An 86-year-old man was referred to our hospital with pulmonary tuberculosis developed during postoperative chemotherapy for gastric cancer. We initiated treatment with an anti-tuberculosis drug. Following confirmation of the effectiveness of this regimen, we combined the treatment with anti-cancer drugs. Tuberculosis treatment was completed without any drug interactions or serious side effects due to multidrug administration. For cancer patients who developed tuberculosis, combination treatment requires careful observation; however, it is a treatment option that can control both diseases.

We encountered 3 cases suggesting that coadministration of herbal medicines may reduce the side effects of anticancer drugs and reinforce cancer growth control. In 2 cases, on observing anticancer drug resistance, it was possible to regain control of cancer growth by coadministering herbal medicines. In the remaining 1 case, thrombocytopenia was observed during chemotherapy, which could be avoided by coadministering a herbal medicine. If the expected effect is not obtained even after herbal medicine administration, it is important to consider additional herbal medications.

Nutrients are essential for all living organisms. Because growing cancer cells have strong metabolic demands, nutrient transporters are constitutively increased to facilitate the nutrient uptake. Among these nutrient transporters, L-type amino acid transporter 1 (LAT1), which transports large neutral amino acids including essential amino acids, is critical for cancer growth. Therefore, LAT1 has been considered as an attractive target for diagnosis and therapy of cancers. We have developed several lines of compounds for cancer diagnosis and therapy. To diagnose cancer by using positron emission tomography (PET) probes, we have created amino acid derivatives which are selectively transported by LAT1 and accumulated in cancer cells. In addition to amino acid derivatives as the LAT1 inhibitors, we also have made non-amino acid small compounds as anti-cancer drugs which inhibit LAT1 function and suppress tumor growth. The LAT1 targeting anti-cancer drug showed low toxicity but strong effects on various types of cancer cells in animal models. The novel PET probe is approved for clinical research and the new anti-cancer drug has been under clinical trial. Small compounds targeting the amino acid transporter bring us new tools for cancer diagnosis and therapy.

The patient was a 34-year-old woman. Surgical resection and chemotherapy had been performed on diagnosis of malignant melanoma in year X-9. Chronic thyroiditis was diagnosed in year X-8, but her thyroid function was normal. In November of the year X-1, the patient, who had metastasis to the left lung and the left main bronchus and radically unresectable metastases with distant metastases, was treated with the anti-PD-1 antibody nivolumab. In December X-1, we initiated levothyroxine sodium for hypothyroidism after the patient suffered indolent thyroiditis due to nivolumab. In March X, the nivolumab treatment was stopped because it proved to be ineffective, then in April, anorexia, fever, and general malaise were noted. Cortisol 5.0 and ACTH 17.5 were confirmed by blood test, and the patient was diagnosed with adrenal insufficiency and was admitted to the hospital. Head MRI showed no organic lesions, and a stress test showed abnormalities only in a CRH test (low response to both ACTH and cortisol). The patient was diagnosed with isolated ACTH deficiency due to nivolumab. Side effects of thyroid dysfunction due to nivolumab are frequently observed in Japan at a rate of 14.3%, and overseas at 5.9%. However, secondary adrenocortical dysfunction is observed in overseas clinical trials at a frequency of only about 0.3%. There are few reports of such complications, and we report this as a rare case.

A 75-year-old woman was diagnosed with clinical stage III lung cancer. The patient was treated with chemoradiotherapy and subsequent durvalumab, an anti-PD-L1 antibody immune checkpoint inhibitor (ICI). Liver dysfunction was observed 14 days after the start of durvalumab therapy (aspartate transaminase, 218U/l;alanine aminotransferase, 169U/l). This corresponded to a grade 3 adverse event according to the Common Terminology Criteria for Adverse Events. The second course of durvalumab was withheld. The patient was hospitalized 31 days after durvalumab therapy because of worsening liver dysfunction. Laboratory findings and imaging examinations suggested liver injury due to an immune-related adverse event (irAE). Liver biopsy performed 38 days after durvalumab therapy showed severe lymphocyte and plasma cell infiltration into the portal tract, focal necrosis in the hepatic lobules, and necrotic changes around the hepatic lobules. These findings were similar to those of autoimmune hepatitis (AIH). Immunohistochemical results revealed infiltration of CD3- and CD8-positive lymphocytes and mild infiltration of CD4-positive lymphocytes. Pathological findings in the liver tissue were consistent with an irAE. Jaundice worsened and the prothrombin time was prolonged, leading to a risk of progression to liver failure. Thus, pulse steroid therapy was performed with methylprednisolone (mPSL) starting at 0.8mg/kg. Liver dysfunction lessened and the mPSL dose was gradually reduced. Moreover, ICIs exert antitumor effects by inhibiting the immune checkpoint system but can cause irAEs in various organs. Liver injury is also relatively common. Liver tissue findings are similar to those in AIH, but immunostaining reveals the presence of numerous CD8-positive lymphocytes. Fewer CD4-positive lymphocytes exist in irAE-associated liver injury than in AIH. Medical departments must cooperate and effectively manage irAEs because ICIs are increasingly being used and can occur in organs throughout the body. In principle, irAEs are treated with steroids. Thus, high-dose steroids diminishing the therapeutic effect of ICIs is a concern, and it is important to control irAEs with low-dose steroids that are started earlier.

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

Occupational exposure to anticancer drugs may increase the risk of cancer and the risk of miscarriage and stillbirth, and cause other adverse events such as hypersensitivity reactions, skin/mucous reactions, and digestive symptoms. Several studies have investigated the use of closed-system drug-transfer devices (CSTDs) to reduce the environmental pollution by hazardous drugs. However, few reports have verified whether CSTDs contain the hazardous drugs within the vials. The BD PhaSealTM System is a CSTD that is frequently used in Japan. However, the fit of each anti-cancer drug vial has not been investigated. We investigated the fit of 71 major anti-cancer drug vials and protectors released and frequently used in Japan by means of a pressure compatibility test that we developed. The pressure compatibility test involved attaching a three-way stopcock to a Luer lock syringe and attaching an injector in line with the syringe. The pressure tubing was connected to the other side of the three-way stopcock and connected to the pressure inlet of the pressure gauge. The pressure in the anti-cancer drug vial was raised to 100 kPa and connected/disconnected repeatedly. If the pressure fluctuation during the 10th connection was within 6%, it was defined as "no change", and the compatibility of the protector and the vial was evaluated. The median pressure reduction rates at the 10th connection ranged from -1.98% to -4.95%. All drugs surveyed had an error rate within 6%. The BD PhaSealTM Protector was shown to be compatible with the 71 anti-cancer drugs we surveyed.

This article reviews the clinical features of toxicity in the peripheral and central nervous systems from anticancer drugs, including conventional cytotoxic chemotherapy, biologics, and targeted therapies, and excluding newer immunotherapies (immune checkpoint inhibitors and chimeric antigen receptor T cells). Neurologic complications from chemotherapy can be substantially disabling to patients and are being seen with increasing frequency because patients with cancer therapy are living longer and receiving multiple courses of anticancer regimens with combinations and longer duration. Clinicians, including neurologists, must know treatment-related neurotoxicity since discontinuation of the offending agent or dose adjustment may prevent further or permanent neurologic injury.

Management of chemotherapy-induced adverse effects and the associated pharmaceutical interventions as well as supportive care evidence creation are the most important responsibilities of oncology pharmacists. We have evaluated the (1) efficacy of long-term and successive pharmaceutical care in outpatient chemotherapy and (2) nephroprotective effects of magnesium (Mg) against cisplatin-induced nephrotoxicity (CIN). The results revealed that the adoption rate of pharmaceutical proposals was 98%, and that approximately 70% of the proposals attenuated painful symptoms. Moreover, approximately 60% of pharmaceutical interventions were established after the third visit; in particular, approximately 20% were suggested after the tenth visit. These results have shown that long-term and successive pharmaceutical care by oncology pharmacists in outpatient chemotherapy contributes to a safe and less onerous chemotherapy implementation. CIN frequency and serum creatinine elevation were significantly attenuated by Mg premedication during the cisplatin, docetaxel, and fluorouracil regimen, without changes in adverse effects and response rate. Mg premedication has been suggested to exert a protective effect against CIN without influencing on adverse effects and anti-tumor efficacy. The nephroprotective effect of Mg against CIN was evaluated using Wistar rats. Cisplatin (2.5 mg/kg) was administered once or three times weekly with or without 40 mg/kg MgSO4. The results revealed that Mg regulates the expression of organic cation transporter 2, multidrug and toxin extrusion protein 1, and copper transporter 1, leading to reduced renal platinum accumulation, which results in CIN attenuation. In conclusion, evaluation of pharmaceutical care and supportive care by oncology pharmacists is necessary for advanced care of cancer patients.

Antitumor immune response is generally suppressed in different ways in many types of tumors. In fact, a variety of immunosuppressive cells, such as regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, surround the tumor modulate antigen-presenting cells and effector T cells. The strategy to abreact the immunosuppressive conditions is necessary for a successful immunotherapy against cancers. Particularly, the improvement of the tumor microenvironment (TME) from this point is important for cancer immunotherapy. The checkpoint blockade as the representative success of the cancer immunotherapy can reactive the suppressed T cells. However, the efficacy of this treatment is limited. Therefore, it is necessary to evaluate the TME to establish more valid cancer immunotherapies. In addition, we need to pay attention to the relation of the therapy to immune responses. When tumor cells are killed by the antitumor agents, such as anticancer drugs, it is important that the cell death guides a secondary immune response by the antigen-presenting cells, particularly dendritic cells. Here, we discuss how the positive and negative effects by immune regulatory cells or stimulatory cells influence the subsequent immune dynamics in the TME. This will also lead to the development of new therapies to activate immunosuppressive conditions in the TME.

A 74-year-old man, who received pembrolizumab for the treatment for non-small cell lung cancer, developed quadriparesis 10 days after the first course of treatment accompanied by gait disturbance. Dysesthesia was observed in the distal extremities, and tendon reflexes were absent. Neurological examination and peripheral nerve conduction study supported the diagnosis of Guillain-Barré syndrome-like acute inflammatory demyelinating polyneuropathy caused by pembrolizumab. The administration of pembrolizumab was discontinued. Moreover, he was initially treated with intravenous immunoglobulin therapy, followed by intravenous methylprednisolone therapy and oral prednisolone. The limb weakness improved to a degree that he could walk alone on discharge. Pembrolizumab, which is an immune checkpoint inhibitor with a high anti-tumor effect, is reported to cause various adverse events. However, neuromuscular complications following cancer treatment with immune checkpoint inhibitors are relatively rare. Treatment with corticosteroids is considered to be effective for treating immune-related adverse events. Corticosteroids were effective in treating peripheral neuropathy caused by immune checkpoint inhibitors in this patient. Thorough treatment should be considered with a combination of corticosteroids and immunoglobulin therapy, in addition to discontinuation of immune checkpoint inhibitors, for this rare entity, which differs from that for idiopathic Guillain-Barré syndrome.

A 74-year-old man was administered nivolumab to treat recurrent squamous cell carcinoma of the lungs. He developed fatigue, redness on the front of his neck, muscle weakness, and difficulty in swallowing after receiving the third course of nivolumab. Physical and neurological examinations showed proximal limb muscle weakness, periorbital erythema, and erythema of the front of his neck as well as fingers. Laboratory investigations revealed elevated serum CK and aldolase levels, and he was diagnosed with dermatomyositis. We initiated steroid pulse therapy and intravenous immunoglobulin therapy; however, he died of advanced lung cancer. Immune checkpoint inhibitor-induced neuromuscular disease is increasingly being observed in clinical practice. We report a rare case of dermatomyositis with squamous cell carcinoma of the lungs secondary to nivolumab treatment.

Metabolome analysis is an approach to investigate cell characteristics from the metabolites that are constantly produced and changed by those cells. We conducted a metabolome analysis of the response of 786-O renal cell carcinoma (RCC) cells to histone deacetylase (HDAC) inhibitors, which are expected to increase anticancer drug sensitivity, and compared the response with that of drug-resistant cells. Trichostatin A (TSA), an HDAC inhibitor, increased the sensitivity of 786-O cells to sunitinib. Moreover, TCA cycle and nucleotide metabolism of the cells were promoted. The findings that acetylated p53 (active form) and early apoptotic cells were increased suggests that the mechanism involved enhancement of mitochondrial metabolism and function. In addition, established sunitinib-resistant RCC cells were exposed to a combination of sunitinib and TSA, resulting in significant growth inhibition. Principal component analysis revealed that the parent and resistant cells were obviously different, but approximately half their fluctuations were illustrated by the same pathways. In summary, it was suggested that TSA reduced sunitinib resistance by triggering intracellular metabolome shifts in energy metabolism. This was the first recognized mechanism of action of TSA as an HDAC inhibitor.

Ascertaining the absorption, distribution, metabolism, and excretion (ADME) profile of drugs is one of the most crucial factors in the process of drug discovery. Since it is important to combine water solubility and cell permeability within the compound to achieve the desired ADME properties, an appropriate balance between lipophilicity and hydrophilicity is required. It is often necessary to facilitate hydrophilicity of very hydrophobic candidates, because quite lipophobic molecules are rarely hit as positive in molecular-targeted or cell-based screenings. For that purpose, it has been popular to conjugate hydrophobic molecules with polyethylene glycol (PEG). However, PEG is a polymer, and PEG-conjugated molecules are not uniform. Besides, the dosage should be much increased compared with the original molecule due to the increase in molecular weight. Therefore we have been developing alternative ways to endow hydrophobic compounds with extra hydrophilicity by conjugating with symmetrically branched glycerol oligomers. This technology is versatile and easily applicable to various hydrophobic compounds. Water-solubility of fenofibrate, one of the most hydrophobic medicines in clinical use, was facilitated by a factor of more than 2000, and its lipid-lowering effect in vivo improved more than ten-fold, by simply conjugating with branched glycerol trimer, for instance. Here we will briefly introduce the basic concepts and our successful experiences of applying branched glycerol oligomers including antitumor agents in terms of water-solubility, pharmacological effects, and pharmacokinetics, and merits and current issues will be discussed in this review.

Cisplatin and ifosfamide are well-known nephrotoxic agents that can cause acute and chronic glomerular and/or tubular toxicity. We examined 2 adolescent patients who were receiving cisplatin and ifosfamide treatments. Pathological findings of patient 1 showed acute tubular necrosis-like patchy injury. Tubulointerstitial nephrosis and glomerular sclerosing were revealed in patient 2. These findings were consistent with the known damages induced by cisplatin and ifosfamide. Proteinuria and mild decline of eGFR were noticed after more than 10 months after the completion of the treatment. It is important to monitor such consequences in long-term follow up. Adult based medical services are required for childhood and adolescent cancer survivors.

The patient, a man in his 80s, presented with diarrhea following one year of treatment for non-small cell lung cancer with Nivolumab. CT results showed discontinuous wall thickening of the large bowel and cholangitis. Blood and stool culture tests ruled out immune-related adverse events and identified Edwardsiella tarda;bacterial colitis was diagnosed in the patient. This case confirmed that basic examination should not be neglected, and culture tests should be performed.

Screening for total pain and sharing of patient information including adverse events for patients receiving chemotherapy by medical staff is needed in clinical practice. We introduced a sharing system for patient-oriented outcome sheets via a touch panel at an outpatient chemotherapy clinic. This study aimed to assess whether the system contributes to the improved management of treatment-related adverse events. We retrospectively analyzed data from a total of 215 patients at Ehime University Hospital using their electronic medical records from April to August 2015. Forty of these patients had received interventions relating to treatment-related adverse events. The proportion of a total number of interventions before and after the sharing system was 42/282(14.9%)and 45/215(20.9%), respectively. The proportion of a total number of interventions at the first course of outpatient chemotherapy also increased from 9/40(22.5%)to 14/40(35%)compared with before the sharing system. The purpose of interventions were for insomnia, anorexia, and cancer-related pain, etc., listed in order of degree of frequency. These results suggest that a sharing system of patient-reported interview sheets contributes to tracking treatment -related adverse events and aids in ensuring interventions can be efficiently performed by multidisciplinary team members.

Taxanes, which are used to treat breast cancer, damage the microtubules of normal nerve cells, causing numbness of the fingers related to chemotherapy-induced peripheral neuropathy(CIPN); therefore, effective methods for reducing numbness are needed. In 2017, it was reported that physical stimuli related to massage improved finger blood flow volumes, contributing to the regeneration of damaged nerves. We developed a method of hand therapy for breast cancer patients complaining of numbness related to anticancer drug administration, and examined its effects on numbness. Hand therapy was performed by a single therapist who received lectures at the Sophia Phytotherapy College, which is accredited by the Japan Handcare Association. The fingertips to wrist, ankle, metacarpal bones, palm, and elbow were massaged using the bilateral arms/fingers for 15minutes. We investigated the influences of daily living status(Support Team Assessment Sched- ule-Japan: STAS-J), age, body mass index(BMI), severity/site of numbness, type of numbness, type of drug, duration of breast cancer, duration of numbness, and presence or absence of lymph node dissection, and evaluated the severity of numbness using a 10-cm Visual Analog Scale(VAS). The study included 51 breast cancer patients complaining of numbness of the fingers, with a mean age of 59 years. In patients with relatively mild numbness(STAS-J 1), the VAS scores before and after hand therapy were 4.7±1.8 and 1.9±1.3, respectively, showing a marked decrease. In STAS-J 2 patients, the values were 4.9 ±1.4 and 2.1±1.3, respectively, also showing a marked decrease. Thus, this hand therapy reduced numbness in mild- and moderate-status patients. Statistical comparisons were performed between the STAS-J 1/2(mild/moderate numbness)and STAS-J 3/4(severe numbness)groups. Although the severity of numbness was not correlated with age, BMI, type of drug, lymph node dissection, or duration of breast cancer, the proportion of patients with a B1-year history of numbness was significantly larger in the STAS-J 1/2 group. The most frequent site of numbness was from the proximal interphalangeal joints to the fingertips. Concerning the severity of numbness, many patients complained of severe numbness, as represented by that after sitting straight. These results suggest that this hand therapy is effective for reducing numbness in patients receiving taxanes and complaining of mild to moderate numbness.

In recent years, osimertinib has been increasingly used as a therapeutic drug for epidermal growth factor receptor(EGFR)mutation-positive lung cancer, with heart failure rarely reported as an adverse event. We report here a case of a significantly decreased ejection fraction and heart failure that were induced by osimertinib. We consider the case important and include a discussion of relevant previous reports.