Antitumor activity of α-pinene in T-cell tumors.

T-cell acute leukemia and lymphoma have a poor prognosis. Although new therapeutic agents have been developed, their therapeutic effects are suboptimal. α-Pinene, a monoterpene compound, has an antitumor effect on solid tumors; however, few comprehensive investigations have been conducted on its impact on hematologic malignancies. This report provides a comprehensive analysis of the potential benefits of using α-pinene as an antitumor agent for the treatment of T-cell tumors. We found that α-pinene inhibited the proliferation of hematologic malignancies, especially in T-cell tumor cell lines EL-4 and Molt-4, induced mitochondrial dysfunction and reactive oxygen species accumulation, and inhibited NF-κB p65 translocation into the nucleus, leading to robust apoptosis in EL-4 cells. Collectively, these findings suggest that α-pinene has potential as a therapeutic agent for T-cell malignancies, and further investigation is warranted.

Efficient granulocyte collection method using high concentrations of medium molecular weight hydroxyethyl starch.

BACKGROUND: Granulocyte transfusion therapy is a rational therapeutic option for patients with prolonged, severe neutropenia. Although high molecular weight hydroxyethyl starch (hHES) facilitates the separation of red blood cells during granulocyte collection, renal dysfunction has been noted as a potential side effect. HES130/0.4 (Voluven®) is a medium molecular weight HES (mHES) with superior safety profiles compared to hHES. Although HES130/0.4 is reportedly effective in the collection of granulocytes, we lack studies comparing the efficiency of granulocyte collection using HES130/0.4 and hHES. STUDY DESIGN AND METHODS: We retrospectively collected the data from 60 consecutive apheresis procedures performed on 40 healthy donors at the Okayama University Hospital between July 2013 and December 2021. All procedures were performed using the Spectra Optia system. Based on the HES130/0.4 concentration in the separation chamber, granulocyte collection methods using HES130/0.4 were classified into m0.46, m0.44, m0.37, and m0.8 groups. We used HES130/0.4 and hHES groups to compare the various sample collection methods. RESULTS: The median granulocyte collection efficiency (CE) was approximately 24.0% and 28.1% in the m0.8 and hHES groups, respectively, which were significantly higher than those in the m0.46, m0.44, and m0.37 groups. One month following granulocyte collection with HES130/0.4, no significant changes were observed in serum creatinine levels compared to those before the donation. CONCLUSION: Therefore, we propose a granulocyte collection approach employing HES130/0.4, which is comparable to the use of hHES in terms of the granulocyte CE. A high concentration of HES130/0.4 in the separation chamber was considered crucial for granulocyte collection.

A case of perforated immune-related colitis complicated by cytomegalovirus infection during treatment of immune-related adverse effect in lung cancer immunotherapy.

Although immune checkpoint inhibitors (ICIs) can be used for lung cancer treatment, the activated immune response may cause immune-related adverse effects (irAEs). We present here a case of cytomegalovirus (CMV) enterocolitis during steroid therapy for an irAE. A 70-year-old man diagnosed with small-cell lung carcinoma (limited disease) received radiotherapy plus two chemotherapy cycles of cisplatin and etoposide. The tumor exhibited complete response but recurred after 3 years. After treatment with two cycles of carboplatin, etoposide, and atezolizumab, an inhibitors of programmed cell death receptor-1, he was switched to atezolizumab every 3 weeks for maintenance therapy. Diarrhea occurred after nine atezolizumab doses. With a strong suspicion of ICI-induced colitis, we administered methylprednisolone 500 mg for 3 days, followed by oral prednisolone 40 mg/day. Total colonoscopy during the treatment revealed mucosal inflammation of the total colon, suggesting immune-related colitis. Biopsies from the ulceration revealed crypt abscess with highly infiltrative plasma cells and lymphocytes. Furthermore, immunohistochemical staining showed positivity for CMV. With no improvement in watery diarrhea, the prednisolone dose was increased to 80 mg/day on the 11th day, and ganciclovir was additionally administered twice daily on the 26th day. On the 28th day, the patient had abdominal pain, and abdominal computed tomography revealed free air, resulting in the diagnosis of colon perforation. He underwent subtotal colectomy followed by ileostomy as emergency surgery. A colon specimen revealed colitis with CMV infection. We describe colon perforation in a patient with CMV enterocolitis complicated by refractory immune-related colitis.

Idiopathic Pneumonia Syndrome Refractory to Ruxolitinib after Post-Transplant Cyclophosphamide-based Haploidentical Hematopoietic Stem Cell Transplantation: Lung Pathological Findings from an Autopsy Case.

A 69-year-old Japanese man with acute leukemia received post-transplant cyclophosphamide-based haploidentical stem cell transplantation (PTCY-haplo-SCT) but was readmitted with dyspnea and ground-glass-opacities of the lungs. Bronchoscopy showed inflammatory changes with no signs of infection. He received steroids but required intubation as his condition deteriorated. In addition to antithymocyte globulin and cyclophosphamide, we administered ruxolitinib but failed to save him. Autopsy findings revealed fibrotic nonspecific interstitial pneumonia (NSIP) without evidence of organizing pneumonia or infection. Thus, we diagnosed idiopathic pneumonia syndrome (IPS). As far as our knowledge, this is the first case of IPS with NSIP histology after PTCY-haplo-SCT.

Acute undifferentiated leukemia limited to neck lymph nodes and a large mediastinal mass.

In the 2016 update of the World Health Organization (WHO) classification of myeloid neoplasms, acute undifferentiated leukemia (AUL) was defined by a lack of lineage-specific markers. AUL has very poor prognosis and no established therapies due to its rarity. We report a case of a 31-year-old man with AUL who showed complete molecular response to an acute lymphoblastic leukemia (ALL)-based regimen and received allogeneic hematopoietic stem cell transplantation. The patient's blast cells were CD7-positive and localized to lymph nodes in the neck and to a large mediastinal mass; there was also rearrangement of the T-cell receptor delta locus. Although the tumor showed characteristics of T-cell lymphoblastic lymphoma, it was categorized as AUL based on WHO classification. This case suggests that a high-intensity conditioning regimen could be effective for rare cases of AUL that present only in the extramedullary mass, and chemotherapy for AUL should be selected based on the characteristics of the blasts.

Successful management of recurrent allergic bronchopulmonary aspergillosis after changing from mepolizumab to dupilumab: A case report.

An 81-year-old woman presented to our hospital due to an abnormal shadow on a chest X-ray and a 4-week-old persistent cough. Laboratory examination revealed increased serum eosinophils and immunoglobulin E. The Asthma Control Test (ACT) score and forced expiratory volume in 1 sec indicated airway obstruction. Chest computed tomography (CT) revealed mucoid impaction in the dilated left-lingular lobar bronchus. She was diagnosed with bronchial asthma and treated with a high-dose inhaled corticosteroid/long-acting ß2 agonist. Two months later, her mucoid impaction in the CT image worsened; moreover, bronchoscopy revealed the white mucus plug with Charcot-Leyden crystals and filamentous fungi. The patient was diagnosed with Allergic bronchopulmonary aspergillosis (ABPA) and treatment with 30 mg/day prednisolone was started. Both the blood eosinophil count and the chest image improved almost substantially, and the steroid was discontinued after a year. Sixteen months after cessation of prednisolone treatment, peripheral eosinophilia and mucoid impaction in the left B3b recurred. For the treatment of bronchial asthma and recurrent ABPA, administration of mepolizumab was initiated. Subsequently, although her peripheral eosinophils count decreased, chest CT showed expansion of the mucoid impaction and IgE increased despite mepolizumab treatment. Alternative subcutaneous injection therapy with dupilumab improved chest image, serum IgE level, and her ACT score. After changing from mepolizumab to dupilumab, her ABPA, asthma, and pulmonary function improved remarkably. This case illustrates the potential utility of dupilumab for ABPA without re-administration of oral prednisolone. Additional research is needed to identify an effective therapy for ABPA with asthma.

Effect of high-dose delivery on the attachment of meningiomas in Gamma Knife surgery: a retrospective study.

BACKGROUND: Meningiomas have vascular supply from the tumor attachment on the dura mater. Gamma Knife radiosurgery (GKS) is known to have a vascular obliterating effect. This study aims to determine the benefits of high-dose irradiation to the tumor attachment compared to conventional dose planning in the long-term control of tumor growth with GKS. METHODS: Two different dose plannings were retrospectively compared in 75 patients with meningioma treated with GKS as a primary treatment. Forty-three patients were irradiated over 20 Gy to the tumor attachment. The remaining 32 patients were treated with conventional-dose planning. Tumor growth control, reduction of enhancement on the gadolinium-enhanced magnetic resonance imaging (MRI), and neurological status were retrospectively assessed. RESULTS: The maximum dose on the tumor attachment was significantly higher in the high-dose group (23 Gy) than in the conventional group (16 Gy). The tumor margin was irradiated with the median of the 50% isodose line in both groups. The prescription doses resulted in 14 Gy and 12 Gy, respectively. The tumor control rate achieved 91% in both groups during the median follow-up period of 54 months. A decrease of enhancement on follow-up MRI was noted in one patient in each group. Kaplan-Meier analysis revealed no statistical difference in the progression-free survival between the two groups. The number of patients with improved neurological status showed no statistical difference. CONCLUSIONS: No obvious benefit of high-dose irradiation to the tumor attachment and margin was found in tumor control and neurological status in the long term.

Successful neutrophil engraftment supported by granulocyte transfusion in adult allogeneic transplant patients with peri-transplant active infection.

Active infection at the time of allogeneic hematopoietic stem cell transplantation (HSCT) is a risk for non-relapse mortality (NRM) after HSCT. Granulocyte transfusion (GTX) has been used to prevent or treat life-threatening infections in patients with severe neutropenia. However, data are limited on the clinical benefits of GTX during HSCT. We retrospectively analyzed the transplant outcomes of HSCT patients who had undergone GTX between 2012 and 2020. Altogether, 20 patients with documented infection had received 55 GTXs during HSCT. No adverse events were observed during the GTX infusion. The average number of granulocytes was 0.40 (range, 0.10-1.59) × 109/kg. The median neutrophil increment one day after GTX was 515 (range, -6 to 6630)/µl, which was significantly correlated with the infused granulocyte dose (p = 0.0007). A total of 17 of 20 patients achieved neutrophil engraftment. The number of infused granulocytes tended to higher in clinical responders (p = 0.12), and patients receiving ≥ 0.5 × 109/kg showed trend toward to better transplant outcomes (GTX-high vs. GTX-low, 1-year OS; 33% vs. 11%, p = 0.19. 1-year NRM; 44% vs.77%, p = 0.11). The type of red blood sedimenting agents was significantly correlated with the amounts of granulocyte collection. In conclusion, GTX, especially with a high amount of containing granulocytes, could be a safe bridging therapy for neutrophil engraftment after HSCT in patients with active infection.

Tocilizumab and Baricitinib for Recovery From Acute Exacerbation of Combined Pulmonary Fibrosis and Emphysema Secondary to COVID-19 Infection: A Case Report.

Pneumonia secondary to coronavirus disease 2019 (COVID-19) is exacerbated by a disproportionate increase in the systemic inflammatory response and cytokine storm due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Herein, we report the successful treatment of severe COVID-19 pneumonia using a combination of tocilizumab and baricitinib in a patient with combined pulmonary fibrosis and emphysema (CPFE). A 67-year-old male with type 2 diabetes mellitus and CPFE presented with fever and dyspnea and was diagnosed with COVID-19. Upon admission, his respiratory failure was managed using high-flow nasal cannula (HFNC) therapy; however, despite treatment with remdesivir and systemic steroids, his respiratory failure continued to worsen. Therefore, baricitinib was administered from the ninth day of hospitalization for 14 days. Furthermore, his blood interleukin-6 (IL-6) levels showed an increase until day 13. Thus, tocilizumab was administered on the 13th day, which led to symptomatic improvement by day 18. The patient was discharged from our hospital on day 42. This case indicates that combination therapy with tocilizumab and baricitinib improves the efficacy of COVID-19 treatment in patients with comorbidities.

Clinical characteristics and treatment of elderly onset adult-onset Still's disease.

Adult-onset Still's disease (AOSD)-a systemic inflammatory disease-often occurs at a young age. Recently, elderly onset patient proportion has been increasing; however, data are limited. To evaluate the characteristics of elderly patients with AOSD in a multicenter cohort, we retrospectively analyzed 62 patients with AOSD at five hospitals during April 2008-December 2020. Patients were divided into two groups according to age at disease onset: younger-onset (≤ 64 years) and elderly onset (≥ 65 years). Clinical symptoms, complications, laboratory findings, treatment, and outcomes were compared. Twenty-six (41.9%) patients developed AOSD at age ≥ 65 years. The elderly onset group had a lower frequency of sore throat (53.8% vs. 86.1%), higher frequency of pleuritis (46.2% vs. 16.7%), and higher complication rates of disseminated intravascular coagulation (30.8% vs. 8.3%) and macrophage activation syndrome (19.2% vs. 2.8%) than the younger onset group. Cytomegalovirus infections were frequent in elderly onset patients (38.5% vs. 13.9%) but decreased with early glucocorticoid dose reduction and increased immunosuppressant and tocilizumab use. Elderly AOSD is not uncommon; these patients have different characteristics than younger-onset patients. Devising a way to control disease activity quickly while managing infections may be an important goal in elderly AOSD.

Low hematocrit reduces the efficiency of CD34+ cell collection when using the Spectra Optia continuous mononuclear cell collection procedure.

BACKGROUND: CD34+ cell collection efficiency (CE) is the determining factor when calculating processed blood volume (PBV) for leukapheresis (LP). However, the factors affecting CE in the continuous mononuclear cell collection (cMNC) protocol performed by the Spectra Optia apheresis system are not well established. STUDY DESIGN AND METHODS: We retrospectively collected the data from 147 consecutive apheresis procedures across 106 healthy donors and 27 patients completed between July 2016 and December 2020 at the Okayama University Hospital. All procedures were performed using the Optia cMNC protocol. RESULTS: The median CD34+ CE2 was significantly higher in the donor samples (64.3%) than in the patient samples (46.8%) (p < .0001). WBC counts, hematocrit, and platelet counts were all significantly higher in the donors than in the patients, and there was a moderate positive correlation between CD34+ CE2 and hematocrit (r = .47, p < .0001), with the equation of the line being y = 1.23x + 12.23. In contrast, there was only a very weak correlation between CD34+ CE2 and WBC or platelet count. In addition, low hematocrit correlated with an increased time to interface formation. CONCLUSION: These data revealed the negative impact of low hematocrit on the efficiency of CD34+ cell collection when using the Optia cMNC protocol and suggest that hematocrit values should also be considered when determining PBV.

Improvement of peripheral neuropathy in a patient with antineutrophil cytoplasmic antibody-negative eosinophilic granulomatosis with polyangiitis by additional mepolizumab.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is a vasculitis characterized by abnormally high eosinophils and frequent peripheral neuropathy. Mepolizumab is an approved therapy for EGPA, but its efficacy against peripheral neuropathy remains unknown. CASE PRESENTATION: A 41-year-old woman was admitted in the hospital with dyspnea and neuropathy. Ground glass opacity and infiltrative shadow in the bilateral lungs were evident on chest computed tomography images. Eosinophils were increased in serum, in bronchoalveolar lavage fluid (BALF), and in transbronchial lung biopsy, and bacteria were not detected in BALF. EGPA resulting in severe eosinophilic asthma, sinusitis, pulmonary infiltrates, and peripheral neuropathy was diagnosed. Prednisolone (50 mg/day) caused remission of eosinophilic pneumonia and sinusitis, but not peripheral neuropathy. During prednisolone tapering (7 mg/day, 10 months after treatment), eosinophils were increased, and peripheral neuropathy relapsed. The humanized anti-IL-5 antibody mepolizumab (300 mg) was initially administered, followed by prednisolone. Mepolizumab caused sustained peripheral neuropathy remission and effective prednisolone tapering. CONCLUSIONS: Introduction of mepolizumab combined with prednisolone may improve peripheral neuropathy.

A rare case of urachal carcinoma with multiple lung metastasis that required differentiation from primary lung carcinoma.

Urachal carcinoma is a rare malignancy of all bladder carcinomas. Metastatic lung tumours showing multiple nodules are rare without a local recurrence. We describe a case of multiple metastatic lung cancer from urachal carcinoma that required differentiation from primary lung cancer.

Duodenal Metastasis of Pulmonary Pleomorphic Carcinoma: A Case Report.

Pulmonary pleomorphic carcinoma (PPC) is a rare subtype of lung sarcomatoid carcinoma that has a poor prognosis, and no standard therapy has been established. Here, we report the case of a 74-year-old man with PCC who showed rare duodenal metastasis. He was referred to our hospital with a mass shadow in the right lung. The patient was diagnosed with PPC clinical stage II B on the basis of immunohistochemical staining from bronchoscopy, and the tumor proportion score of programmed death-ligand 1 was 80%. He did not want any treatment. A year and a half later, progressive anemia was detected. The primary tumor was stable; however, abdominal computed tomography and esophagogastroduodenoscopy revealed a duodenal tumor with stenosis. He was diagnosed with duodenal metastasis from PPC, and he underwent gastrojejunal bypass surgery to prevent bowel obstruction. After surgery, he received pembrolizumab for chemotherapy. However, owing to the progression of peritoneum dissemination, he died 2 months later due to the onset of melena.

Endovascular therapy for cerebral infarction due to Trousseau syndrome in a patient with non-small cell lung cancer.

We describe a case of Trousseau's syndrome in a patient with lung carcinoma. A 69-year-old man presented with pleural effusion. Further evaluation revealed EGFR mutation-positive non-small cell carcinoma in the upper lobe with extensive lymph node, bone, and brain metastases. Administration of osimertinib, an EGFR tyrosine kinase inhibitor, resulted in partial tumor response, but caused osimertinib-induced pneumonitis 10 weeks later. Prednisolone restrained lung injury progression and was gradually tapered. However, he presented with impaired consciousness and right hemiplegia. Magnetic resonance imaging revealed a left middle cerebral artery M1 segment occlusion. D-dimer level was elevated to 19.5 µg/mL. In the absence of atherosclerotic or cardiogenic thrombi, these findings led to the diagnosis of Trousseau syndrome. Endovascular therapy, but not tissue plasminogen activator, improved his condition with no recurrences. These treatment strategies are crucial to restore function in patients with potentially disabling cerebral infarction due to Trousseau syndrome.

Assessment of the rapid effect of dupilumab in two cases of severe asthma comorbid with recurrent eosinophilic chronic rhinosinusitis after endoscopic sinus surgery.

Dupilumab, a human monoclonal antibody against interleukin-4 (IL-4) and IL-13, has been approved for treating severe asthma and eosinophilic chronic rhinosinusitis (ECRS). Patients with ECRS are often candidates for endoscopic sinus surgery (ESS). However, a considerable number of patients have recurrent ECRS. ECRS is an important factor influencing asthma control. Here, we present two cases of severe asthma and recurrent ECRS after ESS. Although they had been treated with inhaled corticosteroids and a long-acting ß2-agonist, they experienced frequent asthma exacerbations. Laboratory examinations revealed increased serum eosinophils and immunoglobulin E (IgE). Furthermore, the Asthma Control Test (ACT) score and forced expiratory volume in 1 sec (FEV1) were indicative of airway obstruction. After treatment with dupilumab, asthma, rhinosinusitis symptoms, and pulmonary function improved remarkably. Dupilumab therapy improved quality of life in these patients with severe asthma and ECRS.

Effectiveness of supplemental oral calcium drink in preventing citrate-related adverse effects in peripheral blood progenitor cell collection.

Peripheral blood progenitor cells (PBPCs) are a predominant graft source in allogeneic hematopoietic cell transplantation. Citrate-induced hypocalcemia remains the most frequent side effect of PBPC apheresis. Although the method for preventing severe adverse events is established, more efficient prophylaxis is required so that volunteer donors can donate PBPCs without pain and anxiety. We studied 80 healthy donors who underwent PBPC harvest between February 2014 and June 2020. Of these, 23 donors who underwent apheresis between February 2014 and December 2015 received only the standard prophylaxis of intravenous calcium gluconate. Oral calcium drinks were provided to 57 donors who underwent apheresis from January 2016 to June 2020 to supplement intravenous calcium gluconate prophylaxis. The ionized calcium (ICa) levels at multiple time intervals and the hypocalcemic symptoms were evaluated. Oral supplementation with a calcium drink maintained significantly higher ICa levels. Analysis using the inverse probability weighted regression adjustment method suggested that calcium drinks reduced the frequency of citrate-related reactions by 39.2 %. Administering a prophylactic oral calcium drink before apheresis with intravenous administration of calcium gluconate is promising to further reduce citrate-induced hypocalcemia in volunteer donors.

Remarkable response of non-small cell lung cancer to nintedanib treatment in a patient with idiopathic pulmonary fibrosis.

Nintedanib is a multi-target receptor tyrosine kinase inhibitor that reduces the decline in forced vital capacity (FVC) and prevents acute exacerbations in idiopathic pulmonary fibrosis (IPF), which is a risk factor for lung cancer. However, it remains unclear whether nintedanib is an effective treatment for lung cancer in patients with IPF. Here, we describe an 82-year-old man with non-small cell lung carcinoma complicated by IPF who was treated with nintedanib. High-resolution computed tomography (HRCT) showed a subpleural basal-predominant reticular shadow and traction bronchiectasis with a honeycomb pattern. His FVC decreased over time, and his 6-min walk test showed oxygen desaturation. Furthermore, an enlarged nodular lesion was detected after 6 months of referral. Biopsy confirmed non-small cell carcinoma. Because of the risk of acute exacerbation of IPF by chemotherapy, supportive care was selected. Nintedanib was started as treatment for the IPF. Nine months later, HRCT revealed partial remission without exacerbation of IPF. This case indicates the possibility of nintedanib monotherapy in suppressing lung cancer complicated by IPF. Patients with lung cancer complicated by IPF in whom treatment is effective remain unknown. Additional research is needed to identify effective therapy for lung cancer with IPF.