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A 52-year-old woman was presented with abdominal distension. Chest-abdominal CT showed some tumors in the left breast, enlarged axillary lymph nodes, ovary metastasis peritoneal thickening, a large amount of ascites. The diagnosis of needle biopsy in the breast mass was invasive ductal carcinoma, Luminal A type. The large amount of ascites decreased after the start of administration of fulvestrant and CDK4/6 inhibitor(PAL). Also chest and abdominal CT showed reduction of all lesions. We found the high expression of cyclin D1 protein and the negative of p16 protein in tissues of the needle biopsy. Fifty months later, she continues to do good ADL and PR status. We experienced a case of metastatic breast cancer with massive ascites and peritoneal metastasis that was successfully treated with a CDK4/6 inhibitor(PAL)and achieved long- term survival.

The patient is a 51-year-old female with comorbidity of schizophrenia. At the age of 41, she underwent surgery for bilateral breast cancer. Both sides were of the Luminal type, with Stage ⅢC on the right and Stage 0 on the left. She started to receive adjuvant chemotherapy but it was interrupted according to her wish. Approximately 3 years ago, she developed carcinomatous pleuritis, multiple liver metastases, and bone metastases. Despite receiving chemotherapy, her condition worsened. A BRACAnalysis revealed pathogenic variants in BRCA2. Upon initiating treatment with olaparib, both her liver metastases and carcinomatous pleuritis have shown reductions, and her tumor markers have also started to decline. Approximately 5 months after treatment with olaparib, it has been possible to continue without any side effects. Olaparib has shown good results in patients with germline BRCA1/2 mutation-positive HER2-negative advanced/recurrent breast cancer who have a history of receiving anthracycline and taxane-based therapies. It was considered that even in recurrent breast cancer, the presence or absence of BRCA1/2 mutations should be actively sought even in advanced cases, and the administration of olaparib should be considered.

We herein describe our experience with patients who had been diagnosed with BRCA1/2 pathogenic variants and metastatic breast cancer. Three patients who experienced postoperative recurrences had received chemotherapy before recurrence, while an additional patient with stage Ⅳ disease at diagnosis required chemotherapy before olaparib administration. Prior anthracycline and/or taxane-based therapies needed prior to administration of poly(adenosine diphosphate ribose) polymerase inhibitors might still be controversial in terms of patient benefits.

This report describes a 69-year-old man with eosinophilia that was detected during a medical check-up. A review of his medical history revealed that his absolute eosinophil count was 990/µl at the age of 55 and increased to 5,380/µl at the age of 69. Electrocardiogram revealed first-degree atrioventricular block at the age of 58, followed by ST-segment depression and a negative T wave at the age of 65. The echocardiogram was normal at the age of 65. We diagnosed him with FIP1L1::PDGFRA-positive chronic eosinophilic leukemia by detecting the FIP1L1::PDGFRA fusion gene by fluorescence in situ hybridization. He had no symptoms at the first visit; however, echocardiography and contrast-enhanced computed tomography revealed an abnormal structure, considered a thrombus, within the left ventricular apex and apex wall thickening. We initiated imatinib (100 mg/day), and the eosinophilia disappeared in a month. However, his cardiac impairment worsened, and he gradually developed symptoms of heart failure. This case is valuable because it shows the long-term course of the disease, with 15 years of laboratory findings until diagnosis. Our findings suggest that in cases of eosinophilia with an abnormal electrocardiogram, contrast-enhanced cardiac magnetic resonance imaging should be considered earlier.

The patient is a 67-year-old woman who underwent surgery for left breast cancer in 1990 and right breast cancer in 2003. In 2013, local recurrence of right breast cancer was detected. Then she underwent removal of the local recurrence, axillary lymph node dissection, and post mastectomy irradiation. In 2017 lung metastasis appeared, and she underwent endocrine therapy and chemotherapy. BRCA1/2 analysis showed BRCA1 mutation, so olaparib was started in 2020. The metastatic lesions were reduced markedly, and the skin metastases were crusted over. Although it is necessary to decide when to use olaparib in each case, there is a possibility that olaparib may be effective even in the terminal stage, and it may be considered as one of the treatment options.

Palbociclib, a CDK4/6 inhibitor, is found to be an effective therapeutic drug in the treatment of estrogen receptor positive (ER+)metastatic breast cancer. In this report, we describe a case of rapid progression of life-threatening multiple bone metastases of breast cancer treated with a combination of fulvestrant and palbociclib. The patient, a 58-year-old postmenopausal woman, was diagnosed with left breast cancer at the age of 43 years and underwent breast-conserving surgery. After the completion of postoperative adjuvant endocrine therapy and radiotherapy, the patient was placed on regular follow-up. Eleven years after the surgery, multiple bone metastases and multiple lymph node metastases occurred, and the patient was treated with letrozole as first-line therapy for recurrent breast cancer. Although she continued to receive this treatment for 2 years and 10 months, her general condition worsened due to the occurrence of new liver metastases and the rapid progression of existing metastatic lesions. Thus, she was sent to an emergency room. Marked hypercalcemia and a severe decrease in erythrocyte and platelet counts were observed, which could be the cause of her worsening general condition. Her performance status(PS)was 4, and palliative treatment was also considered. However, she received treatment for hypercalcemia and red blood cell transfusion; as a result, she recovered to the PS 2 where she could begin chemotherapy. Then, she began a treatment consisting of a combination of fulvestrant and palbociclib as a second-line treatment for the recurrence. The patient responded well to the treatment, and her general condition improved to PS 1. She has since maintained a good quality of life for 2 years and 11 months without serious adverse events. In conclusion, the combination of fulvestrant and palbociclib has a low risk of serious adverse events and is a worthwhile treatment for rapidly progressing, life-threatening multiple bone metastases of breast cancer.

A 44-years-old woman who underwent bilateral mastectomy was treated with chemotherapy after axillary lymph nodes and liver metastases recurrence. She was referred to our hospital for BRCA1/2 germline test and the test revealed BRCA2 pathogenic mutation. Before the administration of olaparib as the fourth-line therapy, liver dysfunction, caused by extensive liver metastasis, was observed. The liver damage improved, and tumor markers decreased immediately as shown in the blood test and CT examination results after 2 months; indicating marked reduction of liver metastasis. In the OlympiAD trial, the patients received olaparib as either the first-, second- or third-line treatment; however, few data on the efficacy of olaparib in the patients, as a late line treatment, were reported. In this article, we report a case of a woman in whom olaparib was used as the fourth-line treatment for metastatic recurrent breast cancer. A high therapeutic effect was obtained and the quality of life has been maintained in her for the past 1 year.

Olaparib, an anticancer drug, requires daily administration, frequently causing nausea. Elucidation of the influential factors for nausea is important for continuing treatment. We retrospectively examined 23 patients who received olaparib treatment and were divided into nausea and no-nausea groups, according to antiemetic prescriptions during treatment. We compared the patients' background and laboratory values between the 2 groups. Nine patients developed nausea and 14 did not, with mean body weights at treatment initiation of 49.9±9.8 kg and 60.0±13.9 kg, respectively. Body weights were significantly lower in the nausea than in the no-nausea group. Four weeks after olaparib administration, the logarithmic difference in the fluctuation of the neutrophil count was -0.145±0.154 and 0.095±0.242, while the fluctuation of the lymphocyte count was -0.169±0.053 and -0.060±0.110 in the nausea and no-nausea groups, respectively, with the former significantly lower than the latter. The treatment period for the nausea group was significantly longer than that for the no-nausea group. Since olaparib is administrated as a flat dose, the dose per body weight increased in underweight patients. Thus, being underweight might have impacted the efficacy of olaparib, including the development of side effects such as nausea and hematotoxicity.

A 58‒year‒post‒menoposal woman was presented with left chest pain and shortness of breath because her breast cancer metastasized to the skin, lung, and pleural dissemination. In late‒line treatment for hormone receptor‒positive HER2‒negative advanced/recurrent breast cancer, we experienced a patient with tumor shrinkage leading to pain relief who was treated with a second combination of a CDK4/6 inhibitor and fulvestrant. Due to her poor performance status, she was treated with combined therapy to avoid severe adverse events. The CDK4/6 inhibitor was reintroduced after 1.5 years withdrawal period of endocrine therapy during anticancer drugs and radiation treatment. It has also been reported that withdrawal of CDK4/6 inhibitors might restore susceptibility related to the inhibitory signal. Rather than sequentially administering combined endocrine therapy with a CDK4/6 inhibitor, the withdrawal strategy of endocrine therapy continuing to administer anticancer drugs should be considered in case of reintroduction of CDK4/6 inhibitor.

We report the case of a 72‒year‒old woman with ER(+), PgR(+), HER2(-)metastatic breast cancer with liver involvement. The patient received palbociclib(125 mg daily po 3 weeks on/1 week off)and fulvestrant(500 mg im on days 1, 15, and 29, and once monthly thereafter)as second‒line endocrine therapy. Her metastatic liver lesions initially decreased in size and the tumor‒marker CA15‒3 level decreased. However, they progressed after seven months of therapy. She was subsequently switched to abemaciclib(150 mg twice/daily po)with fulvestrant as third‒line therapy, resulting in a decrease in the same liver lesions. She has continued treatment for 12 months. Based on this case, abemaciclib may be clinically useful for breast cancer that is not responsive or has become resistant to palbociclib, another selective CDK4/6 inhibitor.

Breast cancer patient(invasive ductal carcinoma, ER[+], PgR[+], HER2[3+], Ki-67: 30%)had neoadjuvant chemotherapy( FEC followed by docetaxel plus trastuzumab). After surgical operation(mastectomy and Ax)was performed and she received trastuzumab plus hormone therapy. After 2 years later, she had liver metastasis that showed IDC, ER(+), PgR (+), HER2(-). In addition, BRCA positive was shown. Therefore, the patient received olaparib tablets(300 mg twice daily). After 2 months later, liver metastasis reduced dramatically.

In 2018, olaparib, a PARP inhibitor, was approved for the treatment of BRCA1/2 gene-mutation positive and HER2-negative inoperable and recurrent breast cancer; BRCA1/2 gene testing was also listed as a companion diagnostics. Here, we identified microRNAs(miRNAs) expressed after treatment with olaparib, which differed in the presence or absence of BRCA1 mutations in triple negative breast cancer(TNBC), and examined the changes in miRNAs after exposure to the combination of the PARP-1 inhibitor and a chemotherapeutic agent. After exposure to the PARP-1 inhibitor, the expression of miR-141, miR-155, miR-205, and miR-223 decreased in MDA-MB-231, HCC1143, and BT549 cells and increased more than 10 times in MDA-MB-436 cells. Moreover, the expression of miR-141 in MDA-MB-436 cells treated with the PARP-1 inhibitor together with gemcitabine increased more than 10 times; additionally, the expression of miR-205 increased more in the context of combination therapy versus single exposure to olaparib. The miR-200 family(including miR-141)and miR- 205 are known to function as ZEB1/2 targets and to act as epithelial-to-mesenchymal transition(EMT)-suppressors. Overall, these results suggest that it may be possible to recover the sensitivity of TNBC cells to chemotherapy via the suppressing EMT through the use of a PARP-1 inhibitor in the context of BRCA1 mutation.

We reviewed our clinical experience of olaparib treatment for patients with platinum-sensitive recurrent ovarian, fallopian tube, and peritoneal cancer. Of the 10 cases, the primary sites of cancer were the ovaries, fallopian tubes, and peritoneum in 7, 1 and 2 cases, respectively. The median period of treatment administration was 10 months. The observed Grade 3 or 4 adverse events as per the Common Terminology Criteria for Adverse Events version 4.0 were: anemia, leukopenia and neut r openia in 4, 4 and 3 cases, respectively. Eight cases needed treatment to be interrupted, and 5 cases required a reduction in dose. Three patients were treated for more than 12 months, while the others had to discontinue due to disease progression. However, none of the patients had to discontinue treatment due to adverse events. Therefore, it appears that olaparib can be safely used despite some patients requiring a withdrawal or reduction in treatment.

The study subjects consisted of 54 patients with inoperable or recurrent breast cancer who were administered a combination of palbociclib plus endocrine therapy. We examined the onset of neutropenia during the first course of treatment and evaluated the influence that various risk factors had on treatment continuity. Patients with neutropenia Grade≥3 had significantly lower relative dose intensity(RDI) values during the first course of treatment than did patients with neutropenia Grade ≤2. Patients with neutropenia Grade≥3 showed significantly longer treatment to failure than did patients with neutropenia Grade≤2. These results suggest that the degree of neutropenia during the first course of treatment might contribute to treatment continuity and that it is important to improve the curative effect by maintaining appropriate RDI and by continuously administering palbociclib in patients with neutropenia Grade≥3.

A 67-year-old man presented with abdominal pain and fever. Many abdominal tumors were detected by enhanced computed tomography(CT). The largest tumor, measuring 20 cm, had perforated the ileum and formed an abscess. Emergency surgery was performed to remove multiple tumors in the peritoneal cavity as much as possible. Immunostaining showed c-kit and CD34 positivity, and the tumors were diagnosed as gastrointestinal stromal tumor(GIST). During postoperative imatinib therapy for the residual tumor, low-dose intermittent administration was required due to side effects, but the disease was controlled for over 91months. For advanced GIST with peritoneal dissemination, 200mg/day imatinib or intermittent administration after volume reduction surgery might be effective depending on the patient's general condition.

We report a case of gastrointestinal stromal tumor(GIST)with long-term survival treated by multidisciplinary therapy, including surgery and imatinib to prevent repeated recurrence. A 76-year-old woman visited our hospital with difficulty in defecation and bloody bowel discharge. She was diagnosed with rectal GIST and underwent transanal partial resection of the rectum. Local recurrence occurred 1 year after the operation, and the tumor was resected transanally. Hepatic metastasis occurred 8 months after the second operation. The patient was administered imatinib for 2 months, which caused the tumor to shrink, and extended left lobectomy was performed. Imatinib was administered for 2 years after hepatectomy. After another 2 years, metastasis to the liver and thoracic and lumbar vertebrae occurred. The recurrent tumors reverted to cystic lesions after 6 months of imatinib treatment. She has been alive without tumor progression during re-treatment with imatinib for 7 years(13 years after the first surgery).

Kinase cascades are involved in all stages of tumorigenesis through modulation of transformation and differentiation, cell-cycle progression, and motility. Advances in molecular targeted drug development allow the design and synthesis of inhibitors targeting cancer-associated signal transduction pathways. Potent selective inhibitors with low toxicity can benefit patients especially with several malignancies harboring an oncogenic driver addictive signal. This article evaluates information on solid tumor-related kinase signals and inhibitors, including receptor tyrosine kinase or serine/threonine kinase signals that lead to successful application in clinical settings. In addition, the resistant mechanisms to the inhibitors is summarized.

We report a case of a large gastric gastrointestinal stromal tumor (GIST), which became resectable and achieved pathological complete response after neoadjuvant chemotherapy with imatinib mesylate. A 59-year-old man presented with left hypochondrial pain. Abdominal computed tomography (CT) revealed gastric GIST invading the spleen and the diaphragm. Administration of imatinib mesylate was initiated as neoadjuvant chemotherapy. Six months after neoadjuvant chemotherapy with imatinib mesylate, abdominal CT revealed a reduction in tumor size. We judged the tumor resectable and performed partial gastrectomy and splenectomy. Histologically, number of myofibroblasts increased, but no viable tumor cells were observed. Pathological complete response was obtained.

Primary effusion lymphoma (PEL) is a rare B-cell lymphoma, characterized by human herpes virus 8 (HHV8) infection and serous effusions without detectable tumor masses. However, cases with HHV8 unrelated PEL have also been reported, mainly in Japan, and these are referred to as PEL-like lymphoma (PEL-LL). We describe a 70-year-old man with cardiac comorbidity who developed PEL-LL with pleural effusion. The patient achieved a complete response (CR) after treatment with oral low-dose sobuzoxane and etoposide combined with rituximab. To date, the patient has been in CR for about 7 months without chemotherapy. PEL-LL reportedly has a better prognosis than PEL. Because PEL-LL is positive for CD20, unlike PEL, combination therapy including rituximab may be effective. PEL-LL mainly affects elderly people, so that further investigation of tolerable and effective regimens is required.

The patient was an 82-year-old man who had undergone resection of a gastrointestinal stromal tumor(GIST)of the small intestine in January 2000, when he was 69 years old. As peritoneal recurrences were diagnosed in June 2002, we performed peritoneal tumorectomy twice, and the perirectal tumor was controlled with imatinib for over 7 years. Resistance to imatinib was diagnosed in March 2011, and treatment was switched to sunitinib. Administration of sunitinib was started at 50mg/day for 28 days followed by treatment withdrawal for 14 days; however, the dose needed to be reduced twice and then discontinued owing to the occurrence of side effects and pemphigoid. During discontinuation of sunitinib, the tumor increased in size and cancer pain appeared; therefore, sunitinib was re-administered at a very low-dose of 12.5mg every alternate day. Low dose sunitinib was effective; the perirectal tumor was reduced and cancer pain disappeared.

Dolutegravir (DTG) is a once-daily, unboosted integrase inhibitor that has been shown to be effective by once daily dosing. The impact of race on dolutegravir pharmacokinetics has not yet been fully characterized. This study was a Phase 1, open label, single dose study to determine pharmacokinetics (PK), safety and tolerability of DTG following 50mg single oral administration in the fasted state in healthy adult Japanese subjects. Subjects had a screening visit within 30 days prior to the administration of study drug, and a follow-up visit within 7 to 14 days after the administration of study drug. Safety evaluation and serial PK samplings were performed pre-dose and for 72 hours after dosing. Non-compartmental analysis was performed for PK parameter calculation. Data were compared to historical values from a similar Phase 1 study conducted in non-Asian, healthy adult subjects (n = 18, 17 Caucasian and 1 Arabic/North African). Ten subjects were enrolled and completed the study. DTG was well tolerated with no adverse events reported throughout the study period. Geometric means (CV%) of single dose DTG PK parameters in Japanese subjects for C(max), AUC(inf), t1/2 and C24 were 2.14microg/mL (47%), 43.4 microg x hr/mL (46%), 14.6 hours (10%) and 0.67 microg/mL (45%). The pharmacokinetics and safety profiles of DTG following single dose oral administration to Japanese healthy adult subjects were consistent with findings previously observed in non-Japanese healthy adult subjects. DTG may be given to Japanese subjects without dose-adjustment.

In recent years, many analogs of narcotics have been widely distributed as easily available psychotropic substances and have become a serious problem in Japan. To counter the spread of these non-controlled substances, the Pharmaceutical Affairs Law in Japan was amended in 2006 to establish a new category; Designated Substances in order to more strictly control these substances. In April 2007, 31 compounds and 1 plant were first controlled as Designated Substances. Before 2007, the major compounds distributed in the Japanese illegal drug market were tryptamines, phenethylamines and piperazines. Alkyl nitrites, such as isobutyl nitrite and isopentyl nitrite, were also widely distributed. After they were listed as Narcotics or Designated Substances in 2007, these compounds, especially the tryptamines, quickly disappeared from the market. In their place, cathinone derivatives have been widely distributed, as well as different phenethylamines and piperazines. Additionally, in recent years, new herbal products containing synthetic cannabinoids have appeared globally. As at July 2012, 78 substances (including 1 plant; Salvia divinorum) were listed in the category of Designated Substances. They were 13 tryptamines, 17 phenethylamines, 11 cathinones, 4 piperazines, 23 synthetic cannabinoids, 6 alkyl nitrites, 3 other compounds and 1 plant. In this review, we show our survey of the spread of new designer drugs in Japan, focusing especially on synthetic cannabinoids and cathinone derivatives. Also, the prevalence and legal status of these substances in other countries will be presented.

A 77-year-old man with cough and dyspnea was admitted to hospital. Chest X-ray demonstrated reticulated shadows in the bilateral inferior lung fields and marked eosinophilia was detected in peripheral blood. Although he received steroid pulse therapy, eosinophilia became more serious and he was referred to our hospital. Bone marrow examination demonstrated a hypercellular marrow that consisted predominantly of dysplastic eosinophils with differentiation. FISH analysis of bone marrow cells demonstrated 4q12 deletion and RT-PCR analysis detected FIP1L1-PDGFRA fusion gene, leading to the diagnosis of chronic eosinophilic leukemia (CEL). Treatment with low-dose imatinib was immediately initiated; however, drug-induced systemic edema was progressive and became intolerable. Therefore, we changed imatinib to low-dose dasatinib (20 mg/day), resulting in complete molecular response of CEL after 3 months without any severe adverse effects. This is the first report on the efficacy of low-dose dasatinib for the treatment of CEL. The peak level (Cmax) of dasatinib in this patient was 55.3 nM, which exceeded the concentration of dasatinib required to inhibit cells with FIP1L1-PDGFRA by 50%. Thus, low-dose dasatinib with therapeutic drug monitoring can be a useful therapy for imatinib-intolerant CEL even in elderly patients.

Various kinases phosphorylate their substrates and thereby switch on or off their functions. Dysregulation of kinases that regulate cell growth signals induces carcinogenesis or malignant phenotypes in cancer. Therefore, kinases are considered to be most promising therapeutic targets in cancer treatment, and the development of kinase inhibitors has been the most hot area. In this article, the present status and the perspective of kinase inhibitors were described.

Chronic myeloid leukemia (CML) is a paradigm for neoplasias that are defined by a unique genetic aberration, the BCR-ABL1 fusion gene. CML is also the best example for molecular target therapy. The development of protein tyrosine kinase inhibitor, imatinib, has entirely changed the strategy of therapy for CML. Nonetheless, many fields of pathogenesis for CML have not been elucidated, such as the mechanisms of blastic crisis, the causes of genetic instability including the inactivation of tumor suppressor genes, and oncogenic signaling pathways downstreams of the BCR-ABL1 fusion gene product. Herein, we review current knowledge on the molecular pathogenesis of CML.

Calcium channel blockers are most commonly used in hypertensive patients in Japan. However, information on the efficacy and safety of generic calcium channel blockers is insufficient. The objective of the present study was to retrospectively evaluate the efficacy and safety of manidipine hydrochloride in 21 essential hypertensive patients (mean age; 70.6+/-10.6 years, male/female; 14/7) in Sendai Postal Services Agency Hospital who were switched (substituted) from a brand product (Calslot) to a generic product (Manidip). For this retrospective study, we used data from patient medical records and drug prescription information. Data from patients who were taking both types of manidipine hydrochloride, whose regimen were not changed for > 6 months before and after switching, and who provided informed consent were included in the analysis. Control values of blood pressure were not significantly different between before and after substitution (systolic/diastolic; from 137.9+/-9.1/78.7+/-5.4 mmHg to 137.3+/-9.1/77.8+/-6.3 mmHg, p=0.73/p=0.36). The level of patient compliance for the antihypertensive drugs was also not different between before and after substitution (from 94.0+/-8.8% to 93.1+/-9.6%, p=0.72). There were 8 cases of adverse effects before substitution and 4 after substitution. No patient stopped taking the generic drug due to an adverse effect. In conclusion, significant differences in the efficacy, safety, and patient compliance were not observed between the brand product and generic product among patients who were switched from the brand product to the generic product.

Some selective serotonin reuptake inhibitors (SSRIs) have recently been approved for the treatment of anxiety disorders such as obsessive-compulsive disorder, panic disorder and social anxiety disorder, and they are considered first-line treatment for anxiety disorders in Japan as well as in other countries. Previous clinical studies have suggested that the 5-HT2C receptors in subjects with anxiety disorders are hypersensitive. We recently reported that chronic treatment with fluvoxamine or paroxetine desensitized 5-HT2C receptor function. The desensitization of 5-H T2C receptor function has also been reported with other SSRIs and is considered to be a common mechanism of action of SSRIs in the treatment of anxiety disorders. In addition, some studies have suggested that 5-HT2A receptors and 5-HTIA receptors participate in anxiety disorders and the therapeutic mechanism. Both clinical studies and animal studies have indicated that the amygdala plays an essential role in anxiety and fear response. Thus, it may be important to elucidate functional changes in these 5-HT receptor subtypes in brain regions including the amygdala under the chronic administration of SSRIs to understand the anxiolytic mechanism of SSRIs.

Alpha(1)-adrenoceptors are widely distributed in the human body and play important physiologic roles. Three alpha(1)-adrenoceptor subtypes (alpha(1A), alpha(1B) and alpha(1D)) have been cloned and show different pharmacologic profiles. In addition, a putative alpha(1)-adrenoceptor (alpha(1L) subtype) has also been proposed. Recently, three drugs (tamsulosin, naftopidil, and silodosin) have been developed in Japan for the treatment of urinary obstruction in patients with benign prostatic hyperplasia. In this review, we describe recent alpha(1)-adrenoceptor subclassifications and the pharmacologic characteristics (subtype selectivity and clinical relevance) of alpha(1)-adrenoceptor antagonists.

Increasing knowledge of the mechanism of the initiation and progression of various cancers is the catalyst for developing new anticancer therapeutics that target specific molecules expressed in cancer cells. STI571 (imatinib mesylate) is an example of the successful development of a rationally designed and targeted agent. Its target is the constitutively active tyrosine kinase, BCR-ABL in chronic myelogenous leukemia (CML). Clinical studies with STI571 in CML demonstrated that many patients with advanced stage disease respond initially but then relapse. Drug resistance is associated with the reactivation of BCR-ABL signal transduction. Another targeted protein-tyrosine kinase inhibitor that was approved for clinical use is ZD1839 (Iressa). ZD1839 is an orally active and selective inhibitor for epidermal growth factor receptor (EGFR) tyrosine kinase. HER2 is overexpressed in 25-30% of breast cancers and associated with shorter time to relapse and lower survival rate. Specific targeting of these cancers can be accomplished with Herceptin directed against the extracellular domain of the HER2 protein. However, even in the selected group of patients with high levels of HER2, the response to Herceptin is limited in magnitude and duration. The mechanisms of the resistance to these targeted agents were reviewed.

Two cases of metastatic gastrointestinal stromal tumors (GIST) that had responded to the treatment with STI571 were presented. Case 1 was a 49-year-old woman who had undergone proximal gastrectomy because of a giant submucosal tumor of the stomach. For 21 months after surgery, the patient received repeated tumor removal four times due to hepatic metastasis and/or peritoneal recurrence. Thereafter, the treatment with STI571 at a dose of 400 mg/day was initiated. Eight months after the administration, only a small hepatic metastasis was detected on a film of CT scan, and any signs of peritoneal recurrence were observed. Case 2 was a 61-year-old man who underwent emergency surgery for a retroperitoneal tumor that had caused massive intestinal hemorrhage resulting in critical shock. The patient underwent the surgery three times for recurrent lesions. Because further tumor removal had become nearly impossible, STI571 at a dose of 400 mg/day was administered 35 months after initial surgery. Six months after treatment the hepatic lesions were shrunk, but the number of retroperitoneal lesions increased. At present, the patient has no abdominal complaints and has a good quality of life. GIST was confirmed in both cases, by histopathological analyses of the resected specimens: positive expression of c-kit and CD34. These clinical observations suggest that ST1571 therapy for metastatic lesions from GIST may be preferred over aggressive, repeated tumor removal.

The emergence of tumors resistant to anticancer agents has been recognized as one of the major obstacles to effective cancer chemotherapy. Recent studies have elucidated various mechanisms in this resistance, such as induction of drug efflux pumps, in particular certain of the ABC transporters. Experiments to predict the sensitivity of tumors to anticancer agents using DNA microarray and SNPs analyses are ongoing. The development of the new anticancer agent ST1571 and the emergence of tumors resistant to ST1571 indicate the urgent need for clinically available reversing agents.

Recent advances in molecular diagnosis in the hematological laboratory have greatly contributed to the diagnosis and treatment of hematologic malignancies, such as leukemia and lymphoma. The pathogenesis of leukemia and lymphoma has been disclosed by the analyses of genetic abnormalities in patients; abnormal gene expression may induce derangement in the control of cellular proliferation. Based on these genetic abnormalities, gene-targeted therapy has been introduced as a new approach to treating hematologic malignancies. We discuss here the usefulness of the molecular diagnosis in clinical hematology.

Our understanding of the pathological molecular events underlying chronic myelogenous leukemia(CML) has rapidly grown over the past 2 decades. At the same time, new therapeutic modalities for CML which can cure or prolong survival in this formerly incurable disease, including interferon alpha administration and allogeneic hematopoietic stem cell transplantation, have been established. Now, a new molecule-specific drug, a ABL tyrosine kinase inhibitor(STI571), are developing, which is offering new hope for expanded treatment options for patients with CML. Clinical investigators and medical doctors will have responsibility in helping newly diagnosed patients with CML to properly elect treatment planning among the increased options available now. This specific number of JJ CO will be hoped to provide information to many medical oncologists beyond the hematology speciality.

STI571(imatinib) selectively inhibits the ABL-tyrosine kinase, the activity of which is activated by the formation of chimeric BCR/ABL. Phase I study in USA showed a remarkable effectiveness of STI571 in interferon-refractory chronic myelogenous leukemia with little adverse effects. STI571 will plausibly become the first choice drug prior to stem cell transplantation and interferon in the treatment of this leukemia.

Since STI571, a BCR-ABL tyrosine kinase inhibitor, has made a great therapeutic advance in the management of CML, we have to reconsider the treatment protocol for chronic phase CML. Interferon-alpha (IFN-alpha) will be replaced with STI571 therapy. However, some patients are reported to become refractory to STI571, and it is unclear whether STI571 therapy alone may be sufficient to induce long-term survival in CML. There are also important progress in the field of allogeneic hematopoietic stem cell transplantation (SCT); i.e. minitransplant(non-myeloablative SCT) and cord blood stem cell transplantation. Currently, newly-diagnosed CML patients in chronic phase should be initially treated with STI571. If the patients are appropriate candidates for allogeneic SCT and have HLA-indentical sibling donors, allogeneic SCT should be conducted within one year. The other patients should also receive related or unrelated allogeneic SCT if Ph suppression is insufficient with STI571 therapy for several months. The patients who are not candidates for allogeneic SCT may be treated with IFN-alpha and/or Hydrea(or cytosine arabinoside) in addition to STI571 if they become refractory to STI571. Since each therapeutic modality has different risk and benefits, informed consent is very important to determine the treatment plan for individual patients.

STI571, a BCA-ABL tyrosine kinase inhibitor, has appeared in molecular targeted therapy as a new treatment option for patients with chronic myelogenous leukemia (CML) through rational drug development. In a phase I study in the USA, adverse effects were minimal. Complete hematologic response was observed in 98% of patients with chronic phase CML treated with a daily dose of 300 mg or more, and cytogenetic response was seen in 31% of patients. STI571 has substantial activity in the blast crisis of CML and Ph + ALL. Stem cell transplantation (SCT) may be compared with interferon-alpha (IFN-alpha) therapy from three analyses reported according to risk assessment. These studies indicated that SCT increased survival only in patients who were younger and at intermediate or high risk; however, survival with SCT in older patients at higher risk was no better than with IFN-alpha therapy in a Japanese prospective study. An individualized risk assessment-based approach is useful in prioritizing SCT and IFN-alpha in patients with chronic phase CML.