Discovery of a potent, selective, and orally available EGFR C797S mutant inhibitor (DS06652923) with in vivo antitumor activity.

The C797S mutation is one of the major factors behind resistance to the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Herein, we describe the discovery of DS06652923, a novel, potent, and orally available EGFR-triple-mutant inhibitor. Through scaffold hopping from the previously reported nicotinamide derivative, a novel biaryl scaffold was obtained. The potency was successfully enhanced by the introduction of basic substituents based on analysis of the docking study results. In addition, the difluoromethoxy group on the pyrazole ring improved the kinase selectivity by inducing steric clash with the other kinases. The most optimized compound, DS06652923, achieved tumor regression in the Ba/F3 allograft model upon its oral administration.

Gadolinium-enhanced MR improved motion sensitized driven equilibrium (iMSDE) for intracranial vessel imaging in giant cell arteritis.

BACKGROUND: Giant cell arteritis (GCA) generally affects extracranial large and medium-sized vessels. It rarely causes intracranial vessel stenosis, presenting as cerebral infarction (CI). Consequently, accurate diagnosis of CI induced by GCA is often challenging. Improved motion-sensitized driven-equilibrium (iMSDE) is one of the advanced high-resolution magnetic resonance (MR) vessel wall imaging techniques that enables direct visualization of the vessel wall because of a strong reduction in blood flow artifacts, leading to higher quality images. Herein, we effectively used gadolinium-enhanced MR iMSDE imaging to diagnose a patient presenting with recurrent CI due to right intracranial internal carotid artery (ICA) stenosis as GCA. CASE DESCRIPTION: A 64-year-old man with polymyalgia rheumatica for several years and who had experienced CI due to moderate intracranial ICA stenosis one year ago, presented to the emergency room with dysarthria and left hemiparesis. Diffusion-weighted MR imaging showed high signals in the right centrum ovale, and MR angiography revealed severe stenosis of the right intracranial ICA. Gadolinium-enhanced MR iMSDE imaging showed marked concentric enhancement in the vessel wall of the right stenosed ICA, which led to a definitive diagnosis of GCA via biopsy from the right superficial temporal artery. The patient's symptoms gradually improved after initiation of steroid treatment. Three months later, gadolinium-enhanced MR iMSDE imaging revealed improvement in the contrast enhancement in the vessel wall and vascular stenosis. CONCLUSION: Gadolinium-enhanced MR iMSDE imaging is useful to diagnose and evaluate GCA with intracranial vessel involvement.

Effects of the xanthine oxidase inhibitor, febuxostat, on the expression of monocyte chemoattractant protein-1 and synchronous genes in MDCK cells treated with calcium oxalate monohydrate crystals.

OBJECTIVES: To examine the effects of the selective xanthine oxidase inhibitor febuxostat on the expression of inflammation-related genes involved in stone formation. METHODS: Madin-Darby canine kidney cells were exposed to febuxostat, followed by calcium oxalate monohydrate crystals. Monocyte chemoattractant protein-1 messenger ribonucleic acid expression levels were determined by real-time reverse transcription polymerase chain reaction analysis. Deoxyribonucleic acid microarray analysis was utilized to evaluate gene expression. RESULTS: Calcium oxalate monohydrate crystals activated monocyte chemoattractant protein-1 messenger ribonucleic acid expression in a time- and concentration-dependent manner. Febuxostat suppressed monocyte chemoattractant protein-1 expression. The expression levels of a group of inflammatory genes, including interleukin-8 and chemokine (C-X-C motif) ligand 10, which are downstream of reactive oxygen species, fluctuated similarly to the observed monocyte chemoattractant protein-1 fluctuations and were reduced by febuxostat pretreatment. CONCLUSIONS: Febuxostat exerts preventive effects against reactive oxygen species production and oxidative stress, and might represent a potential treatment for calcium oxalate stones. In the present study, febuxostat downregulated the calcium oxalate monohydrate crystal-induced monocyte chemoattractant protein-1 messenger ribonucleic acid expression.

Prediction of Severe Cisplatin-Induced Neutropenia Using Serum Albumin Concentration-A Retrospective Study.

BACKGROUND: Cisplatin that is used in the treatment of gastric cancer not only has gastrointestinal side effects but also has a high serum protein-bound fraction. Reduction of serum albumin concentration may cause increase the risk of cisplatin- induced neutropenia. Hence, alteration of serum albumin concentration poses a major safety issue during anticancer therapy. METHODS: For gastric cancer patients who received cisplatin plus S-1 therapy, we investigated the relationship between the serum albumin concentration before cisplatin administration in the treatment course during which the neutrophil count reached nadir and the neutrophil count fluctuation after cisplatin administration. RESULTS: In the grade 3-4 neutropenia and grade 0-2 neutropenia groups, the mean serum albumin concentration before cisplatin administration was 3.39±0.60 and 3.85±0.59 g/dL, respectively; in the former group were significantly lower than in the latter group(p=0.006). Lower serum albumin concentrations before cisplatin administration were significantly correlated with a decrease in neutrophil count after cisplatin administration(r=0.463, p<0.001). According to the receiver operating characteristic curve analysis, patients with serum albumin concentrations below 3.25 g/dL before cisplatin administration exhibited a significantly higher incidence of grade 3-4 neutropenia(odds ratio: 4.33). CONCLUSIONS: Decreased serum albumin levels were found to be strongly associated with the prediction of the development of severe neutropenia. Our findings emphasize serum albumin concentration needs to be evaluated before each administration of cisplatin.

[Elucidation of Influential Factors on Nausea Associated with Olaparib Administration].

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.

High-salt diet promotes crystal deposition through hypertension in Dahl salt-sensitive rat model.

OBJECTIVES: To study the promotive effect of salt-induced hypertension on crystal deposition and urolithiasis using a salt-sensitive rat hypertension model. METHODS: Hyperoxaluria and hypercalciuria were induced in male Dahl salt-sensitive rats with administration of ethylene glycol and alfacalcidol. Hypertension was induced by a high-salt diet. Eplerenone, a selective mineralocorticoid receptor antagonist, was given. Blood and urine were collected to evaluate renal function, electrolytes and the blood renin-angiotensin-aldosterone system. Renal calcium content was also evaluated. Histological examination, transcriptome analysis with DNA microarray and semiquantitative reverse transcriptase polymerase chain reaction were carried out. RESULTS: A high-salt diet increased crystal deposition in Dahl salt-sensitive rats with hypertension, and eplerenone administration significantly suppressed it. The mRNA expression profile was associated with crystal formation, growth, adhesion and cellular injury, and it was regulated in the group exposed to a high-salt diet and ethylene glycol. CONCLUSIONS: A high-salt diet has a promotive effect on salt-sensitive hypertension and urolithiasis. This promotive effect can be prevented by eplerenone administration. Hence, salt-sensitive hypertension has promotive effects on crystal deposition in Dahl salt-sensitive rats.

[Identification of the Risk Factors for Cabazitaxel-Induced Neutropenia with Preventive Administration of Pegfilgrastim].

Prophylaxis using pegfilgrastim is recommended to prevent cabazitaxel-induced neutropenia. We observed GradeB3 neutropenia in a patient after administration of cabazitaxel, despite prophylaxis using pegfilgrastim. To identify the risk factors associated with GradeB3 neutropenia, we retrospectively investigated the records of 10 patients who received prophylaxis with pegfilgrastim after administration of cabazitaxel. They were divided into GradeB3 neutropenia and non-GradeB3 neutropenia groups, and we compared the background data and laboratory values between the 2 groups. A univariate analysis revealed that hypoalbuminemia was significantly observed in patients with cabazitaxel-induced GradeB3 neutropenia. The incidence of GradeB3 neutropenia was significantly high in patients with serum albumin levels<3.6 g/dL. Cabazitaxel has a high rate of protein binding; moreover, serum albumin levels<3.6 g/dL might be associated with high concentrations of unbound cabazitaxel, and thus an increase in the incidence of GradeB3 neutropenia. Therefore, hypoalbuminemia at the time of administration of cabazitaxel may be a risk factor related to the development of GradeB3 neutropenia.

[Effect of Hypoalbuminemia on Severe Neutropenia Induced by Paclitaxel Monotherapy and Paclitaxel plus Ramucirumab Combination Therapy in Patients with Gastric Cancer].

Hypoalbuminemia is often observed in patients receiving chemotherapy for gastric cancer. The risk of hematologic toxicity is increased by the pharmacokinetic alteration of paclitaxel(PTX)owing to high serum protein binding in patients with hypoalbuminemia. Here, we examined the relationshipbetween the frequency of GradeB3 neutropenia and serum albumin concentration in 30 patients receiving PTX monotherapy, and 29 patients receiving PTX plus ramucirumab(RAM)combination therapy-a second-line treatment for advanced/recurrent gastric cancer. The number of patients who developed GradeB3 neutropenia was 8(27%)and 14(48%)of those who received monotherapy and combination therapy, respectively, with mean serum albumin concentrations of 3.31 g/dL and 3.15 g/dL, respectively. Serum albumin concentrations were significantly lower in the GradeB3 neutropenia group than in the non-GradeB3 neutropenia group in both regimens. When the serum albumin concentration of patients receiving PTX or PTX plus RAM was below the cut-off values of 3.75 g/dL and 3.45 g/dL, respectively, the odds ratio of GradeB3 neutropenia was 12.25 and 7.33, respectively. Hypoalbuminemia was associated with the development of chemotherapy-induced GradeB3 neutropenia, in patients with gastric cancer treated with either PTX monotherapy or PTX plus RAM combination therapy. Therefore, not only neutrophils but also serum albumin concentration should be monitored during chemotherapy.

[Retrospective Investigation of the Risk Factors for Severity in Panitumumab-Induced Hypomagnesemia].

Hypomagnesemia caused by panitumumab can often lead to severe adverse effects, such as arrhythmia. However, the risk factors are still controversial. To clarify the risk factors and time to onset of panitumumab-induced hypomagnesemia, we retrospectively investigated the records of 30 patients who had received panitumumab. They were divided into Grade B2 hypomagnesemia and non-Grade B2 hypomagnesemia groups, according to their serum magnesium levels, and we compared patients' backgrounds, laboratory values, and concomitant drugs between the 2 groups. Univariate analysis revealed that hypocalcemia and non-administration of an oral magnesium preparation were significantly associated with Grade B2 hypomagnesemia induced by panitumumab. Incipient grade 1 hypocalcemia was observed after incipient Grade 1 hypomagnesemia in both groups. The occurrence of these complications was significant in the Grade B2 hypomagnesemia group. Thereafter, in all patients of the Grade B2 hypomagnesemia group that exhibited both complications, hypomagnesemia developed to Grade 2 or higher. The development of Grade 3 and Grade 4 hypomagnesemia without the development of Grade 2 hypomagnesemia was observed in 2 patients each. Thus, aggravation of hypomagnesemia can be expected upon the administration of panitumumab, and therefore, not only serum magnesium levels, but also serum calcium levels need to be monitored.

[Clinical Study on the Efficacy and Continuous Docetaxel Based Chemotherapy Treatment for Castration-Resistant Prostate Cancer].

We report a retrospective study on the efficacy, adverse events and the factors for continuous docetaxel (DOC) therapy for patients with castration-resistant prostate cancer (CRPC). Between April 2007 and April 2015, 37 CRPC patients were treated with DOC therapy at Kanazawa Medical University Hospital. DOC was administered every 3 weeks at 70 mg/m2. Prostatic specific antigen (PSA) level, adverse events, cycles of DOC therapy, survival time and clinical passage were examined. Fifteen patients showed a decrease in PSA level of 50% or more, 9 patients showed less than 50% decrease in PSA level and 13 patients showed no decrease in PSA level. Adverse effect of grade 3 consisted of neutropenia in 29.7% and leukocytopenia in 10.8%. The median number of treatment cycles was 11.7 courses. The patients were divided into two groups ; the first group comprised of 26 patients who received short-term DOC therapy (≤10 cycles) and the second group comprised of 11 patients who received long-term DOC therapy (≥11 cycles). The 1-year survival rate was 59 and 100% for the short-term and long-term groups, respectively. Long-term treatment was related to pretreatment PSA nadir, time to progression of CRPC and serum lactate dehydrogenase level.

Risk factors and prevention for surgical intestinal disorders in extremely low birth weight infants.

PURPOSE: Surgical intestinal disorders (SID), such as necrotizing enterocolitis (NEC), focal intestinal perforation (FIP), and meconium-related ileus (MRI), are serious morbidities in extremely low birth weight (ELBW, birth weight <1000 g) infants. From 2010, we performed enteral antifungal prophylaxis (EAP) in ELBWI to prevent for SID. The aim of this study was to identify disease-specific risk factors and to evaluate the efficacy of prevention for SID in ELBW infants. METHODS: A retrospective chart review of all consecutive patients between January 2006 and March 2015, which included 323 ELBW infants who were admitted to Shizuoka Children's Hospital, was conducted. RESULTS: The number of infants with NEC, FIP, and MRI was 9, 12, and 13, respectively; 28 in 323 ELBW infants died. The control group defined the cases were not SID. In-hospital mortality was higher in infants with NEC relative to those in the control group. On logistic regression analysis, low gestational age and cardiac malformations were associated with increased risk of NEC. IUGR were associated with increased risk of MRI. EAP decreased risk of NEC and FIP. Low gestational weight and NEC were associated with increased risk of death. CONCLUSION: Survival to hospital discharge after operation for NEC in ELBW infants remains poor. EAP decreased risk of NEC and FIP in ELBW infants.

THE EFFECT OF RADIATION THERAPY FOR BONE METASTASIS IN URINARY ORGAN CANCER.

(Objective) Bone metastasis symptoms are complications that greatly reduce the quality of life (QOL) of cancer patients. We report a retrospective study on the efficacy of radiation therapy for patients with bone metastasis in urinary organ cancer. (Subjects and methods) Subjects are comprised of 17 patients; total irradiated areas consist of 25 sites. There are 5 patients diagnosed with renal cell carcinoma, 1 patient with bladder cancer and 11 patients with prostatic cancer. All of them have undergone radiation therapy for bone metastasis in urinary organ cancer between April 2007 and March 2014 in the Department of Urology, Kanazawa Medical University. The mean age of the patients was 66.7 years old. We looked at irradiated areas, exposure dose and changes of symptom in all patients. (Results) Irradiated areas are thoracolumbar vertebrae (14 sites), cranial base (2 sites), pubic bone (1 site), ilium bone (2 sites), sacral bone (1 site), rib bone (1 site) and hip joint (1 site). The mean exposure dose of one area is 37.5 Gy (13.5-60). 19 irradiated sites which were previously reported to have sharp pain have gained improvement at 16 sites. These 16 sites have comparatively lesser pain or no pain. 8 cases in acknowledgment of walk difficulty, it was with 7 cases walking alone possibility again. (Conclusion) This study showed that radiation therapy have significant improvement in terms of symptoms and QOL for the patients with bone metastasis in urinary organ cancer.

A Case of Hyperglycemia-Induced Epileptic Homonymous Hemianopsia.

Hyperglycemia sometimes initially presents with neurological manifestations, including seizures, visual hallucinations, choreoathetosis, hemiballismus, myoclonus, tremor, and consciousness disturbance. Epileptic seizures induced by hyperglycemia are reported to occur predominantly in the occipital lobe, and the epileptic form is mainly epilepsia partialis continua. Of the two patterns of hyperglycemia (ketotic or nonketotic), nonketotic hyperglycemia is more commonly associated with seizures because ketosis has an anticonvulsive effect, so hyperglycemia-induced seizures are generally seen in nonketotic patients. Here, we report a 51-year-old Japanese male with intermittent homonymous hemianopsia who presented high hemoglobin A1c (19.1%). He had been drinking 3 L of the sugared soft beverage every day. After admission, he showed left-sided hemiconvulsion. Anti-seizure medications and insulin treatment were administered, and his seizure was aborted. The magnetic resonance imaging (MRI) showed a high-intensity lesion in the diffusion-weighted image and fluid-attenuated inversion recovery with gadolinium enhancement in the occipital lobe. In hyperglycemic convulsions, MRI sometimes shows leptomeningeal or parenchymal gadolinium enhancement. In addition, most hyperglycemic seizures are associated with nonketotic hyperglycemia and show occipital-dominant imaging abnormalities. We report this case by reviewing the differential diagnosis.

Lumbar Subarachnoid-Peritoneal Shunting Deteriorates Superficial Siderosis Associated with a Dural Defect.

Superficial siderosis is a disease in which hemosiderin is deposited under the leptomeninges and subpial layers of hindbrain structures, e.g., the cerebellum, brainstem, and eighth cranial nerve. The main symptoms of superficial siderosis are cerebellar ataxia, hearing loss, cognitive decline, and myelopathy. The activities of daily living of patients with superficial siderosis are severely impaired due to the progressive symptoms. Here, we report a patient with superficial siderosis whose symptoms deteriorated after lumbar subarachnoid-peritoneal (L-P) shunt surgery. She received L-P shunt surgery based on the diagnosis of idiopathic normal pressure hydrocephalus at another hospital. The patient had a history of cervical surgery, and a dural defect was identified at the C4-5 level by a detailed magnetic resonance imaging study. We hypothesized that the L-P shunt reduced cerebrospinal pressure and increased bleeding from the fragile vessels in the dural defect, which might have increased hemosiderin deposition.

Bilateral Phrenic Nerve Palsy Associated With Neuralgic Amyotrophy.

Neuralgic amyotrophy (NA) is a multifocal inflammatory neuropathy accompanied by acute pain and muscle atrophy. NA commonly affects the upper extremities, but rarely affects the phrenic nerve. Here, we report a male with neck pain, orthopnea, difficulty sleeping in the supine position, and inability to slurp. His saturated oxygen level decreased from 97% to 86% in the supine position. His right shoulder showed muscle atrophy. Chest X-ray examination in the supine position and a nerve conduction study showed phrenic palsy. We diagnosed it as bilateral phrenic nerve palsy associated with NA. NA sometimes causes phrenic nerve palsy and may cause slurping difficulty.

Serum perampanel levels in patients with seizures are not affected by hemodialysis.

Perampanel belongs to a novel class of antiseizure medications (ASMs). Studies examining the effect of hemodialysis on perampanel serum levels in clinical settings are lacking. We aimed to evaluate the changes in serum perampanel levels during hemodialysis. We studied patients with seizures who received oral perampanel between April 2020 and March 2023 and whose serum concentration of perampanel was measured before and after hemodialysis. We analyzed the serum concentrations of levetiracetam and lacosamide for comparison. Fourteen patients, with a mean age of 76.1 ± 7.88 years, were included. The dose of perampanel was 2.14 ± 1.27 mg. The hemodialysis clearance rate of perampanel, levetiracetam, and lacosamide was 0 ± 13%, 69 ± 11%, and 59.6 ± 8.2%, respectively. The post-dialysis CD ratio decreased significantly with levetiracetam but not with perampanel. Adverse but acceptable effects of perampanel were observed in two patients. The serum concentrations of several ASMs have been shown to be reduced during hemodialysis. Our study revealed that the serum perampanel concentration does not decrease during hemodialysis. Owing to the low rate of adverse effects and the stability of perampanel serum concentration during hemodialysis, perampanel could be a favorable choice as an ASM for patients with seizures undergoing hemodialysis. PLAIN LANGUAGE SUMMARY: Our study looked at how hemodialysis affects the serum levels of perampanel, a new type of medication for seizures. In 14 patients who started treatment between April 2020 and March 2023, perampanel serum levels did not decrease during hemodialysis, unlike other seizure medications. This shows that perampanel can be a good option for patients with seizures who need hemodialysis, with fewer side effects compared to other medications.

Septic neonate rescued by polymyxin B hemoperfusion.

Sepsis caused by group B streptococcus has been well controlled with aminobenzylpenicillin, but the incidence of Escherichia coli sepsis has increased in proportion. E. coli is a Gram-negative bacillus associated with poor prognosis due to the release of endotoxins. Conventional treatment with antibiotics alone may not be sufficient because the inflammatory response exacerbates the unstable hemodynamic status. Polymyxin B hemoperfusion has been established as a treatment option for septic shock in adults. Polymyxin B hemoperfusion adsorbs endotoxins and cannabinoids such as anandamide and 2-arachidonoylglycerol. Reported herein is a case of severe septic shock induced by E. coli. The concomitant use of polymyxin B hemoperfusion rapidly reduced the requirement for catecholamines and the patient was discharged without short-term neurological or respiratory sequelae. It is suggested that polymyxin B hemoperfusion might be an innovative therapy for severe sepsis, and could improve outcome.

Ultrashort Echo Time Magnetic Resonance Angiography as an Alternative Tool to Digital Subtraction Angiography in the Follow-up of Stent-Assisted Coil Embolization Outcomes.

BACKGROUND: Follow-up of aneurysms treated with stent-assisted coil embolization has been performed using digital subtraction angiography (DSA) because in time-of-flight magnetic resonance angiography, metal artifacts from the stent often affect visualization. OBJECTIVE: To confirm whether ultrashort echo time (TE) MRA may be an alternative for DSA during follow-up. METHODS: Patients with unruptured aneurysms initially treated with stent-assisted coil embolization between April 2019 and March 2021 were enrolled. After 3 months of treatment, follow-up DSA and ultrashort TE MRA were performed. All images were independently reviewed by neurosurgeons to evaluate in-stent flow and rated from 1 (not visible) to 4 (excellent). Aneurysmal embolization status was assessed as complete obliteration, residual neck, or residual aneurysm. Ultrashort TE MRA findings were classified as evaluative or nonevaluative state based on the presence of metal artifacts. We investigated the types of aneurysms that were evaluative and the agreement between ultrashort TE and DSA. RESULTS: Overall, 89 aneurysms were examined, of which 74% (n = 66) were classified as evaluative on ultrashort TE. Significant differences were observed in size and stent type. Evaluative cases had an aneurysm size of <7 mm ( P = .0007) and a higher rate of Neuroform Atlas ( P = .0006). The rate of agreement between ultrashort TE with evaluative state and DSA was 95%. CONCLUSION: Ultrashort TE MRA could evaluate an embolization status treated with stenting, and the findings are in excellent agreement with those of DSA. Aneurysms measuring <7 mm and treated with Neuroform Atlas are evaluative on ultrashort TE, and DSA might not be necessary.

Highly potent, orally active novel small-molecule HPK1 inhibitor DS21150768 induces anti-tumor responses in multiple syngeneic tumor mouse models.

Augmenting T-cell activity is a promising approach to enhance the efficacy of cancer immunotherapy treatment. Hematopoietic progenitor kinase 1 (HPK1) is predominantly expressed in immune cells and negatively regulates T-cell receptor signaling. It is reported that inhibition of the kinase function of HPK1 results in tumor growth suppression by enhancing cancer immunity. Thus, developing HPK1 inhibitors has attracted considerable attention as a future cancer immunotherapy approach. However, despite recent progress in HPK1 biology and pharmacology, various challenges still remain, such as developing HPK1 inhibitors with favorable pharmacological profiles and identifying tumor characteristics that can be applied to define susceptibility to HPK1 inhibition. Here, we present the identification and pharmacological evaluation of DS21150768, a potent small-molecule HPK1 inhibitor with a novel chemical scaffold. DS21150768 shows remarkable inhibition of HPK1 kinase activity, and in vitro studies demonstrated its potent activity to enhance T-cell function. DS21150768 is orally bioavailable and shows sustained plasma exposure, which leads to enhanced cytokine responses in vivo. We conducted a comparison of the anti-tumor efficacy of DS21150768 alone or in combination with anti-PD-1 antibody in 12 different mouse cancer cell models, and observed that the treatments suppressed tumor growth in multiple models. Furthermore, Gene Set Enrichment Analysis demonstrated significant enrichment of immune-related gene signatures in the tumor models responsive to DS21150768 treatment. Our results provide a path forward for the future development of HPK1 inhibitors and fundamental insights into biomarkers of HPK1-targeted therapy.

Necessity of neutrophil-to-lymphocyte ratio monitoring for hypothyroidism using nivolumab in patients with cancer.

BACKGROUND: Low neutrophil-to-lymphocyte ratio (NLR) has been shown to be associated with a favorable therapeutic response to nivolumab. The activation of immunocompetent cells such as lymphocytes exhibits an antitumor effect; however, the development of excessive immune responses in autologous organs along with the breakdown of self-tolerance causes immune-related adverse events, including hypothyroidism. Therefore, the possibility that NLR is associated with immune response shows that NLR can be not only a predictive factor for good response to nivolumab but also a predictive factor for the development of hypothyroidism. AIM: To evaluate whether continuous NLR monitoring during nivolumab treatment is useful for predicting the incidence and onset period of hypothyroidism. METHODS: This retrospective study comprised patients who received nivolumab for treating all types of cancer at our hospital between January 2015 and December 2019. The NLRs of patients were measured before each administration, and the patients were followed up till the administration of 12 doses. NLR at treatment initiation was compared between patients with and without hypothyroidism. Patients who developed hypothyroidism were categorized into three groups: those with NLR < 3.5, 3.5 to < 5, and ≥ 5 according to their maximum NLR from treatment initiation to hypothyroidism development. Further, the onset periods of hypothyroidism were compared between the groups. RESULTS: Overall, 104 patients were included in the analysis. Twenty-one patients developed hypothyroidism throughout the observation period. NLR at treatment initiation was significantly lower (2.54 ± 1.21 vs 4.58 ± 4.03; P = 0.017) in patients with hypothyroidism than in those without hypothyroidism, and patients with NLR < 5 had a significantly higher incidence of hypothyroidism than those with NLR ≥ 5 (26%: 20 of 78 patients vs 4%: 1 of 26 patients; P = 0.022). Additionally, treatment continuity in patients with hypothyroidism was significantly longer than in those without hypothyroidism (median not reached vs 7 times administration, P = 0.010). Patients with maximum NLR < 3.5 until the development of hypothyroidism had a significantly earlier onset of hypothyroidism than those with maximum NLR ≥ 5 (hazard ratio for low tertile [NLR < 3.5] vs high tertile [NLR ≥ 5]: 5.33, P = 0.011). CONCLUSION: Low NLR at treatment initiation increases the incidence of treatment-induced hypothyroidism. Furthermore, its persistence may be a risk factor for the early onset of hypothyroidism.