Lenalidomide for anemia correction in lower-risk del(5q) myelodysplastic syndrome patients of Asian ethnicity

Background@#To estimate real-world outcomes in East Asian populations, we conducted a nationwide retrospective analysis of the efficacy and safety of lenalidomide for del(5q) myelodysplastic syndrome (MDS) patients with transfusion-dependent anemia in Korea. @*Methods@#Patients aged ≥19 years who had received lenalidomide for the treatment of lower-risk, red blood cell (RBC) transfusion-dependent del(5q) MDS were selected. A filled case report form (CRF) with information from electronic medical records was requested from members of the acute myeloid leukemia (AML)/MDS Working Party of the Korean Society of Hematology. All the CRFs were gathered and analyzed. @*Results@#A total of 31 patients were included in this study. Of 28 evaluable patients, 19 (67.9%) achieved RBC transfusion independence (RBC-TI). Female sex and the development of thrombocytopenia during treatment were associated with achieving RBC-TI. The most common non-hematologic toxicities were pruritus, fatigue, and rashes. All non-hematologic toxicities of grades ≥3 were limited to rash (12.9%) and pruritus (6.5%). Dose reduction was required in 15 of the 19 responders (78.9%). The most common final stable dosing schedule for the responders was 5 mg once every other day (31.6%). @*Conclusion@#Lenalidomide efficacy and tolerability were similar in the Asian del(5q) MDS patients and western patients. Dose reduction during treatment was common, but it was not associated with inferior outcomes.

Lenalidomide for anemia correction in lower-risk del(5q) myelodysplastic syndrome patients of Asian ethnicity

Background@#To estimate real-world outcomes in East Asian populations, we conducted a nationwide retrospective analysis of the efficacy and safety of lenalidomide for del(5q) myelodysplastic syndrome (MDS) patients with transfusion-dependent anemia in Korea. @*Methods@#Patients aged ≥19 years who had received lenalidomide for the treatment of lower-risk, red blood cell (RBC) transfusion-dependent del(5q) MDS were selected. A filled case report form (CRF) with information from electronic medical records was requested from members of the acute myeloid leukemia (AML)/MDS Working Party of the Korean Society of Hematology. All the CRFs were gathered and analyzed. @*Results@#A total of 31 patients were included in this study. Of 28 evaluable patients, 19 (67.9%) achieved RBC transfusion independence (RBC-TI). Female sex and the development of thrombocytopenia during treatment were associated with achieving RBC-TI. The most common non-hematologic toxicities were pruritus, fatigue, and rashes. All non-hematologic toxicities of grades ≥3 were limited to rash (12.9%) and pruritus (6.5%). Dose reduction was required in 15 of the 19 responders (78.9%). The most common final stable dosing schedule for the responders was 5 mg once every other day (31.6%). @*Conclusion@#Lenalidomide efficacy and tolerability were similar in the Asian del(5q) MDS patients and western patients. Dose reduction during treatment was common, but it was not associated with inferior outcomes.

The efficacy of low-dose transdermal fentanyl in opioid-naive cancer patients with moderate-to-severe pain

BACKGROUND/AIMS: Little is known about the efficacy of low-dose transdermal fentanyl (TDF) patches in opioid-naive patients with moderate-to-severe cancer pain. METHODS: This study had an open-label, prospective design, and was conducted between April 2007 and February 2009 in seven tertiary cancer hospitals; 98 patients were enrolled. TDF was started using a low-dose formulation (12.5 microg/hr), and the dose was adjusted according to the clinical situation of individual patients. Pain intensity, the TDF doses used, and adverse events (AEs) were monitored over 4 weeks. Data were analyzed using the intent-to-treat and per-protocol principles. RESULTS: Of the 98 patients enrolled, 64 (65%) completed the study. The median pain intensity decreased from 6.0 to 3.0 (p < 0.001) at the follow-up visit. The efficacy of low-dose TDF on pain relief was consistent across groups separated according to gender (p < 0.001), age (p < 0.001), metastasis (p < 0.001), previous treatment (p < 0.001), and baseline pain intensity (p < 0.001). The decrease in pain intensity was significantly greater in the severe group compared with the moderate group (mean +/- SD, 5.10 +/- 2.48 vs. 2.48 +/- 1.56; p < 0.001). TDF dose (27.8 microg/hr vs. 24.8 microg/hr, p = 0.423) and the mean treatment time (7.5 days vs. 7.9 days, p = 0.740) required for pain control were not different between the two pain-intensity groups. Patients had AEs of only mild or moderate intensity; among these, nausea (38%) was the most common, followed by vomiting (22%) and somnolence (22%). CONCLUSIONS: Low-dose TDF was an effective treatment for patients with cancer pain of moderate-to-severe intensity. Further randomized trials assessing the efficacy of TDF for severe pain and/or optimal starting doses are warranted.

A Case of T-Lymphoblastic Lymphoma/Leukemia with Bilateral Primary Adrenal Involvement / 대한내과학회지

T-lymphoblastic leukemia/lymphoma is an aggressive condition with frequent involvement of the mediastinum, occurring most frequently in older children, adolescents, and young adults. The involvement of extranodal sites is less common, and abdominal dissemination is unusual, but when present it primarily involves the liver and spleen. However, primary lymphoma of the adrenal glands is rare. The majority of reported cases presented with a B-cell immunophenotype. Herein, we report the case of a patient with T-lymphoblastic leukemia/lymphoma who presented predominantly with bilateral adrenal masses without lymphadenopathy, and whose clinical course deteriorated rapidly.

Efficacy and feasibility of gemcitabine and carboplatin as first-line chemotherapy in elderly patients with advanced non-small cell lung cancer / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Although platinum-based chemotherapy is a standard first-line treatment in advanced non-small cell lung cancer (NSCLC), further research for the safety and efficacy of combination chemotherapy in elderly patients has been required. The purpose of this study was to evaluate the efficacy and safety of gemcitabine and carboplatin as first-line treatment in elderly patients with advanced NSCLC and to evaluate the prognostic factors.</p><p><b>METHODS</b>Eligibility included: (1) age of 70 years or more, (2) histologically confirmed NSCLC, (3) chemotherapy-naïve, (4) advanced disease with stage IIIB or IV, (5) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2, (6) adequate organ function. Patients received intravenous carboplatin (area under curve (AUC) = 5) on day 1 and gemcitabine (1000 mg/m2) on days 1 and 8, every 3 weeks.</p><p><b>RESULTS</b>The medical records of forty patients were reviewed retrospectively. Median age was 73.9 years (range, 70-84.6), and there were 27 men (67.5%). Thirty-seven patients (92.5%) had ECOG PS 0-1. Adenocarcinoma was found in 57.5%. Median cycles were administrated with 4.5 per person (range: 1-6). Best responses were partial response in 22 (55.0%) patients and stable disease (SD) in 13 (32.5%). The median progression free survival (PFS) and overall survival (OS) were 5.9 months (95% CI: 4.5-7.3 months) and 9.6 months (95% CI: 8.2-11.0 months), respectively. Grade 4 hematologic toxicities for neutropenia (7.5%), thrombocytopenia (7.5%) and anemia (5.0%) were observed. Histology was significant prognostic factor for PFS (P = 0.024).</p><p><b>CONCLUSION</b>Gemcitabine and carboplatin combination chemotherapy is an effective and manageable treatment option in elderly advanced NSCLC patients with good performance status.</p>

Interstitial Pneumonitis after Treatment with Pemetrexed for Non-small Cell Lung Cancer / Journal of the Korean Cancer Association, 대한암학회지

Pemetrexed is approved as a first-line treatment for advanced non-squamous non-small cell lung cancer (NSCLC) with cisplatin and as a single agent for second-line treatment or for patients who show no disease progression after four cycles of platinum-based doublet induction chemotherapy as maintenance therapy. Pemetrexed has a modest toxicity profile and has not traditionally been regarded as a cause of interstitial pneumonitis. Here, we report on a rare case of pemetrexed-induced pneumonitis in a patient with NSCLC.

A Case of Eosinophilia as a Manifestation of Paraneoplastic Syndrome in Non-Small-Cell Lung Cancer / 대한내과학회지

Eosinophilia is most frequently associated with asthma, allergic conditions, and parasitic infestation. Eosinophilia can also be associated with many forms of cancer. However, eosinophilia is infrequently associated with solid tumors. We experienced a 73-year-old-woman with eosinophilia as a manifestation of paraneoplastic syndrome that was combined with non-small-cell lung cancer (NSCLC). Initially, she was diagnosed with idiopathic hypereosinophilic syndrome, but was diagnosed with NSCLC 1 month later. Here, we report this case with a brief review of the literature.

Delayed Transfer of Major Trauma Patients Under the Current Emergency Medical System in Korea

PURPOSE: Major trauma patients should be transferred to a definitive care facility as early as possible because prompt management will prevent death. This study was designed to discover the obstacles leading to delayed transfers under the current emergency medical system in Korea and whether there are any negative outcomes associated with conducting procedures at primary care hospitals prior to transferring patients to higher levels of care. METHODS: The medical records of major trauma patients with an Injury Severity Score above 15 within the past year were reviewed. Patients were divided three groups as follows: (A) came directly to our emergency center, (B) were transferred without CT or MRI scan at the primary care hospital and (C) transferred with CT or MRI scans. The transfer time of each group were compared and analyzed statistically. Additionally, the number and type of imaging performed at the primary care hospital were analyzed. RESULTS: All qualified patients (n=276) were enrolled in this study: 121 patients in group A; 104 in group B; 51 in group C. There was a statistically significant difference in the transfer time between the three groups (p-value<0.001), and 79 (28.6%) were transferred to an emergency medical center within one hour. In group C, CT or MRI scans were performed an average of 1.86 times at the primary care hospital, and the median transfer time was 4 hours 5 minutes. CONCLUSION: Only 28.6% of the cases in the study arrived within the golden hour at a definitive care facility. Such delays are in part the result of prolonged times at the primary care hospital for radiologic examinations, such as CT or MRI scans. Major multiple trauma patients should be transferred to a definitive care facility directly or as soon as the primary survey and the resuscitation of Advanced Trauma Life Support guideline are completed at the primary care hospital.

Experience with the Treatment of Patients with Major Trauma at the Department of Trauma Surgery in One Regional Emergency Medical Center for One Year

PURPOSE: Recently, social interest in an organized trauma system for the treatment of patients has been increasing in government and academia and the establishment of trauma center is being considered across the country. However, establishing such a system has not been easy in Korea, because enormous experiences and resources are necessary. The objectives of this study were (1) to estimate a trauma patient's demands during the course of treatment and (2) to provide appropriate direction for trauma centers to be established in Korea. METHODS: The records of 207 patients who were admitted to the Department of Trauma Surgery in Ajou University Medical Center due to trauma were retrospectively reviewed for a 1 year period from March 2010 to February 2011. Patients were reviewed for general characteristics, number of hospital days, numbers and kinds of surgeries, numbers and kinds of consultations, ISS (Injury Severity Score) and number of patients with ISS more than 15. RESULTS: All 207 patients were enrolled. The average number of hospital days was 36.7 days. The ICU stay was 15.9 days, and the general ward stay was 20.8 days. Admitted patients occupied 9.02 beds in ICU and 11.80 beds in the general ward per day. The average number of surgeries per patient was 1.4, and surgery at the Department of Trauma Surgery was most common. Number of consultations per patient was 14.23, and consultations with orthopedic surgeons were most common. The average ISS was 18.6. The number of patients with ISS more than 15 was 141 (61.8%) and the average number of patients treated per trauma surgeon as a major trauma patient was 94.3. The number of mortalities was 20, and the mortality rate was 9.7%. CONCLUSION: To reduce mortality and to provide proper treatment of patients with major trauma, hospitals need some number of beds, especially in the ICU, to treat patients and to prepare them for emergent surgery. An appropriate number of trauma surgeons and various specialists for consultation are also needed.

A Case of Immune Thrombocytopenic Purpura Developing after Treatment for Non-Hodgkin's Lymphoma / 대한혈액학회지

Immune thrombocytopenic purpura (ITP) can be classified as primary or secondary according to the presence of an underlying non-malignant or malignant disorder, including lymphoproliferative disorders. The estimated prevalence of ITP in patients with Hodgkin's lymphoma is about 1%, and its clinical course has been reported in approximately 50 patients. ITP is an unusual and poorly documented complication in patients with non-Hodgkin's lymphoma. Some cases have been described in patients who have undergone high-dose chemotherapy and autologous bone marrow/peripheral blood stem cell transplantation. Rare cases appear to be coincidental. Here, we report on a rare case of a 61-year-old man who had ITP after being in a state of complete remission of non-Hodgkin's lymphoma for about 15 months.

Communication Skills Improvement of Medial Students According to Length and Methods of Preclinical Training / 한국의학교육

PURPOSE: The purpose of this study is to evaluate the changing pattern of communication skills of medical students according to length and methods of training. METHODS: We evaluated a 1-week communications training course in 2003, a 1-year course in 2004, and a 1-semester course in 2005 during development of our curriculum. We have conducted the 10-minute CPX on abdominal pain annually since 2002 to assess the clinical performance of medical students who have completed the 3rd year clerkship. We selected CPX videos that were appropriate for assessment. One hundred sixty-four videos were available (1-week didactics: 42 cases, 1-week training: 28 cases, 1-semester training: 50 cases, 1-year training: 44 cases). We developed a 10-item global rating checklist to assess communication skills. A 5-point Likert scale was used to evaluate each item (4-very likely, 0-least likely). Two expert standardized patient (SP) raters evaluated the communication skills of students independently. We analyzed the outcomes based on the training length and methods. The reliability (G coefficient) was 0.825 with 2 SPs and 1 station. RESULTS: The communication skills of students improved with practice and longer training, especially with regard to opening the interview, expressing empathy, understanding the patient's perspective, and preparing for the physical examination. Rapport-building, organization of the interview, understandable explanation, nonverbal communication, active listening and consideration during the physical examination was unchanged between durations of training. The scores for empathetic expression, active listening and understanding the patient's perspective were low across all groups. CONCLUSION: We should concentrate our efforts to improve students' skills in empathetic expression, active listening and understanding the patient's perspective.

Clear Cell Carcinoma of the Pancreas: A Case Report and Review of the Literature / Journal of the Korean Cancer Association, 대한암학회지

Most of the malignant neoplasms of the pancreas demonstrate features that are consistent with adenocarcinoma. According to the WHO classification, primary clear cell carcinoma of the pancreas is rare and it is classified as a "miscellaneous" carcinoma. In addition, there is not an adequate systematic overview that can demonstrate its true existence as a definable entity. We report here on an unusual case of primary pancreatic clear cell carcinoma, which is the first such reported case in Korea. A 66 year old woman presented with abdominal pain and significant weight loss over the previous three weeks. On the abdominal computed tomography (CT), we detected an abdominal mass involving the pancreas tail and liver, and clear cell carcinoma with rhabdoid feature was seen on the histologic evaluation. The tumor cells showed well defined cell membranes, clear cytoplasm and prominent cell boundaries. The immunohistochemical stains showed positive reactions to antibodies against pan-cytokeratin, cytokeratin 7, carcinoembryonic antigen (CEA) and epithelial membrane antigen (EMA). On the other hand, there was a negative reaction for cytokeratin 20, chromogranin, synaptophysin, smooth muscle actin and HMB-45. She was diagnosed with a primary pancreatic clear cell carcinoma with hepatic metastasis and she received palliative gemcitabine chemotherapy. The patient died one month later of pancreatic cancer progression.

Evaluation of the Genotypes of the Lewis Blood Group in a Korean Population Using Direct Sequencing / 대한혈액학회지

BACKGROUND: The FUT2 and FUT3 genes determine the Lewis phenotype of red blood cells (RBCs). Recently, the Lewis genes, the secretor genes, and several mutations that cause Lewis negative and nonsecretor phenotypes have been identified. The purpose of this study was to analyze the gene frequency of FUT2 and FUT3 in a Korean population by comparing the use of the direct sequencing method to the use of the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method for mutation detection in the FUT2 and FUT3 genes. METHODS: RBCs and peripheral blood leukocytes were obtained from 225 apparently healthy volunteers to determine the phenotype and genotype of the FUT2 and FUT3 genes. Lewis phenotypes were determined on K3EDTA-stablized fresh blood samples using the column agglutination method. Lewis blood group genotyping was performed by use of the direct sequencing method. For the detection of T59G, C357T, and A385T mutations, the PCR-RFLP method was performed. RESULTS: The frequencies of the Lewis blood group phenotype were 12.4% for Le(a+b-), 70.7% for Le(a-b+), 11.1% for Le(a-b-) and 5.8% for Le(a+b+), respectively. Direct Sequencing of the FUT2 gene identified 92.2% C357T, 56.9% A385T, 0.4% G244A mutations and 1.8% del396. Direct Sequencing of the FUT3 gene identified 46.9% T59G, 30.4% G508A, 1.1% T202C, 1.1% C314T, 0.7% A1029G, 3.0% T1067A and 13.3% G1242A mutations. The PCR-RFLP method results were discordant in nine cases (1 case for C357T, 4 cases for A385T and 2 cases for T59G) as compared to the direct sequencing method results. CONCLUSION: We have determined the frequencies of FUT2 and FUT3 gene mutations in a Korean population. The use of the direct sequencing method was more accurate than the use of the PCR-RFLP method for the determination of the genotype of the FUT2 and FUT3 genes.

Experience of Clinical Performance Examination in Ethical Dilemma / 한국의학교육

PURPOSE: Ethics objective structured clinical examination (OSCE) scenarios was developed and were applied to medical students to see whether it would be suitable for assessing the students' ethical behaviors. METHODS: The data for this study were gathered from the end-of-clerkship patient-doctor-society OSCE, involving third-year medical students along the academic year of 2006. 54 students who participated in the ethics OSCE, which consisted of three stations, responded. Nine standardized patients (SPs) participated in the evaluation. The SPs were trained for 4 hours to conduct the medical interview and for 2 hours for evaluating students' performance using the checklist for each station. RESULTS: The consistency (Cronbach's alpha) of the SPs was 0.796. Mean score was 57.33. There was no difference among circuits and gender. CONCLUSION: We found that the ethics OSCE was adequate for evaluating students' performances.

A Case of Polycythemia Vera Combined with Focal Segmental Glomerulosclerosis / 대한혈액학회지

Polycythemia vera (PV) is a myeloproliferative disorder that results from clonal expansion of a transformed hematopoietic stem cell, and this is associated with a prominent overproduction of erythrocytes, and to a lesser extent, expansion of the granulocytic and megakaryocytic elements. Secondary polycythemia is occasionally associated with renal diseases such as renal tumors, cysts, hydronephorosis, renal transplantation, renal artery stenosis and Bartter's syndrome, and it is rarely associated with nephritic syndrome, nephrosclerosis, chronic glomerulonephritis (GN) and membranous nephropathy. Although cases of erythrocytosis with concomitant GN have occasionally been reported, there are few reports regarding PV. Focal segmental glomerulosclerosis (FSGS) is one of the most frequent forms of GN. However, its association with PV has rarely been described. We report here on one patient with concomitant PV and FSGS along with a review of the previously reported literature.

A case of Wegener's granulomatosis complicated by non-small cell lung cancer / 대한내과학회지

Vasculitis may be a manifestation of the paraneoplastic syndrome in association with solid and hematological cancers. There are few reports of paraneoplastic antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in patients with solid tumors. Wegener's granulomatosis is a systemic vasculitis characterized by necrotizing granulomatous vasculitis of the upper and lower respiratory tracts together with glomerulonephritis and are ANCA-positive. We experienced a case of Wegener's granulomatosis complicated by non-small cell lung carcinoma (NSCLC) and we report this case with a brief review of the literature.

Two Cases of Intravascular Lymphomatosis / 대한혈액학회지

Intravascular lymphomatosis is a rare lymphoma characterized by neoplastic proliferation of malignant cells within the lumen of small blood vessels, usually presenting in the central nervous system or on the skin. Intravascular lymphomatosis is manifested clinically by fever, dementia, cutaneous nodules or plaques, and occasionally, dyspnea. The diagnosis of intravascular lymphomatosis is difficult because of misleading clinical features mimiking vasculitis, infection, stroke, or other neoplasm. We report two cases of intravascular lymphomatosis pesented as fever and skin rash. Those are confirmed by involved tissue biopsy. All cases were treated by combination chemotherapy, but the response was not good. Infectious problems were complicated and disease were progressed.

Docetaxel and cisplatin combination chemotherapy for advanced gastric cancer failed to 5-fluorouracil-based chemotherapy / 대한내과학회지

BACKGROUND: There is no effective treatment in patients with advanced gastric cancer failed to first-line chemotherapy. Taxane is one of new drugs identified as having substantial activity in gastric cancer. We performed a phase II trial to evaluate the efficacy and toxicity of docetaxel plus cisplatin regimen as a salvage chemotherapy for advanced gastric cancer failed to 5-fluorouracil (5-FU)-based chemotherapy. METHODS: Metastatic or recurrent gastric cancer patients failed to 5-FU-based regimen with an Eastern Cooperative Oncology Group (ECOG) performance score < or = 2 were eligible in this trial. Docetaxel (60 mg/m2) was infused over 1 hour, before cisplatin (60 mg/m2) infused over 2 hours on day 1, once every 3 weeks until disease progression or unacceptable toxicity was detected. Response to treatment was assessed every two or three cycles. RESULTS: From October 1999 to December 2000, forty-one patients were enrolled in this study. Twenty-eight of forty-one patients were assessable for response. Partial response was observed in seven patients and stable disease in four patients. The response rate was 25.0% (95% confidence interval: 20.4~29.6%) and median duration of response was 22 weeks (range: 11~53 weeks). The median survival of all enrolled patients was 24 weeks (range: 7~65 weeks). For a total of 112 cycles of chemotherapy, grade 3 and 4 toxicity was 8.9% for neutropenia, 4.5% for nausea/vomiting and 1.8% for mucositis. CONCLUSION: Salvage chemotherapy with docetaxel plus cisplatin regimen in gastric cancer was active with acceptable toxicities.

Adenocarcinoma of Unknown Primary Site

BACKGROUND: Metastatic cancer of unknown primary site occupies 0.5~10% of all diagnosed cancer patients and includes various tumors with diverse responses to systemic chemotherapy. Adenocarcinoma of unknown primary site (ACUPS), the most common subtype, has no standard treatment, rarely responds to conventional treatment and has a poor survival rate. METHODS: The retrospective study was performed to investigate the clinical characteristics and the treatment outcomes of ACUPS. RESULTS: Eighty-one patients with ACUPS diagnosed at Samsung Medical Center from May 1995 to July 1999 were included. The median age was 58 years (range, 29~77). The common sites of metastases were the lymph node, liver, lung and bone in order. In 49 of 81 patients (60.5%), the dominant tumor location was below the diaphragm. The majority of patients (76 of 81) were initially treated with systemic chemotherapy including cisplatin. Responses were evaluable in 70 of 76. Eighteen of 70 patients (25.7%) responded to chemotherapy and complete remission was observed in 6 patients. The overall median survival of 81 patients was 5.6 months. The median survival of the responding patients was 18.3 months but the median survival of the nonresponding patients was 4.6 months (p<0.01). In univariate and multivariate analysis, age, performance status and response to initial chemotherapy were significant prognostic factors for overall survival. CONCLUSION: We observed poor response to the treatment and survival rate in ACUPS, but complete remission and long-term survival were observed in a small number of patients.

A case of MALT lymphoma of the urinary bladder / 대한내과학회지

Primary lymphoma of the urinary bladder is a rare non-epithelial bladder tumor accounting for less than 1% of all bladder tumors. Approximately 17 cases of MALT lymphomas of bladder have been reported in the literature. Most reported MALT lymphomas of bladder have a female sexual preponderance with a mean age of 58 years with common presenting symptoms of hematuria, dysuria and urinary frequency. The reported prognosis of MALT lymphoma of the urinary bladder is excellent. We report a case of MALT lymphoma of urinary bladder in a 57-year-old woman patient who presented with a two-year history of persistent dysuria and urinary frequency. An intravenous pyelogram and cystoscopy revealed a 1 cm focal elevated lesion at the base of urinary bladder. The tissue obtained by transurethral resection (TUR) showed plasma cell infiltration consistent with low grade marginal zone B cell lymphoma. The immunohistochemical studies showed an immunoglobulin restriction to lambda light chain while the nested polymerase chain reaction analysis of the tissue showed a monoclonal Ig heavy-chain gene rearrangement. The clinical staging protocol revealed that the tumor was primarily arising from the urinary bladder with no evidence of other site involvements. The patient received radiation therapy of 3060 cGy in 17 fractions.