A case in which TAS-102 produced disease control without severe adverse events in a patient with recurrent colorectal cancer and dihydropyrimidine dehydrogenase deficiency

Fluoropyrimidine is commonly used to treat unresectable cases of metastatic colorectal cancer or as an adjuvant therapy for colorectal cancer. Dihydropyrimidine dehydrogenase (DPD) is an enzyme encoded by the DPYD gene, which is responsible for the rate-limiting step in pyrimidine catabolism and breaks down >80% of standard doses of 5-fluorouracil (5-FU). Reductions in DPD activity increase the half-life of 5-FU, resulting in excess 5-FU accumulation and toxicity, which can lead to life-threatening side effects. There have been several published case reports about DPD deficiency in colorectal cancer patients from Western countries. However, case reports of DPD deficiency in Japanese colorectal cancer patients are rare because the measurement of DPD activity is not covered by the public medical insurance system in Japan, and DPD activity is not currently measured in daily clinical practice. Furthermore, there have not been any reports about anticancer drug therapy for Japanese patients with DPD deficiency. In this report, we describe a case in which a Japanese patient with colorectal cancer was diagnosed with DPD deficiency. The DPD deficiency arose as a severe adverse effect of mFOLFOX6/CapOX treatment for recurrent colorectal cancer, and the patient was subsequently treated with TAS-102, without experiencing any severe adverse effects. We report this case along with a review of the literature.

Herbal Medicine for Functional Dyspepsia with Psychological Symptoms: A Systematic Review and Meta-Analysis

Purpose: Functional dyspepsia (FD) is a chronic syndrome accompanied by repetitive digestive symptoms that appear in the upper gastrointestinal tract and are not caused by specific diseases. Psychological symptoms like anxiety, depression, insomnia, and somatization are frequently observed in FD. The purpose of this study was to review the effect of herbal medicine on the psychological symptoms that accompany FD.Methods: Database search (PubMed, EMBASE, KISS, Kmbase, KoreanMed, NDSL, OASIS, CNKI) was performed on February 24, 2021; a total of 1825 studies were searched. After the screening, 22 studies were included.Results: The studies were assessed by Cochrane RoB 2 and sorted into a table according to psychological symptoms. Meta-analysis was performed to estimate the effect of herbal medicine. Twenty of the twenty-two studies reported that herbal medicine was significantly more effective than the control group. Only three of the studies did not have a high risk of bias.Conclusion: Herbal medicine was significantly effective with or without Western medicine and had fewer adverse effects. Severe adverse effect was not reported. Psychological symptoms in FD affect onset and duration of FD, and some FD patients want to be treated for their anxiety before other symptoms. Reliable information about treatment for the psychological symptoms of FD is lacking. We reviewed the effect of herbal medicine treatment in this study, the results of which could be selected for primary or secondary treatment for FD.

Intensive Home Care for COVID-19 to Reduce Admissions

Hospitalization for COVID-19 has placed a significant financial and logistical burden on hospitals and health care systems. Limitations on visitation and isolation precautions have made hospitalization more isolating for patients in the time of COVID-19. Increasing the provision of healthcare delivered at home has the potential to decrease healthcare costs by providing care at home which may be preferred for many patients. We describe a series of 39 patients who were treated with intravenous remdesivir at home in addition to oxygen, dexamethasone, and anticoagulants. These patients were at high risk for decompensation due to COVID-19 and met accepted criteria for admission—need for supplemental oxygen and intravenous remdesivir. All patients had home lab monitoring and frequent telehealth visits. Over the study period 13 (33%) of patients were admitted for worsening COVID-19 and 5 (13%) died. Twenty-six patients avoided admission, and none experienced a severe adverse effect from in-home treatment. The expanded use of telehealth services due to the COVID-19 pandemic has the potential to increase the frequency of patient monitoring by physicians and the provision of care and monitoring usually restricted to hospitalized patients.

Anti-Platelet Factor 4 Antibodies Causing VITT do not Cross-React with SARS-CoV-2 Spike Protein

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe adverse effect of ChAdOx1 nCoV-19 COVID-19 vaccine (Vaxzevria) and COVID-19 vaccine Janssen (Ad26.COV2.S), and associated with unusual thrombosis. VITT is caused by anti-platelet factor 4 (PF4) antibodies activating platelets through their FcgRIIa receptors. Antibodies activating platelets through FcgRIIa receptors have also been identified in COVID-19 patients. These findings raise concern that vaccination-induced antibodies against anti-SARS-CoV-2 spike protein cause thrombosis by cross-reacting with PF4. Immunogenic epitopes of PF4 and SARS-CoV-2 spike protein were compared using in-silico prediction tools and 3D-modelling. The SARS-CoV-2 spike protein and PF4 share at least one similar epitope. Reactivity of purified anti-PF4 antibodies from patients with VITT was tested against recombinant SARS-CoV-2 spike protein. However, none of the affinity-purified anti-PF4 antibodies from 14 VITT patients cross-reacted with SARS-CoV-2 spike protein. Sera from 222 PCR-confirmed COVID-19 patients from five European centers were tested by PF4/heparin ELISA and PF4-dependent platelet activation assays. We found anti-PF4 antibodies in 19 of 222 (8.6%) COVID-19 patient sera. However, only four showed weak to moderate platelet activation in the presence of PF4, and none of these patients developed thrombotic complications. Among 10 of 222 (4.5%) COVID-19 patients with thrombosis, none showed PF4-dependent platelet-activating antibodies. In conclusion, antibodies against PF4 induced by vaccination do not cross-react with the SARS-CoV-2 spike protein, indicating that the intended vaccine-induced immune response against SARS-CoV-2 spike protein is not the trigger of VITT. PF4-reactive antibodies found in COVID-19 patients of the present study were not associated with thrombotic complications.

A case of palmar hypopigmentation induced by capecitabine in a gastrointestinal cancer patient

Introduction Capecitabine is an antimetabolite antineoplastic agent widely used in the treatment gastrointestinal cancers. The common frequently reported cutaneous adverse drug reaction associated with capecitabin are a palmar-plantar erythrodysesthesia syndrome, rash and hyperpigmentation. This case reports a capecitabine-induced palmar hypopigmentation. Case report We report the case of a 74-years old patient with jejunum adenocarcinoma treated by capecitabine. The patient developed a pseudo-vitiligo after 2 cycles capecitabine and without history of cutaneous disorders. The skin lesions were characterized with skin hypopigmentation on both hands. Management and outcome: The hypopigmentation slowly recovered after capecitabine discontinuation. Conclusion This is the first described case of pseudo-vitiligo induced by capecitabine. This impressive but non-severe adverse effect should be known by oncologists and oncology pharmacists to reassure the patients in particular about the possible recovery after discontinuation of capecitabine.

Case Report: Polyvinylpyrrolidone deposition disease from repeated injection of opioid substitution drugs: report of a case with a fatal outcome

Background: Intravenous injection of oral opioid substitution drugs (OSD) is widespread among injecting drug users. Several OSDs contain the polymer polyvinylpyrrolidone (PVP) as an excipient. Parenterally administered PVP of high molecular weight may accumulate in tissues and organs. This phenomenon was first described in the 1950s, when PVP was utilised in medication for parenteral use. We report a case of an opioid-addicted patient with extensive PVP–deposition caused by repeated injections of OSDs. Case presentation: A 30-year-old male drug addicted patient in opioid substitution therapy (OST) was repeatedly referred to his local hospital in a poor general condition. Work-up revealed severe normocytic anaemia, renal insufficiency, pancreas insufficiency and pathological fractures. Biopsies from fractured bones, bone marrow and gastric mucosa showed extensive infiltrates of histiocytes with intracytoplasmic vacuoles. Vacuole content stained slightly bluish in hematoxylin and eosin stain, red in Congo red stain and black in periodic acid methenamine silver stain. The morphological appearance and staining properties were in accordance with the diagnosis of PVP deposition. The patient had been injecting both buprenorphine tablets and a specific methadone syrup for several years. The methadone syrup contained large amounts of high molecular weight PVP, making it the most likely cause of the deposition. His health quickly deteriorated and he died, impaired by multi-organ failure and cachexia, five years after the first diagnosis of PVP-deposition. The autopsy revealed extensive PVP-deposition in all sampled organs and tissues. Conclusions: Histological investigation and the correct identification of PVP in the biopsies led to the discovery of a severe adverse effect from long-standing misuse of a drug. The disseminated PVP deposition likely contributed to multi-organ dysfunction and cachexia with a fatal outcome. The deposited PVP likely originated from repeated injections of a certain methadone syrup.

Incorporating outlier information into diffusion MR tractogram filtering for robust structural brain connectivity and microstructural analyses

The white matter structures of the human brain can be represented via diffusion tractography. Unfortunately, tractography is prone to find false-positive streamlines causing a severe decline in its specificity and limiting its feasibility in accurate structural brain connectivity analyses. Filtering algorithms have been proposed to reduce the number of invalid streamlines but the currently available filtering algorithms are not suitable to process data that contains motion artefacts that are typical in clinical research. We augmented the Convex Optimization Modelling for Microstructure Informed Tractography (COMMIT) filtering algorithm to adjust for signal drop-out artifacts due to subject motion present in diffusion-weighted images. We demonstrate with comprehensive Monte-Carlo whole brain simulations and in vivo infant data that our robust algorithm is capable to properly filter tractography reconstructions despite these artefacts. We evaluated the results using parametric and non-parametric statistics and our results demonstrate that if not accounted for, motion artefacts can have severe adverse effect in the human brain structural connectivity analyses as well as in microstructural property mappings. In conclusion, the usage of robust filtering methods to mitigate motion related errors in tractogram filtering is highly beneficial especially in clinical studies with uncooperative patient groups such as infants. With our presented robust augmentation and open-source implementation, robust tractogram filtering is readily available.

Case Report: Polyvinylpyrrolidone deposition disease from repeated injection of opioid substitution drugs: report of a case with a fatal outcome

Background: Intravenous injection of oral opioid substitution drugs (OSD) is widespread among injecting drug users. Several OSDs contain the polymer polyvinylpyrrolidone (PVP) as an excipient. Parenterally administered PVP of high molecular weight may accumulate in tissues and organs. This phenomenon was first described in the 1950s, when PVP was utilised in medication for parenteral use. We report a case of an opioid-addicted patient with extensive PVP–deposition caused by repeated injections of OSDs. Case presentation: A 30-year-old male drug addicted patient in opioid substitution therapy (OST) was repeatedly referred to his local hospital in a poor general condition. Work-up revealed severe normocytic anaemia, renal insufficiency, pancreas insufficiency and pathological fractures. Biopsies from fractured bones, bone marrow and gastric mucosa showed extensive infiltrates of histiocytes with intracytoplasmic vacuoles. Vacuole content stained slightly bluish in hematoxylin and eosin stain, red in Congo red stain and black in periodic acid methenamine silver stain. The morphological appearance and staining properties were in accordance with the diagnosis of PVP deposition. The patient had been injecting both buprenorphine tablets and a specific methadone syrup for several years. The methadone syrup contained large amounts of high molecular weight PVP, making it the most likely cause of the deposition. His health quickly deteriorated and he died, impaired by multi-organ failure and cachexia, five years after the first diagnosis of PVP-deposition. The autopsy revealed extensive PVP-deposition in all sampled organs and tissues. Conclusions: Histological investigation and the correct identification of PVP in the biopsies led to the discovery of a severe adverse effect from long-standing misuse of a drug. The disseminated PVP deposition likely contributed to multi-organ dysfunction and cachexia with a fatal outcome. The deposited PVP likely originated from repeated injections of a certain methadone syrup.

Risk Factors of Daptomycin-Induced Eosinophilic Pneumonia in a Population with Osteoarticular Infection

Background: Daptomycin-induced eosinophilic pneumonia (DEP) is a rare but severe adverse effect and the risk factors are unknown. The aim of this study was to determine risk factors for DEP. Methods: A retrospective cohort study was performed at the Bone and Joint Infection Unit of the Hospital Universitari Bellvitge (January 2014–December 2018). To identify risk factors for DEP, cases were divided into two groups: those who developed DEP and those without DEP. Results: Among the whole cohort (n = 229) we identified 11 DEP cases (4.8%) and this percentage almost doubled in the subgroup of patients ≥70 years (8.1%). The risk factors for DEP were age ≥70 years (HR 10.19, 95%CI 1.28–80.93), therapy >14 days (7.71, 1.98–30.09) and total cumulative dose of daptomycin ≥10 g (5.30, 1.14–24.66). Conclusions: Clinicians should monitor cumulative daptomycin dosage to minimize DEP risk, and be cautious particularly in older patients when the total dose of daptomycin exceeds 10 g.

The Bioequivalence of Emulsified Isoflurane With a New Formulation of Emulsion: A Single-Center, Single-Dose, Double-Blinded, Randomized, Two-Period Crossover Study

Background: Emulsified isoflurane is a novel intravenous general anesthetic obtained by encapsulating isoflurane molecules into emulsion. The formulation of emulsion has been improved according to the latest regulations of the China Food and Drug Administration. This study was designed to compare the bioequivalence of the new and previous formulation emulsion of isoflurane.Methods: In a single-center, single-dose, double-blinded, randomized, two-period crossover study, healthy volunteers received intravenous injection of 30 mg/kg of isoflurane with either previous formulation of emulsion isoflurane (PFEI) or new formulation of emulsion isoflurane (NFEI). Arterial and venous blood samples were obtained for geometric mean test/reference ratios of Cmax, AUC0-t, and AUC0-∞, as well as their 90% confidence interval (CI90) as the primary outcome. The secondary outcomes were safety measurements such as vital signs, 12-lead electrocardiography, adverse effects, and laboratory tests; and anesthesia efficacy was assessed by Modified Observer’s Assessment of Alertness/Sedation (MOAA/S) score, bispectral index (BIS), and loss/recovery of eyelash reflex.Results: 24 subjects were eligible, of which 21 completed the whole experiment (NFEI n = 21, PFEI n = 23). Arterial geometric mean test/reference ratios of Cmax, AUC0-t, and AUC0-∞ were 104.50% (CI90 92.81%–117.65%), 108.23% (94.51%–123.96%), and 106.53% (93.94%∼120.80%), respectively. The most commonly seen adverse effects for NFEI and PFEI were injection pain (38.1% vs. 34.8%), hypotension (19.0% vs. 13.0%), apnea (14.3% vs. 17.4%), and upper airway obstruction (14.3% vs. 13.0%). No severe adverse effect was observed. The effectiveness of general anesthesia was similar between the two formulations.Conclusion: The CI90 of Cmax, AUC0-t, AUC0-∞, NFEI, and PFEI were within the range of 80%–125%, suggesting bioequivalence between NFEI and PFEI. The safety and anesthesia effectiveness were also similar.