Simultaneous Detection Method of 11 Respiratory Drug Substances Including Theobromine, Oxymetazoline, etc. in Adulterated Dietary Supplements Using Liquid Chromatography-Electrospray Ionization-Tandem Mass Spectrometry and Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry Analysis.

Recently, the demand for respiratory disease-related products has surged due to the influence of coronavirus disease 2019, prompting warnings about illegal dietary supplements containing unauthorized substances. Additionally, adulterated dietary supplements are continuously detected in open markets, posing significant public health safety problem. In this study, we developed and validated an analytical method for 11 respiratory drug substances using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) and proposed optimal conditions for LC-quadrupole time-of-flight MS (LC-QTOF-MS) to determine the fragmentation patterns of each substance. This method underwent thorough validation considering specificity, linearity, limits of detection and quantification, accuracy, precision, matrix effect, stability, etc. All results met international guidelines. These validated methods were applied to 52 dietary supplements advertised for treating respiratory diseases and enhancing respiratory function, among which one sample was found to contain 313.7 mg/g of theobromine. This determination was made by comparing the product ion ratios with the standards and subsequent quantification. To re-confirm the detected substances, their fragmentation patterns were compared with those of the standards using LC-QTOF-MS. In conclusion, the mass-based information, coupled with the LC-ESI-MS/MS method development, can be successfully applied to rapidly identify 11 respiratory drug substances in illegal dietary supplements used for respiratory disease treatment. The developed simultaneous detection method contributes to public health and safety improvements.

Metabolite analysis of 14C-labeled chloromethylisothiazolinone/methylisothiazolinone for toxicological consideration of inhaled isothiazolinone biocides in lungs.

5-Chloro-2-methyl-4-isothiazolin-3-one (CMIT) and 2-methyl-4-isothiazolin-3-one (MIT) used as preservatives in various products, including humidifier disinfectants, presents substantial health hazards. This research delves into the toxicological assessments of CMIT/MIT in the respiratory system using animal models. Through the synthesis of radiolabeled [14C]CMIT and [14C]MIT, we investigated the biological uptake and in vivo behaviors of CMIT/MIT in the respiratory tissues following intratracheal exposure. Quantitative whole-body autoradiography (QWBA) revealed significant persistence of CMIT/MIT in lung tissue. In addition, radio high-performance liquid chromatography (radio-HPLC) with tandem mass spectrometry (LC-MS/MS) was employed for metabolite profiling and identification. Notably, around 28% of the radiolabel was retained in tissue after the extraction step, suggesting covalent binding of CMIT/MIT and their metabolites with pulmonary biomolecules. This observation demonstrates the propensity of the electrophilic isothiazolinone ring in CMIT/MIT to undergo chemical interactions with biothiols in proteins and enzymes, fostering irreversible alterations of biomolecules. Such accumulations of transformations could result in direct toxicity at both cellular and organ levels. Additionally, the detection of metabolites, including a MIT dimer conjugated with glutathione (GSH), as analyzed by mass spectrometry indicates the possible reduction of cellular GSH levels and subsequent oxidative stress. This investigation offers an in-depth insight into the toxic mechanisms of CMIT/MIT, underlying their capability to engage in complex formations with biomacromolecules and induce pronounced respiratory toxicity. These results highlight the imperative for stringent safety assessments of these chemicals, advocating for improved public health and safety measures in the use of chemicals.

Current Status of Trypanosoma grosi and Babesia microti in Small Mammals in the Republic of Korea.

Small mammals, such as rodents and shrews, are natural reservoir hosts of zoonotic diseases, including parasitic protozoa. To assess the risk of rodent-borne parasitic protozoa in the Republic of Korea (ROK), this study investigated the status of parasitic protozoa, namely Trypanosoma, Babesia, and Theileria, in small mammals. In total, 331 blood samples from small mammals were analyzed for parasites using PCR and sequenced. Samples were positive for Trypanosoma grosi (23.9%; n = 79) and Babesia microti (10%; n = 33) but not Theileria. Small mammals from Seogwipo-si showed the highest infection rate of T. grosi (48.4%), while the highest B. microti infection rate was observed in those from Gangneung-si (25.6%). Sequence data revealed T. grosi to be of the AKHA strain. Phylogenetic analysis of B. microti revealed the US and Kobe genotypes. B. microti US-type-infected small mammals were detected throughout the country, but the Kobe type was only detected in Seogwipo-si. To our knowledge, this is the first nationwide survey that confirmed T. grosi and B. microti infections at the species level in small mammals in the ROK and identified the Kobe type of B. microti. These results provide valuable information for further molecular epidemiological studies on these parasites.

Neoadjuvant chemotherapy followed by surgery for HPV-associated tonsillar cancer: Does imaging reflect the pathological response?

OBJECTIVES: The purpose of this study was to present our evaluation of the outcome of tonsillar cancer managed with neoadjuvant chemotherapy followed by surgery as definitive treatment. MATERIALS AND METHODS: Thirty-eight patients with human papilloma virus (HPV)-associated tonsillar cancer were treated with neoadjuvant chemotherapy followed by surgery. The volume reduction response of the tumor to neoadjuvant chemotherapy was evaluated and verified by histopathology. RESULTS: The complete pathologic response (pCR) rates at primary and nodal sites were 60 % and 45 %. Tumor volume reduction ≥78.8 % following neoadjuvant chemotherapy predicted pCR of the cervical node. In addition, the optimal cut-off value to predict pCR at the primary tumor site was 83.4 % volume reduction but was not a significant result. For pCR, neoadjuvant chemotherapy decreased the pathological adverse features, significantly reducing the need for adjuvant therapy. The overall survival of the adjuvant group was 79.2 %, and that of the non-adjuvant group was 87.5 %, with disease-free survival of 65.9 % and 54.2 %. There was no significant difference between the two groups. CONCLUSION: Neoadjuvant chemotherapy followed by surgery proved to be a good therapeutic option for management of HPV-associated tonsillar cancer. A greater reduction in tumor volume in post-neoadjuvant chemotherapy imaging predicts a complete pathologic response.

Oncologic and functional outcomes of neoadjuvant chemotherapy followed by surgery in human papillomavirus-positive tonsillar cancer.

BACKGROUND: Functional outcomes of neoadjuvant chemotherapy in human papillomavirus (HPV)-positive tonsillar cancer remained unclear. METHODS: We retrospectively reviewed the medical records of HPV-positive patients with tonsillar cancer. Of 112 patients, 38 were assigned to a neoadjuvant chemotherapy group and 74 were assigned to an upfront surgery group. RESULTS: Pathological analyses showed that the risks of close or positive resection margins and lymphovascular invasion were lower in patients who received neoadjuvant chemotherapy. The 5-year disease-free survival was significantly higher in the neoadjuvant chemotherapy group than in the upfront surgery group, but the 5-year overall survival was not. The time to commencement of oral feeding and the mean hospital stay were significantly shorter in the neoadjuvant chemotherapy group. The neoadjuvant chemotherapy group was more likely than the upfront surgery group to resume a regular diet. CONCLUSIONS: Compared with upfront surgery, neoadjuvant chemotherapy improved the functional outcomes and 5-year disease-free survival.

Bioaccumulation and in vivo fate of toxic benzylalkyldimethylammonium chloride in rats via the radiotracer analysis.

Benzylalkyldimethylammonium chloride (BAC), a quaternary ammonium compound (QAC), is utilized in industrial and biomedical applications for antimicrobial purposes. Since the coronavirus disease (COVID-19) outbreak, various types of BAC-containing household chemicals have been produced. BACs have several adverse effects; however, their biological uptake, translocation, and excretion in animal models (essential for better understanding in vivo behavior and toxicological impact) remain unclear. In this study, we performed the first biodistribution and whole-body imaging studies of BAC in male Sprague Dawley rats, using two different administration routes. Quantitative whole-body autoradiography (QWBA) data obtained for intranasal 14C-labeled BAC ([14C]C12-BAC) exposure showed substantial uptake values for the respiratory organs (e.g. 346 ng g-1 of lung at 3 h post administration) and the radiotracer was transported to other internal organs. The amount of radiotracer in the heart, adrenal gland, and pancreas were 198, 1410, and 186 ng g-1 tissue respectively at 168 h following exposure. Autoradiograms obtained after intravenous injection also showed high accumulation and slow excretion in these organs. The cumulative excretion analysis revealed that approximately 6.4% of the administered radioactivity remained in rats after a week. The results indicated that continuous inhalation exposure to BAC leads to potential toxic effects in extrapulmonary organs and the respiratory tract. Thus, the radiolabeling method utilized may help assess various synthetic QACs in living subjects.

Imported human babesiosis in the Republic of Korea, 2019: two case reports.

Human babesiosis is a tick-borne disease induced by the genus Babesia and has been significantly reported in the Republic of Korea. This report shows the cases of 2 patients with human babesiosis who traveled to the USA in 2019. The 2 patients experienced fever and had travel histories to babesiosis-endemic regions. The diagnoses of both cases were verified by the identification of Babesia-infected red blood cells on blood smears. One patient was found to be infected with Babesia microti using polymerase chain reaction (PCR) for 18S rRNA, which discovered the phylogenetic link to the B. microti strain endemic in the USA. The 2 patients recovered from fever with subsequent hemoparasite clearance. Babesiosis could be diagnosed in anyone with histories of travel to babesiosis-endemic countries and tick bites. Furthermore, Babesia-specific PCR is required for determining geno-and phenotypic characteristics.

Therapeutic effects of clonazepam in patients with burning mouth syndrome and various symptoms or psychological conditions.

Burning mouth syndrome (BMS) is frequently accompanied by dysgeusia and xerostomia. Clonazepam has been widely prescribed and is effective, but it is unclear whether clonazepam also affects the symptoms that accompany BMS, or whether such symptoms affect treatment outcomes. Here, we investigated the therapeutic outcomes in BMS patients with various symptoms or comorbidities. We retrospectively reviewed 41 patients diagnosed with BMS between June 2010 and June 2021 at a single institution. Patients were instructed to take clonazepam for 6 weeks. Before the first dose, burning pain intensity was measured using a visual analog scale (VAS); the unstimulated salivary flow rate (USFR), psychologic characteristics, site(s) of pain, and any taste disturbance were evaluated. Burning pain intensity was measured again after 6 weeks. Thirty-one of the 41 patents (75.7%) exhibited a depressed mood, whereas more than 67.8% of the patients exhibited anxiety. Subjective xerostomia was reported by ten patients (24.3%). The mean salivary flow rate was 0.69 mL/min and hyposalivation (an unstimulated salivary flow rate ≤ 0.5 mL/min) was apparent in ten patients (24.3%). Dysgeusia was present in 20 patients (48.7%); a bitter taste (n = 15, 75%) was reported by the largest proportion of patients. Patients who reported a bitter taste responded best in terms of burning pain reduction after 6 weeks (n = 4, 26.6%). Overall, 32 patients (78%) reported decreased oral burning pain after clonazepam (mean VAS score changed from 6.56 to 5.34) use. Patients who reported taste disturbances exhibited a significantly greater decrease in burning pain, compared with other patients (mean VAS score changed from 6.41 to 4.58) (p = 0.02). Clonazepam significantly improved burning pain in BMS patients who had taste disturbances.

A Rare Case of Imported Cutaneous Leishmaniasis Caused by Leishmania infantum in the Republic of Korea, 2021.

Leishmaniasis is a neglected tropical disease and an infectious disease transmitted by sandflies that occurs worldwide. In the absence of physicians seeking to identify the causes of disease in non-endemic areas, appropriate diagnoses cannot be made, thereby hampering effective treatment. In this report, we examined a nodular lesion on a patient's chin by performing a biopsy and molecular analysis. The biopsy finding led to the identification of a Leishmania amastigote. On the basis of PCR analysis of the internal transcribed spacer 1 gene and 5.8 S ribosomal RNA with a subsequent BLAST search, we identified the causal organism as Leishmania infantum. The patient, who had visited Spain from 1 July to 31 August 2018, was accordingly diagnosed with cutaneous leishmaniasis and was administered liposomal amphotericin B, which successfully treated the skin lesion. Travel history plays an important role in the diagnosis of leishmaniasis, and physicians should bear in mind that travelers can also introduce diseases and pathogens to non-endemic areas. Identification of Leishmania at the species level will increase the efficacy of treatment.

Predictive factors of distant metastasis in surgically treated HPV-positive tonsil cancer.

BACKGROUND: Human papilloma virus (HPV)-related tonsil cancer is associated with favorable outcomes. OBJECTIVE: The purpose of this study was to define factors affecting distant metastasis in patients with surgically treated HPV-positive tonsil cancer. METHODS: The present study enrolled 76 patients diagnosed with HPV-positive tonsil cancer who underwent primary surgery between January 2010 and December 2021. RESULTS: Twelve (15.7%) patients experienced a distant failure with a median follow-up time of 43 months. Sites of distant metastasis included the lung (n = 10), liver (n = 1), and brain (n = 1). Upon multivariate analysis, an advanced T stage (odds ratio [OR]: 13.94, 95% confidence interval [CI]: 1.29-149.863, p = 0.003) and margin involvement (OR: 5.96, 95% CI: 1.33-26.76, p = 0.02) were independent predictors of distant metastases. The five-year disease-specific survival for the entire cohort was 85%. The multivariate analysis confirmed that distant metastasis (hazard ratio [HR]: 12.688, 95% CI: 3.424-47.016; p < 0.001) and margin involvement (HR: 6.243; 95% CI: 1.681-23.191; p = 0.006) were significant factors associated with the five-year disease-specific survival. CONCLUSION: HPV-positive tonsil cancer patients with an advanced T stage and a positive surgical margin have a substantial risk of distant metastases. Distant metastasis and margin involvement are factors that affect their survival.

Persistent subjective voice symptoms for two years after thyroidectomy.

BACKGROUND: Voice change after thyroidectomy is an important issue in thyroid surgery. However, little is known about long-term voice outcomes after thyroidectomy. This study investigates the long-term voice outcomes of thyroidectomy up to two years after surgery. Also, we analyzed the pattern of recovery through acoustic tests over time. METHODS: We reviewed data from 168 patients who underwent thyroidectomy between January 2020 and August 2020 at a single institution. The Thyroidectomy-related Voice and Symptom Questionnaire (TVSQ) score and acoustic voice analysis results were examined preoperatively and postoperative one, three, and six months, and one and two years after surgery. We divided patients into two groups based on the TVSQ score (≥15 or <15) at two years postoperatively. We investigated the difference of acoustic characteristics between the two groups and analyzed correlations between acoustic parameters and various clinical and surgical factors. RESULTS: Voice parameters tended to recover, but some parameters and TVSQ scores exhibited deterioration two years after surgery. In the subgroups, among the many clinicopathologic factors examined, voice abuse history including professional voice users (p = 0.014), greater extent of thyroidectomy and neck dissection (p = 0.019, p = 0.029), and high pitch voice (F0; p = 0.005, SFF; p = 0.016) were associated with high TVSQ score at two years. CONCLUSIONS: Patients frequently experience voice discomfort after thyroidectomy. After surgery, voice abuse history including professional voice users, greater extent of surgery, and higher pitch voice are associated with worse voice quality and increased risk of persistent voice symptoms over the long-term.

Perineural Invasion Predicts Local Recurrence and Poor Survival in Laryngeal Cancer.

(1) Background: Perineural invasion (PNI) in head and neck cancer is associated with a poor prognosis; however, the effect of PNI on the prognosis of laryngeal cancer remains under debate. This retrospective study aimed to investigate the effect of PNI in fresh or salvaged larynges on survival in patients who had undergone laryngectomy for squamous cell carcinoma. (2) Methods: This study enrolled 240 patients diagnosed with laryngeal cancer who had undergone open surgery at Seoul St. Mary's Hospital, Korea. The effects of PNI, other histopathologic factors, and treatment history on survival and recurrence patterns were assessed. (3) Results: PNI was observed in 30 of 240 patients (12.5%). PNI (HR: 3.05; 95% CI: 1.90-4.88; p = 0.01) was a significant predictor of poor 5-year disease-free survival. In fresh cases, preepiglottic invasion (HR: 2.37; 95% CI: 1.45-3.88; p = 0.01) and PNI (HR: 2.96; 95% CI: 1.62-2.96; p = 0.01) were negative prognostic factors for 5-year disease-free survival. In the salvage group, however, only PNI (HR: 2.74; 95% CI: 1.26-5.92; p = 0.01) was a significant predictor of disease-free survival. Further, PNI significantly influenced high local recurrence (HR: 5.02, 95% CI: 1.28-9.66; p = 0.02). (4) Conclusions: Independent of treatment history, PNI is a prognostic factor for poor survival and local recurrence in laryngeal cancer.

Correlation between serum vitamin D level and benign paroxysmal positional vertigo recurrence.

OBJECTIVE: Benign paroxysmal positional vertigo (BPPV) is the most common cause of dizziness in the general population. BPPV is known to be closely related to the serum vitamin D level. This study aimed to examine the relationship between serum vitamin D levels and BPPV recurrence. METHODS: A retrospective chart review was conducted on 50 patients diagnosed with posterior and lateral canal BPPV. The diagnosis of BPPV was based on the finding of vertigo and nystagmus induced by certain head positions (The Dix-Hallpike maneuver and head roll tests). The patients were classified into BPPV recurrence (Group A) and non-recurrence groups (Group B). Otolith function was assessed by cervical vestibular evoked myogenic potential (cVEMP) and ocular vestibular evoked myogenic potential (oVEMP), and their association with vitamin D levels was evaluated. RESULTS: There were 19 subjects in Group A and 31 in Group B. There were no significant differences in age, sex, cVEMP, and oVEMP between the two groups. The average vitamin D level was 12.9 ± 8.0 ng/mL for Group A and 19.2 ± 8.2 ng/mL for Group B, and the difference between the groups was significant (p = 0.011). In the receiver operating characteristic curve analysis for BPPV recurrence with the best sensitivity and specificity, the optimal cut-off value of total serum vitamin D was determined as 12.74 ng/mL. Furthermore, reclassifying the patients based on the cut-off value showed a significantly higher recurrence rate in the group with a lower serum vitamin D level (70.5% vs. 22.5%, p = 0.007). CONCLUSION: This complex finding highlights the importance of measuring serum vitamin D levels to monitor and evaluate patients at risk of BPPV recurrence.

Are second primary head and neck cancers with previous hematological malignancy more aggressive than de novo head and neck cancers?

OBJECTIVES: Secondary solid tumors can occur after the treatment of hematological malignancies and are associated with a poor prognosis. We evaluated the survival outcomes of patients with second primary head and neck cancers according to the site of cancer origin, type of hematological malignancy, and age. MATERIALS AND METHODS: We enrolled all patients who underwent surgery for second primary head and neck cancer and were previously treated for hematological malignancy between 1997 and 2020. We analyzed the survival outcomes of patients with second primary head and neck cancer, and compared them with 3126 de novo head and neck cancer patients diagnosed during the same period at our hospital. RESULTS: The 5-year overall survival (OS) rate was significantly worse for second primary head and neck cancer patients than de novo cancer patients (52.0 % and 77.9 %, respectively; p = 0.04) and those results were similarly observed in second primary oral cavity cancer (33.3 % and 75.7 %, respectively; p < 0.01). Patients with myelodysplastic syndrome and acute myeloid leukemia showed significantly worse 5-year OS rate than those with other types of hematological malignancies (p = 0.036). Multivariate analysis showed that bone marrow transplantation (BMT) was a risk factor for the recurrence of head and neck cancers (odds ratio = 6.635, p = 0.042). CONCLUSION: Patients with second primary head and neck cancer, particularly of the oral cavity, had a worse prognosis than patients with de novo head and neck cancer. BMT predicts recurrence in second primary head and neck cancer patients.

Predictive Value of 18F-Fluorodeoxyglucose Positron-Emission Tomography Metabolic and Volumetric Parameters for Systemic Metastasis in Tonsillar Cancer.

Although the prognosis of tonsillar cancer (human papillomavirus-positive oropharyngeal squamous cell carcinoma) is improving, disease control failure (distant metastasis) still occurs in some cases. We explored whether several 18F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) parameters can predict metastasis. We retrospectively reviewed the medical records of 55 patients with tonsil squamous cell carcinoma who underwent pretreatment 18F-FDG positron-emission tomography/computed tomography (PET/CT) followed by primary surgery. During the follow-up period, systemic metastases were found in 7 of the 55 patients. The most common sites were the lungs (33%), bone (22%), brain/skull base (22%), small bowel (11%), and liver (11%). Pathologically, P53 mutation was less common in patients with systemic metastasis (41.7% vs. 14.3%, p = 0.054) than without systemic metastasis. In terms of PET parameters, the metabolic tumor volume (MTV2.5) and total lesion glycolysis (TLG2.5) values were lower in the primary tumor, and higher in the metastatic lymph nodes, of human papillomavirus (HPV)-positive compared to HPV-negative patients (all p < 0.05). The MTV2.5, TLG2.5, and tumor−to−liver uptake ratio were 36.07 ± 54.24 cm3, 183.46 ± 298.62, and 4.90 ± 2.77, respectively, in the systemic metastasis group, respectively; all of these values were higher than those of the patients without systemic metastasis (all p < 0.05). The MTV2.5 value was significantly different between the groups even when the values for the primary tumor and metastatic lymph nodes were summed (53.53 ± 57.78 cm3, p = 0.036). The cut-off value, area under the curve (95% confidence interval), sensitivity, and specificity of MTV2.5 for predicting systemic metastasis were 11.250 cm3, 0.584 (0.036−0.832), 0.571, and 0.565, respectively. The MTV2.5 of metastatic lymph nodes and summed MTV2.5 values of the primary tumor and metastatic lymph nodes were significantly higher in tonsillar cancer patients with than without systemic metastases. We suggest PET/CT scanning for pre-treatment cancer work-up and post-treatment surveillance to consider additional systemic therapy in patients with a high risk of disease control failure.

Biodistribution and respiratory toxicity of chloromethylisothiazolinone/methylisothiazolinone following intranasal and intratracheal administration.

A variety of isothiazolinone-containing small molecules have been registered and used as chemical additives in many household products. However, their biodistribution and potential harmful effects on human health, especially respiratory effects, were not yet identified in sufficient detail. The purpose of this study was to investigate whether a biocide comprising a mixture of chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) could reach the lungs and induce lung injury when exposure occurs by two administration routes involving the respiratory tract: intratracheal and intranasal instillation. To investigate the biodistribution of CMIT/MIT, we quantified the uptake of 14C-labeled CMIT/MIT in experimental animals for up to seven days after intratracheal and intranasal instillation. In the toxicity study, lung injury was assessed in mice using total inflammatory cell count in bronchoalveolar lavage fluid (BALF) and lung histopathology. The results of the biodistribution study indicated that CMIT/MIT were rapidly distributed throughout the respiratory tract. Using quantitative whole-body autoradiogram analysis, we confirmed that following intranasal exposure, CMIT/MIT reached the lungs via the respiratory tract (nose-trachea-lung). After 5 min post intratracheal and intranasal instillation, the amount of radiotracer ([14C]CMIT/MIT) in the lungs was 2720 ng g-1 and 752 ng g-1 tissue, respectively, and lung damage was observed. A higher amount of the radiotracer resulted in higher toxicity. Both intratracheal and intranasal instillation of CMIT/MIT increased inflammatory cell counts in the BALF and induced injuries in the alveoli. The frequency and the severity scores of injuries caused by intratracheal instillation were approximately-four to five times higher than those induced by intranasal instillation. Therefore, we concluded that CMIT/MIT could reach the lungs following nasal and intratracheal exposure and cause lung injuries, and the extent of injury was dependent on the exposure dose.

Association between CYP2D6 phenotype and recurrence of Plasmodium vivax infection in south Korean patients.

BACKGROUND: Primaquine is activated by CYP2D6 in the hepatocytes. In Korea, primaquine is the only hypnozoitocidal agent used for patients with vivax malaria. Thus, patients with poor CYP2D6 activity could have an increased risk of primaquine failure and subsequent relapse. The study sought to identify the association between CYP2D6 phenotype and recurrence of malaria in Korean patients. METHODS: A total of 102 patients with vivax malaria were prospectively enrolled from eight institutions in Korea. An additional 38 blood samples from patients with recurred vivax malaria were provided by the Korea Disease Control and Prevention Agency. Malaria recurrence was defined as more than one episode of vivax malaria in the same or consecutive years. CYP2D6 star alleles, phenotypes, and activity scores were examined. RESULTS: Genotyping for CYP2D6 was successful in 101 of the prospectively enrolled patients and 38 samples from the Korea Disease Control and Prevention Agency, of which 91 were included in the no-recurrence group and 48 were included in the recurrence group. Reduced CYP2D6 activity (intermediate metabolizer) phenotype was more common in the recurrence group than in the no-recurrence group (OR, 2.33 (95% CI, 1.14-4.77); p = 0.02). Patients with lower CYP2D6 activity had a higher probability of recurrence (p = 0.029). CONCLUSION: This study suggests that CYP2D6 polymorphism may affect primaquine efficacy and thus Plasmodium vivax recurrence in Korea.

Artesunate drug-loaded 2D nano-shuttle landing on RBCs infected with malaria parasites.

Artesunic acid (AS0), a derivative of artemisinin, is recommended for the treatment of severe and complicated malaria, but its use is limited because of limitations such as a short half-life, non-specific targeting capability, low bioavailability, etc. To overcome these issues, a novel 2D inorganic delivery shuttle system for an AS0 drug to target the malarial host, red blood cells (RBCs), is explored by immobilizing AS0 into 2D metal hydroxides to form AS- (artesunate, the deprotonated form of artesunic acid) nanohybrid drugs. Haemolysis assay showed that the AS- nanohybrids not only are haemo-compatible but also target RBCs due to the electrostatic interaction and hydrogen bonding between RBCs and AS- nanohybrids. As clearly demonstrated by the subsequent parasite lactate dehydrogenase assay, the antimalarial effect of the AS- nanohybrids is determined to be 6 times more effective than that of intact AS0 against malaria. Therefore, the AS- nanohybrids with haemo-compatible 2D inorganic carriers could be the promising drug delivery systems for targeting the malarial host, RBCs.

Close Surgical Margins in Oral and Oropharyngeal Cancer: Do They Impact Prognosis?

Introduction. Mucosal margins exhibit a mean shrinkage of 30−40% after resection of oral and oropharyngeal cancers, and an adequate in situ surgical margin frequently results in a pathological close margin. However, the impact on prognosis remains unclear. We investigated the impact of a pathological close margin on disease-free survival (DFS) and overall survival (OS). Methods. We retrospectively reviewed the clinicopathological data of 418 patients diagnosed with squamous cell carcinomas of the oral cavity or oropharynx who underwent initial surgery (with curative intent) at our institute between 2010 and 2016. Results. Of the total population, the pathological marginal status of 290 (69.4%) patients was reported as clear (>5 mm), 61 (14.6%) as close (>1 mm, ≤5 mm), and 67 (16.0%) as positive (≤1 mm). The 5-year DFSs were 79.3%, 65.1%, and 52% in patients in the negative margin (group 1), close margin (group 2), and positive margin (group 3) groups, respectively. The difference between groups 1 and 2 was not significant (p = 0.213) but the difference between groups 2 and 3 was (p = 0.034). The 5-year OSs were 79.4%, 84%, and 52.3% in groups 1, 2, and 3, respectively. The difference between groups 1 and 2 was not significant (p = 0.824) but the difference between groups 2 and 3 was (p = 0.001). In multivariate analysis, older age, advanced T stage, and a positive margin were independently prognostic of the 5-year DFS and OS. Conclusion. In conclusion, the OS of patients with close margins was no different than that of others when appropriate postoperative adjuvant and/or salvage treatment were/was prescribed. However, we could not determine the impact of close margins on locoregional recurrence given various biases in our study setting. A future prospective study is needed.

Four Times of Relapse of Plasmodium vivax Malaria Despite Primaquine Treatment in a Patient with Impaired Cytochrome P450 2D6 Function.

Plasmodium vivax exhibits dormant liver-stage parasites, called hypnozoites, which can cause relapse of malaria. The only drug currently used for eliminating hypnozoites is primaquine. The antimalarial properties of primaquine are dependent on the production of oxidized metabolites by the cytochrome P450 isoenzyme 2D6 (CYP2D6). Reduced primaquine metabolism may be related to P. vivax relapses. We describe a case of 4 episodes of recurrence of vivax malaria in a patient with decreased CYP2D6 function. The patient was 52-year-old male with body weight of 52 kg. He received total gastrectomy and splenectomy 7 months before the first episode and was under chemotherapy for the gastric cancer. The first episode occurred in March 2019 and each episode had intervals of 34, 41, and 97 days, respectively. At the first and second episodes, primaquine was administered as 15 mg for 14 days. The primaquine dose was increased with 30 mg for 14 days at the third and fourth episodes. Seven gene sequences of P. vivax were analyzed and revealed totally identical for all the 4 samples. The CYP2D6 genotype was analyzed and intermediate metabolizer phenotype with decreased function was identified.