCMA-targeting CAR-T cell products, idecabtagene vicleucel and ciltacabtagene autoleucel, have achieved the highest response rates in heavily treated patients to date. These CAR-T products have been approved for RR-MM previously treated with 3 agents (proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibodies) in Japan. Despite the promising efficacy of CAR-T therapy, several issues remain to be resolved to establish its best use in routine clinical practice. In addition, most patients who receive CAR-T cell therapy eventually relapse after a long or short remission, and a better understanding of mechanisms of resistance and relapse following CAR T-cell therapy for MM will be necessary to overcome resistance to CAR-T therapy. In the near future, early initiation of CAR-T therapy for RR and development of next-generation CAR-T cell products should further improve prognosis in patients with MM.

Hematopoietic cell transplantation (HCT) is the only curative therapy for juvenile myelomonocytic leukemia (JMML). Meanwhile, an established conventional chemotherapy before HCT remains unavailable. Studies have shown that azacitidine (AZA), which is a DNA methyltransferase inhibitor, is clinically effective for JMML as a bridging therapy for HCT; a prospective clinical trial in Japan is ongoing. Herein, we present a case of a patient with JMML who was administered AZA as bridging therapy for both first and second HCT. A 3-year-old boy with neurofibromatosis type 1 was administered with intravenous AZA (75 mg/m 2 /day for 7 days, intervals of 28 days, and four cycles) and received myeloablative HCT (unrelated bone marrow). When relapse occurred on day 123, four additional AZA therapy cycles were administered, and the patient received a second nonmyeloablative HCT (cord blood). After seven AZA therapy cycles as post HCT consolidation, hematological remission was sustained for 16 months after the second HCT. No severe adverse events occurred. AZA is effective for JMML as a bridging therapy for HCT and has robust cytoreductive potential despite the risk of relapse.

We report a case of postoperative multiple recurrence of hepatocellular carcinoma(HCC)treated with atezolizumab plus bevacizumab. A 73-year-old man with a chief complaint of abdominal distention was indicated a 90-mm-sized tumor extending from the lateral hepatic segment to the extrahepatic region by a contrast-enhanced CT scan of the abdomen. He underwent a laparoscopic liver resection of the lateral segment for suspected HCC, and was diagnosed as pStage Ⅱ HCC. Six months after surgery, multiple recurrent at intrahepatic lesions and suspected lymph node recurrence or peritoneal dissemination were observed, and tumor markers were markedly elevated. The patient was diagnosed with multiple intrahepatic and extrahepatic recurrences of postoperative HCC and started combination chemotherapy with atezolizumab (1,200 mg/body)plus bevacizumab(15 mg/kg). After the initiation of the therapy, tumor size reduction and normalization of tumor markers were observed, and at 17 months postoperatively, tumor size reduction has been maintained and tumor markers were in the normal range. We report a case of postoperative intrahepatic and extrahepatic multiple recurrences of he patocellular carcinoma treated with atezolizumab plus bevacizumab.

A 67-year-old man was introduced to examine for abnormal findings in physical examination. Upper gastrointestinal endoscopy detected the 3 lesions and diagnosed multiple gastric cancers with biopsy. Laparoscopic total gastrectomy was performed and final pathological diagnosis was pT2N1M0, pStage ⅡA with HER2 positive(3+). Adjuvant chemotherapy was not administrated. CT findings 6 months after procedure showed 2 liver metastases(S6, S7)and laparoscopic partial liver resection was performed. Pathological findings proved the metastasis of previous gastric cancer. Although adjuvant chemotherapy of S-1 was started 2 months after hepatectomy, CT findings showed second recurrences in liver and right adrenal gland. Chemotherapy was changed to S-1 plus cisplatin(SP)plus trastuzumab. AS these recurrence sites and ascites could not be detected by CT after 6 courses, therapeutic effect was judged as clinical CR(cCR)and SP plus trastuzumab was stopped due to side effect. Since then, regular follow-up CT showed preservation of status of cCR without chemotherapy and he has been alive without recurrence for 8 years and 9 months after gastrectomy. We report a case of recurrent gastric cancer of multiple organ metastasis with long-term survival due to multimodal treatment.

We report a case of a patient with neuromyelitis optica spectrum disorder (NMOSD) who was originally treated for multiple sclerosis (MS) due to a negative anti-aquaporin-4 (AQP4) antibody test, but later the antibody titer became positive. A 58-year-old woman without prior medical history developed acute left facial pain, vomiting, and hiccups. MRI showed an intraparenchymal lesion extending from the medulla oblongata to cervical cord with high T 2 -weighted signal intensity. The patient responded to steroid pulse therapy. However, she developed diplopia and gait disturbance after six months, and follow-up MRI revealed a new lesion in the left middle cerebellar peduncle. The patient was diagnosed with MS due to the dissemination in the time and space of her lesions and negative anti-AQP4 antibody status. There was no relapse for three and a half years on fingolimod therapy. However, a severe relapse occurred four years later that involved optic neuritis and multiple new brain lesions. During this episode, the anti-AQP4 antibody test was positive, and the patient was diagnosed with NMOSD. This case highlights the possibility that seroconversion of anti-AQP4 antibody may occur at any time in NMOSD patients. Therefore, this diagnostically paramount antibody should be measured several times during the treatment of relapsing-remitting MS in patients with repeat frequent recurrences and uncommon symptoms of MS.

In real-world settings, many patients experience single or multiple recurrences of non-cardiogenic cerebral infarction, which is mainly caused by arteriosclerosis. These patients are treated according to set guidelines. While antiplatelet therapy is the standard treatment for preventing recurrence, this therapy alone is insufficient for full prevention of recurrence. Combining the administration of antiplatelet agents with the management of risk factors for recurrent cerebral infarction can maximize the preventive effects of these drugs.

Eight disease-modifying drugs have been approved for treating multiple sclerosis in Japan., The drugs show some differences in for the degree to which they prevent relapses; among them, natalizumab and ofatumumab are significantly effective in preventing relapses. If relapses are not suppressed when treated with natalizumab, the presence of anti-natalizumab antibodies should be investigated. When relapses cannot be suppressed with natalizumab, the patient should be treated with ofatumumab and vice versa. If relapses cannot be suppressed with both natalizumab and ofatumumab, then the diagnosis of multiple sclerosis should be thoroughly reassessed. In cases with atypical symptoms and/or exhibiting factors such as multiple sclerosis, oral steroids, and/or immunosuppressive agents can be administered to prevent relapses.

We report a cases report of colorectal cancer who underwent repeated resection for peritoneal recurrences by laparoscopic surgery. In 2013, a 70-year-old woman diagnosed with an ascending colon cancer underwent laparoscopic right hemicolectomy. The pathological diagnosis was tub2, pT4aN1M0, Stage Ⅲb. Postoperative adjuvant chemotherapy(uracil and tegafur/Leucovorin)was administered. PET-CT performed at 25 months after the surgery because of CEA elevation. It revealed a peritoneal recurrence in the pouch of Douglas. The following peritoneal recurrences were removed by laparoscopic Hartmann's procedure. Chemotherapy(5-fluorouracil/levofolinate/oxaliplatin/bevacizumab)was administered 11 courses and after that chemotherapy(5-fluorouracil/levofolinate/bevacizumab)was administered 6 courses. PET-CT performed 37 months after the second surgery revealed a peritoneal recurrence near the right ovary in the pouch of Douglas. The following peritoneal recurrences was removed. Chemotherapy(tegafur/gimeracil/oteracil/bevacizumab)was administered 11 courses. The long-term survival has been continued for 7 years and 7 months after first operation. It was considered that laparoscopic surgery for peritoneal recurrence in colorectal cancer is contributed to one of the surgical procedures in selected patients.

A 57-year-old man visited the urology department with a painful mass on the dorsal side of the penis. Magnetic resonance imaging sagittal image showed a small nodule. Leukemia recurrence was suspected due to his history of treatment for acute myeloid leukemia treated with allogeneic hematopoietic stem cell transplantation. No recurrence was identified by bone marrow biopsy ; however, two months later, the recurrence of leukemia was strongly suspected because the tumor grew over time and blasts were found in the peripheral blood. A biopsy of the penile tumor and bone marrow was performed, leading to the diagnosis of granulocytic sarcoma. Patients with a history of leukemia may be preceded by a single recurrence to extramedullary organs, even if blood and bone marrow findings suggest remission.

Essential thrombocythemia gradually developed into secondary myelofibrosis and progressed to leukemia eight months later in a 53-year-old man. After remission induction therapy, he achieved remission by undergoing allogeneic hematopoietic stem cell transplantation from unrelated patients in non-remission. However, peripheral blood WT-1 mRNA gradually increased, and the disease relapsed three years and six months after transplantation. He was taking prednisolone (7.5 mg) and tacrolimus (5 mg) for chronic pulmonary graft-versus-host disease (GVHD) and was reluctant to reduce or discontinue immunosuppressive drugs; therefore, donor lymphocyte infusion (DLI) was performed for a total of five times. Four months after the fifth DLI, cutaneous GVHD appeared, a slow decrease in WT-1 mRNA was observed, and blasts in the peripheral blood disappeared. One year and three months after the last DLI, he achieved complete remission. Although DLI for post-transplant relapse in patients with secondary myelofibrosis or leukemia is rare, it can be beneficial for post-relapse therapy.

Inotuzumab ozogamicin (InO) was administered in three cases of relapsed/refractory adult acute lymphoblastic leukemia (ALL) before allogeneic hematopoietic stem cell transplantation (allo-SCT). One case developed extremely severe sinusoidal obstruction syndrome (SOS) but recovered after receiving defibrotide therapy. A gap of 63 days in the SOS case was noted from the last administration of InO to allo-SCT, the duration was 133 and 86 days for the other two cases, and the remaining risk factors for SOS were comparable in the three cases. In contrast to gemtuzumab ozogamicin (GO), the interval between InO exposure and allo-SCT has not been reported as a risk for SOS. Nevertheless, this case suggests that the intervals should be as long as possible.