Both New-Onset and Pre-Existing Hypertension Indicate Favorable Clinical Outcomes in Patients Treated With Anti-Vascular Endothelial Growth Factor Therapy.

BACKGROUND: Hypertension is a frequent adverse event caused by vascular endothelial growth factor signaling pathway (VSP) inhibitors. However, the impact of hypertension on clinical outcomes during VSP inhibitor therapy remains controversial.Methods and Results: We reviewed 3,460 cancer patients treated with VSP inhibitors from the LIFE Study database, comprising Japanese claims data between 2016 and 2020. Patients were stratified into 3 groups based on the timing of hypertension onset: (1) new-onset hypertension (n=569; hypertension developing after VSP inhibitor administration); (2) pre-existing hypertension (n=1,790); and (3) no hypertension (n=1,101). Time to treatment failure (TTF) was used as the primary endpoint as a surrogate for clinical outcomes. The median (interquartile range) TTF in the new-onset and pre-existing hypertension groups was 301 (133-567) and 170 (72-358) days, respectively, compared with 146 (70-309) days in the non-hypertensive group (P<0.001 among all groups). In an adjusted Cox proportional hazard model, new-onset (hazard ratio [HR] 0.58; 95% confidence interval [CI] 0.50-0.68; P<0.001) and pre-existing (HR 0.85; 95% CI 0.73-0.98; P=0.026) hypertension were independent factors for prolonged TTF. The TTF of new-onset hypertension was longer than that of pre-existing hypertension (HR 0.68; 95% CI 0.62-0.76; P<0.001). CONCLUSIONS: This study highlighted that new-onset hypertension induced by VSP inhibitors was an independent factor for favorable clinical outcomes. Pre-existing hypertension before VSP inhibitor initiation was also a significant factor.

Early-onset cardiac dysfunction following allogeneic haematopoietic stem cell transplantation.

OBJECTIVE: Heart failure following allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a serious complication that requires early detection; however, the clinical implications of early-onset cancer therapy-related cardiac dysfunction (CTRCD) following allo-HSCT remain unclear. We investigated the determinants and prognostic impact of early-onset CTRCD in allo-HSCT recipients. METHODS: The records of 136 patients with haematological malignancies who underwent allo-HSCT at our institute were retrospectively reviewed. Early-onset CTRCD was defined as a decrease in left ventricular ejection fraction (LVEF) of ≥10% and an LVEF of ≤53% within 100 days after HSCT. RESULTS: Early-onset CTRCD was diagnosed in 23 out of 136 included patients (17%), and the median duration from HSCT to CTRCD diagnosis was 24 (9-35) days. Patients were followed up for 347 (132-1268) days. In multivariate logistic regression analysis, cumulative doxorubicin dosage (each 10 mg/m2) and severity of acute graft-versus-host disease (GVHD/grade) were independent indicators of early-onset CTRCD (OR (95% CI) 1.04 (1.00 to 1.07); p=0.032; OR (95% CI) 1.87 (1.19 to 2.95), p=0.004, respectively). The overall and primary disease death rates were significantly higher in allo-HSCT recipients with early-onset CTRCD than in those without early-onset CTRCD (HR (95% CI) 1.98 (1.11 to 3.52), p=0.016; HR (95% CI) 2.96 (1.40 to 6.29), p=0.005, respectively), independent of primary disease type, remission status and transplantation type. CONCLUSIONS: Severe acute GVHD and higher cumulative anthracycline are two significant determinants of early-onset CTRCD. Early-onset CTRCD following allo-HSCT regulates survival in patients with haematological malignancies.

Case Report: Bronchogenic Cyst in the Right Atrium of a Young Woman.

A 31-year-old woman was referred to our hospital for evaluation of a cardiac mass in the right atrium. Cardiac magnetic resonance imaging indicated a cystic mass filled with fluid accumulation in the right atrium. The mass was identified as a cardiac cyst and was surgically removed. Pathological examination revealed an extremely rare bronchogenic cyst. Bronchogenic cysts are benign congenital abnormalities of primitive foregut origins that form in the mediastinum during embryonic development. There is unusual clinical dilemmas surrounding the treatment plan for cardiac surgery or biopsy of cardiac masses, especially in patients with rare cardiac cysts. The anatomical location of the cyst can be related to various clinical symptoms and complications. In cases of indeterminate cardiac cysts, direct cyst removal without prior biopsy is of utmost importance.

Case Report: Cardiac Tamponade in Association With Cytokine Release Syndrome Following CAR-T Cell Therapy.

Chimeric antigen receptor T (CAR-T) cell therapy has been shown to have substantial efficacy against refractory hematopoietic malignancies. However, it frequently causes cytokine release syndrome (CRS) as a treatment-specific adverse event. Although cardiovascular events associated with CAR-T cell therapy have been increasingly reported recently, pericardial disease is a rare complication and its clinical course is not well characterized. Here, we report a case of acute pericardial effusion with cardiac tamponade after CAR-T cell therapy. Case Summary: A 59-year-old man with refractory diffuse large B-cell lymphoma underwent CAR-T cell therapy. Grade 2 CRS was observed on day 0; it progressed to grade 4 on day 7 and was accompanied by a fever over 39°C, hypoxia requiring intubation, hypotension requiring the use of a vasopressor agent, and supraventricular tachycardia. Although cardiac function was preserved, marked pericardial effusion with the collapse of the right heart was detected on echocardiography. Since pericardiocentesis was considered to have a high complication risk due to severe myelosuppression, medications for CRS were prioritized. Tocilizumab, an interleukin-6 inhibitor, and high-dose methylprednisolone (1 g/day for 3 days) were administered for the management of severe CRS. On day 8, the pericardial effusion decreased, and the hemodynamic status markedly stabilized. CRS did not exacerbate after the steroid dose was reduced. Further, lymphoma size reduced after the induction of CAR-T cell therapy, and tumor regrowth was not noted at 3 months after CAR-T cell infusion. Conclusion: Interleukin-6 pathway inhibitors and corticosteroid therapy should be considered in the context of CRS for significant pericardial effusion after CAR-T cell therapy in the acute phase.

Effect of renin-angiotensin system inhibitors in patients with cancer treated with anti-VEGF therapy.

BACKGROUND: Cancer treatment with vascular endothelial growth factor signalling pathway (VSP) inhibitors frequently causes hypertension. Although previous reports suggested that the antihypertensive drug renin-angiotensin system inhibitor (RASI) may have a positive synergistic effect with VSP inhibitors, the actual impact on clinical outcomes is unknown. OBJECTIVES: The study aims to clarify whether RASIs exhibit clinical benefits for patients with cancer with hypertension. METHOD: From the Longevity Improvement and Fair Evidence Study database, comprising Japanese claims data between 2016 and 2020, we reviewed 2380 patients treated with VSP inhibitors who received antihypertensive treatment during cancer therapy. The patients were classified into two groups: with-RASI (n=883) and without-RASI (n=1497). In addition, 1803 of these patients treated for hypertension with RASI-only (n=707) or calcium channel blocker-only (n=1096) were also reviewed. The time-to-treatment failure (TTF), the interval from initiation of chemotherapy to its discontinuation, was applied as the primary endpoint. RESULTS: The median TTFs were 167 (60-382) days in the with-RASI group and 161 (63-377) days in the without-RASI group (p=0.587). All models, including Cox proportional hazard models and multiple propensity score models, did not reveal the superiority of with-RASI treatment. In the propensity score matching model, the HR for treatment with-RASI compared with that for without-RASI was 0.96 (95% CI 0.86 to 1.06, p=0.386). In addition, the TTFs of RASI-only were not superior to calcium channel blocker-only (p=0.584). CONCLUSIONS: RASIs for hypertension do not benefit clinical outcomes during cancer therapy with VSP inhibitors. In addition, RASIs and calcium channel blockers have comparable clinical efficacy as first-line antihypertensive.

Successful transition from intravenous epoprostenol to oral selexipag and inhaled iloprost in a case of severe pulmonary arterial hypertension associated with systemic lupus erythematosus.

A 25-year-old woman was admitted to our hospital with severe pulmonary arterial hypertension associated with systemic lupus erythematosus (SLE-PAH). Her mean pulmonary arterial pressure was 56 mmHg, and her SLE Disease Activity Index-2 K score was 14 on admission. In addition to a strong immunosuppressive regimen, which included steroid pulse therapy followed by high-dose oral prednisolone (1 mg/kg) and intravenous cyclophosphamide, an upfront combination of vasodilator therapy, including oral tadalafil, macitentan, and intravenous epoprostenol, was administered in the early phase. Two months later, her mean pulmonary arterial pressure was 29 mmHg, and her other haemodynamic markers showed significant improvement. She refused to start life-long intravenous epoprostenol therapy and so was switched to oral selexipag and inhaled iloprost. The transition was successful, and she has experienced no exacerbations of SLE-PAH during the 10 months since the onset of pulmonary arterial hypertension. To the best of our knowledge, this is the first report of intravenous epoprostenol being switched to alternative oral and inhaled therapy in a patient with SLE-PAH. In combination with adequate immunosuppressive therapy, it is probably easier to make this transition in patients with SLE-PAH than in those with pulmonary arterial hypertension of a different aetiology. Continuous infusion of epoprostenol can have potentially life-threatening complications and a detrimental effect on the quality of life. Our alternative treatment strategy was successful, and we hope that it will prove beneficial in other cases.

Transmission of 100-MHz-range ultrasound through a fused quartz fiber.

PURPOSE: This paper describes an investigation into direct observation of microscopic images of tissue using a thin acoustic wave guide. METHODS: First, the characteristics of the ultrasonic wave propagated in a fused quartz fiber were measured using the reflection method in order to study the insertion loss and the frequency shift of the ultrasonic wave transmitted from the transducer. Next, a receiving transducer was placed close to the end of the fiber, and the characteristics of the ultrasonic waves propagated through the acoustic coupling medium were measured using the penetration method in order to study the insertion loss and the frequency-dependent attenuation of the penetrated waves. Finally, a C-mode image was obtained by optimizing the measuring conditions using the results of the above measurements and scanning the ultrasonic beams on a target (coin) in water. RESULTS: A reflected wave with a peak frequency of approximately 220 MHz was obtained from the end of the fiber. The transmitted ultrasonic waves propagated through the acoustic coupling medium were detected with a frequency range of approximately 125-170 MHz, and the maximum detectable distance of the waves was approximately 1.2 mm within the 100-MHz frequency range. Finally, a high-frequency C-mode image of a coin in water was obtained using a tapered fused quartz fiber. CONCLUSION: The results suggest that it is necessary to improve the signal-to-noise ratio and reduce the insertion loss in the experimental system in order to make it possible to obtain microscopic images of tissue.

Alternate-day treatment with S-1 in patients with gastric cancer: a retrospective study of strategies for reducing toxicity.

BACKGROUND: In patients with adverse events of S-1, the dose is generally reduced or the treatment cycle is shortened. Whether the therapeutic effectiveness of modified regimens is similar to that of the standard dosage remains unclear. METHODS: We retrospectively studied patients with gastric cancer who received S-1 on alternate days. RESULTS: A total of 266 patients received S-1 on alternate days. In 116 patients, S-1 was initially given at the standard dosage but was switched to alternate-day treatment because of toxicity within 28 days on average. The other 150 patients initially received alternate-day treatment because of poor general condition. In the adjuvant chemotherapy group (n = 96), the 3-year survival rate was 88% in patients with stage II, 73% in stage IIIA, and 67% in stage IIIB who underwent D2 lymph-node dissection. In the palliative surgery group (n = 96), the response rate was 13%, with a median survival time (MST) of 624 days. In patients with unresectable/recurrent disease (n = 74), the response rate was 25%, with an MST of 338 days. Among the 116 patients who initially received treatment on consecutive days, 100% had grade 1, 53% had grade 2, and 5.2% had grade 3 adverse events. When S-1 was switched to alternate-day treatment, toxicity decreased in all patients. In the 266 patients who received alternate-day treatment, 8% had grade 1, 6% had grade 2, and 0% had grade 3 adverse events. CONCLUSION: Alternate-day treatment with S-1 may have milder adverse events without compromising therapeutic effectiveness.

Impaired deformability and association with density distribution of erythrocytes in patients with type 2 diabetes mellitus under treatment.

BACKGROUND: Disturbed microcirculation is related to diabetic complications, and erythrocyte deformability is a critical factor regulating microcirculation. OBJECTIVES: To know the relationship between the impaired deformability and density profile in diabetic erythrocytes. METHODS: We recruited patients with type 2 diabetes (n = 15, diabetic group) and age- and sex-matched non-diabetic subjects (n = 15, control group). Erythrocyte density (ED) profile was obtained by the phthalate ester separation technique. ED distribution was fitted by sigmoidal curve, yielding specific gravity of phthalate ester allowing passage of half erythrocytes population (ED50) and slope factor. Erythrocyte deformability was estimated by our specific filtration technique. RESULTS: Diabetic group showed significantly (p < 0.001) higher HbA1c and fasting blood glucose concentration. Erythrocyte deformability in diabetic group was impaired as compared with that in control group (p < 0.001) and proportional to HbA1c (p = 0.009). However, ED50 and the slope factor in diabetic group did not differ from respective parameters in control group. CONCLUSIONS: This study demonstrated that erythrocyte deformability was impaired in diabetic patients even under treatment. HbA1c up to 7.5% is concluded not to alter the erythrocyte density but to impair the deformability, which might be a warning to clinicians for prevention of diabetic complications.

Atrial fibrillation observed in a patient with esophageal cancer treated with fluorouracil.

Fluorouracil (5-FU), a commonly used anticancer agent, has potent cardiotoxicity that is mediated by vascular endothelial injury and vasospasm. Here, we report a patient demonstrating atrial fibrillation (AF), which was most likely induced by vasospasm mediated by 5-FU. A 69-year-old man presented with dysphagia and was diagnosed with advanced esophageal cancer. Frequent paroxysms of atrial fibrillation (AF) were observed during combination chemotherapy including 5-FU. AF was refractory to disopyramide, but was sensitive to antianginal agents (nicorandil and nitroglycerin transdermal patch). Coronary angiography performed within the chemotherapeutic period demonstrated moderate stenosis in the right coronary artery (RCA). Severe spasm at the proximal portion of the atrial branch in RCA was induced by provocation test using acetylcholine. Our case indicated that 5-FU predisposed vasospasm in RCA and the subsequent atrial ischemia may lead to AF. .

Sick Sinus Syndrome Observed in a Patient with Cholinesterase Deficiency.

A 58-year-old woman complained of general fatigue and was diagnosed with sick sinus syndrome (SSS) by ambulatory electrocardiogram, which demonstrated sinus arrest at midnight and paroxysmal atrial fibrillation (AF) at nighttime. Since her plasma cholinesterase (ChE) activity had been persistently zero, she was diagnosed with ChE deficiency. She refused permanent pacemaker implantation, and treatment with positive chronotropic drugs is ongoing. A novel association of ChE deficiency with SSS is theoretically possible rather than coincident, considering that ChE plays a key role in cholinergic influences on the sinus node leading to sinus bradyarrhythmia and on the atria, causing vagally mediated AF.

Gasless laparoscopy-assisted distal gastrectomy is feasible and useful for non-obese patients with early gastric cancer.

BACKGROUND/AIMS: To evaluate the feasibility and usefulness of gasless laparoscopy-assisted distal gastrectomy except when treating obese patients compared with open distal gastrectomy for early cancer. METHODOLOGY: We treated 92 patients with distal gastrectomy for early gastric cancer consecutively. Patients with massive submucosal invasion and/or LN swelling were allocated for the open method, and patients with slightly invasive submucosal cancer were allocated for gasless laparoscopy-assisted surgery. As exceptions we employed open surgery for overweight patients and gasless laparoscopy for elderly and/or feeble patients. RESULTS: We attempted to perform open and laparoscopy-assisted surgery on 52 and 40 patients, respectively. Three cases in the laparoscopy-assisted group were converted to open surgery because of obesity. The age was older and BMI was lower in the laparoscopy-assisted group. In terms of operative time and blood loss as well as postoperative recovery, the results for the laparoscopy-assisted group were superior to those of the open surgery group. There were no cases of cardiopulmonary complications for the laparoscopy-assisted group. CONCLUSIONS: Gasless laparoscopy-assisted distal gastrectomy is feasible and useful for early gastric cancer except when treating obese patients.

Anticoagulation Stability Depends on CHADS2 Score and Hepatorenal Function in Warfarin-treated Patients, Including Those with Atrial Fibrillation.

AIM: Although warfarin remains important despite the widespread use of nonvitamin K antagonist oral anticoagulants (NOACs), to date, the reality of warfarin use in the "NOACs era" is unclear. This multicenter observational study aimed to clarify the key factors contributing to warfarin treatment stability. METHODS: The practical use of warfarin, stability of warfarin therapy, and factors contributing to this stability were investigated in community-based hospitals through a real-world study. Clinical data were retrospectively extracted from the medical records of warfarin-treated Japanese patients (age, 71.3±5.5 years) with atrial fibrillation (AF), prosthetic heart valve, or other concerns requiring anticoagulation. Treatment stability was considered as time in therapeutic range of international normalized ratio of prothrombin time (TTR: %). The factors contributing to TTR were investigated, including CHADS2 score components. RESULTS: Mean CHADS2 score was highest (1.38±0.88, p＜0.001), and most CHADS2 score components in addition to hepatorenal dysfunction were factors contributing to the low TTR in patients with AF (n=176). The similarity was found in overall patients who were prescribed warfarin (n= 518). TTR decreased according to the CHADS2 score component accumulation. Gender, dose and prescription interval of warfarin, and co-administration of antiplatelet agents did not correlate with the low TTR. CONCLUSIONS: This retrospective study demonstrated that the CHADS2 score component accumulation and hepatorenal dysfunction are factors significantly contributing to the low TTR, which is indicative of poor warfarin treatment stability, in patients such as those with AF.

Complex regional pain syndrome induced by pacemaker implantation for sick sinus syndrome.

A 53-year-old woman reported burning pain, muscle weakness, and dysesthesia of the left arm 2 months after permanent pacemaker insertion in the ipsilateral side for the treatment of sick sinus syndrome. Complex regional pain syndrome (CRPS) induced by pacemaker implantation was diagnosed. In 2017, her pulse generator became exhausted and was exchanged carefully to avoid exacerbation of CRPS, under the application of local anesthesia and premedication. Six months later, the patient's grip strength in her left hand remained lower relative to that in her right hand. Although rare, the presence of CRPS following device implantation should be remembered.

Manifestation of J wave induced by acetylcholine applied for a coronary spasm provocation test in a patient with aborted sudden cardiac death.

A 51-year-old man with a resuscitation episode was referred to our hospital. Coronary angiography revealed a focal spasm overlapped with organic stenosis where a bare metal stent was implanted. Acetylcholine (ACh) provocation test did not induce chest pain. It revealed no discernible ST-T changes but unmasked a J wave at the end of the QRS complex, which was associated with short-coupled repetitive premature ventricular beats. A J wave reportedly appears immediately before the onset of ventricular fibrillation caused by vasospastic angina. However, a J wave observed newly after a coronary spasm provocation test using ACh without ST-T changes is informative when considering the mechanisms of the J wave.

Metastatic esophageal cancer presenting as shock by injury of vagus nerve mimicking baroreceptor reflex: A case report.

RATIONALE: Neurogenic shock is generally typified by spinal injury due to bone metastases in cancer patients, but continuous disturbance of the vagus nerve controlling the aortic arch baroreceptor can cause shock by a reflex response through the medulla oblongata. PATIENT CONCERNS: A 43-year-old woman with dysphagia presented to our hospital. Computed tomography showed a primary tumor adjacent to and surrounding half the circumference of the descending aorta, and multiple cervical lymph node metastases, including a 55 × 35-mm lymph node overlapping the root of the left vagus nerve. Squamous esophageal cancer (T4bN3M1, stage IV) was diagnosed. Whereas shock status initially appeared soon after left cervical pain, suggesting pain-induced neutrally-mediated syncope, sustained bradycardia and hypotension occurred even after alleviation of pain by opioids. DIAGNOSIS: Disturbance of the left vagus nerve associated with the aortic arch baroreceptor by a large left cervical lymph node metastasis was considered as the cause of shock, pathologically mimicking the baroreceptor reflex. INTERVENTIONS: Systemic steroid administration was performed, and radiotherapy for both the primary site and lymph node metastasis was started 2 days after initiating steroid treatment. OUTCOMES: Four days after initiating steroid administration, hypotension and bradycardia were improved and stable. LESSONS: Disturbance of the vagus nerve controlling the aortic arch baroreceptor should be kept in mind as a potential cause of neurogenic shock in cancer patients, through a pathological reflex mimicking the baroreceptor reflex.

Sildenafil for primary and secondary pulmonary hypertension.

BACKGROUND: Sildenafil is a selective inhibitor of cyclic guanosine monophosphate-specific phosphodiesterase type 5, an enzyme that is abundant in both lung and penile tissues. Sildenafil is widely used to dilate penile arteries, suggesting that it may also dilate pulmonary arteries in patients with pulmonary hypertension. However, the long-term hemodynamic effects and safety of the drug in pulmonary hypertension are not known. METHODS: One patient with primary pulmonary hypertension and another with secondary pulmonary hypertension caused by collagen disease were given 50 mg oral sildenafil during cardiac catheterization for assessment of the acute hemodynamic effects of the drug. The patients were then given maintenance treatment with 25 mg oral sildenafil twice a day. Long-term hemodynamic effects were evaluated by repeated cardiac catheterization after 3 months, with the last oral dose given 15 hours before the procedure. The acute hemodynamic effects of sildenafil after the long-term treatment were studied during the same cardiac catheterization. RESULTS: Sildenafil did not affect aortic pressure, but it significantly decreased pulmonary artery pressure and increased cardiac index, thereby reducing pulmonary vascular resistance. Long-term maintenance therapy with 25 mg oral sildenafil twice a day remarkably improved the clinical condition of the patients, without causing any adverse effects; New York Heart Association functional classification returned to class II (from class III). The acute efficacy of sildenafil was well preserved after the long-term treatment; there was no tolerance. CONCLUSIONS: The data strongly suggest that sildenafil can be used as a valuable pulmonary vasodilator in patients with pulmonary hypertension, with good long-term hemodynamic effects and safety. The results necessitate larger trials to confirm these observations in a larger cohort of patients.

Gasless laparoscopy-assisted distal gastrectomy for early cancer via mini-laparotomy using an abdominal wall lift.

BACKGROUND/AIMS: To investigate the technical ease and results of gasless laparoscopy-assisted distal gastrectomy with lymph node dissection via mini-laparotomy using abdominal wall lift for early gastric cancer. METHODOLOGY: We submitted 20 patients to laparoscopy-assisted distal gastrectomy for early gastric cancer located in the middle or lower stomach. The initial 10 cases underwent perigastric lymph node dissection (D1), and the subsequent 10 cases received further dissection around the left gastric and common hepatic arteries (D1 + a). Mini-laparotomy was placed at the beginning of the procedure. We lifted up the laparotomy and the subcutaneous tissue around the umbilicus by retractors. We accomplished the dissection, resection and reconstruction mainly via the mini-laparotomy using a direct view and a laparoscopic image. RESULTS: Two cases were converted to open. The operative time was significantly longer in D1 + a (225 +/- 49 min) than in D1 (172 +/- 38 min). Blood loss was significantly more in D1 + a (247 +/- 155 mL) than in D1 (109 +/- 60 mL). There was no difference between the two groups in terms of days to first flatus, first oral intake or discharge from the hospital. Postoperative complications included 2 wound infections each in D1 and D1 + a group, and 1 anastomotic stenosis in D1 + a group. CONCLUSIONS: Gasless laparoscopy-assisted distal gastrectomy with D1 + a via mini-laparotomy using abdominal wall lift seems to be feasible and useful for early gastric cancer.

[A case of type 4 gastric cancer with peritoneal dissemination successfully treated over 2 years by alternate-day administration of TS-1].

We report a patient with unresectable advanced gastric cancer who has been being treated by TS-1 administration on alternate days for 2 years. The patient was a 50-year-old female with type 4 gastric cancer accompanied by Schnitzler metastasis and pleural effusion. TS-1 administration was initiated at a daily dose of 100 mg with a schedule of 4-week administration and 2-week suspension. However, grade 2 hepatic dysfunction and leukocytopenia developed. When the daily TS-1 administration was changed to alternate-day administration at the same dose, no side effects were observed, allowing the continuation of treatment. She has maintained a minor response (MR)-no change (NC) for 1 year and 5 months, and is still symptom-free and being treated on an outpatient basis at present, 2 years after treatment. TS-1 is an anti-cancer drug that plays a central role in chemotherapy for gastric cancer. However, in some patients, side effects sometimes develop using the routine administration method, making continuation of administration difficult. Alternate-day TS-1 administration has great potential as a protocol that produces long-term anti-tumor effects while reducing side effects.