Population Pharmacokinetics, Pharmacogenomics, and Adverse Events of Osimertinib and its Two Active Metabolites, AZ5104 and AZ7550, in Japanese Patients with Advanced Non-small Cell Lung Cancer: a Prospective Observational Study.

BACKGROUND: Potential novel strategies for adverse event (AE) management of osimertinib therapy, including therapeutic drug monitoring and the use of biomarkers, have not yet been fully investigated. This study aimed to evaluate (1) the relationship between exposure to osimertinib, especially its active metabolites (AZ5104 and AZ7550), and AEs, and (2) the relationship between germline polymorphisms and AEs. METHODS: We conducted a prospective, longitudinal observational study of 53 patients with advanced non-small cell lung cancer receiving osimertinib therapy from February 2019 to April 2022. A population pharmacokinetic model was developed to estimate the area under the serum concentration-time curve from 0 to 24 h (AUC0-24) of osimertinib and its metabolites. Germline polymorphisms were analyzed using TaqMan® SNP genotyping and CycleavePCR® assays. RESULTS: There was a significant association between the AUC0-24 of AZ7550 and grade ≥ 2 paronychia (p = 0.043) or anorexia (p = 0.011) and between that of osimertinib or AZ5104 and grade ≥ 2 diarrhea (p = 0.026 and p = 0.049, respectively). Furthermore, the AUC0-24 of AZ5104 was significantly associated with any grade ≥ 2 AEs (p = 0.046). EGFR rs2293348 and rs4947492 were associated with severe AEs (p = 0.019 and p = 0.050, respectively), and ABCG2 rs2231137 and ABCB1 rs1128503 were associated with grade ≥ 2 AEs (p = 0.008 and p = 0.038, respectively). CONCLUSION: Higher exposures to osimertinib, AZ5104, and AZ7550 and polymorphisms in EGFR, ABCG2, and ABCB1 were related to higher severity of AEs; therefore, monitoring these may be beneficial for osimertinib AE management.

[A Case of Non-Small Cell Lung Cancer Successfully Treated with Anti-PD-L1 Therapy after Exacerbation Caused by Anti-PD-1 Therapy].

A 52-year-old male was diagnosed with cT4N3M1b, cStage Ⅳ adenocarcinoma of the lung, and underwent 6 courses of pemetrexed(PEM), carboplatin(CBDCA), and bevacizumab(Bev)therapy, followed by 4 courses of PEM/Bev maintenance therapy. Due to the deterioration of his condition, 4 courses of pembrolizumab(Pembro)therapy were administered as second- line therapy, but the treatment was discontinued due to disease progression. Third-line therapy with docetaxel(DTX)/ ramucirumab(Rmab)was administered, resulting in a partial response, but discontinued due to adverse events. Finally, fourth-line therapy with atezolizumab(Atezo)was initiated. After 6 courses of Atezo therapy, partial response was achieved, and the tumor continued to shrink for 3 years. The aim of the treatment strategy for both PD-1 and PD-L1 antibody drugs is to suppress T-cell exhaustion, and if either drug fails, the other drug may theoretically fail. However, in this case, the PD-L1 antibody drug was effective against non-small cell lung cancer that had shown resistance to PD-1 antibody drugs, suggesting that even if a patient becomes resistant to PD-1 antibody drugs, PD-L1 antibody drugs may result in effective outcomes.

The updated five-year overall survival and long-term oxaliplatin-related neurotoxicity assessment of the FACOS study.

PURPOSE: We previously reported the first evidence of oncological benefits from a Japanese phase II trial of oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (the FACOS study). We herein report the long-term survival and persistent oxaliplatin-related peripheral sensory neuropathy (PSN) for patients enrolled in this trial. METHODS: Patients were scheduled to receive the mFOLFOX6 or CAPOX regimen in the adjuvant setting. The five-year overall survival (OS) rate and persistent PSN were evaluated. RESULTS: A total of 130 patients (mFOLFOX6, n = 73; CAPOX, n = 57) were eligible. The 5-year OS rate was 91.4%. No significant difference in the OS rate was observed between regimens (mFOLFOX6, 94.4%; CAPOX, 87.4%; P = 0.25). The incidence of PSN during adjuvant treatment was 55.4% in grade 1 (G1), 30.0% in G2, and 4.6% in G3. No patients showed G3 PSN at 12 months, but G1 or G2 residual PSN after 5 years was observed in 21.8% (G1, 20%; G2, 1.8%). CONCLUSIONS: Updated results from the FACOS study support the benefits of oxaliplatin-based adjuvant chemotherapy in terms of the long-term survival among Japanese patients with stage III colon cancer. However, long-term persistent PSN occurs in about 20% of survivors, counterbalancing the favorable OS.

[Role of Palliative Care in the Introduction of Chemotherapy in Patients with Poor Performance Status].

Chemotherapy for patients with poor performance status(PS)is not recommended because it increases the risk of death and shortens their survival. We report on 3 cases in which palliative care improved PS and enabled chemotherapy, resulting in a prolonged prognosis. Case 1 involves a 57‒year‒old woman with multiple lung, liver, and bone metastases from breast cancer who was administered celecoxib and oxycodone. She received Mohs paste therapy. Her PS improved from 3 to 2, and paclitaxel and trastuzumab were started; however, the patient died on day 861. Case 2 involves a 53‒year‒old woman with multiple lymph node metastases from carcinoma of an unknown primary cause. She was administered oxycodone, loxoprofen, and dexamethasone. Her PS improved from 4 to 3. The biopsy of her bone marrow showed diffuse large B‒cell lymphoma. The patient is still alive, 6 years and 10 months after the introduction of R‒CHOP. In case 3, a 57‒year‒old man with multiple bone metastases from small cell lung cancer was administered loxoprofen and betamethasone. His PS improved from 4 to 3. Etoposide and carboplatin were administered to him, but the patient died on day 692. Palliative care may enable the introduction of chemotherapy and consequently improve prognosis.

Oxaliplatin-induced increase in splenic volume: experiences from multicenter study in Japan.

BACKGROUND: Chemotherapy with oxaliplatin is known to induce sinusoidal obstruction syndrome (SOS). In a previous single-center study, we reported that oxaliplatin-induced increase in splenic volume (SV) is strongly indicative of SOS, and that this increase in SV persisted for > 1 year after completing chemotherapy. The aim of this study was to confirm the oxaliplatin-induced SV change in a multicenter study in patients with stage III colon cancer in Japan. METHODS: We enrolled 59 patients who underwent curative resection for stage III colon cancer in the FACOS study in a phase II multi-center clinical study. Participants received mFOLFOX6 or CAPOX as adjuvant chemotherapy. SV change was assessed three times by computed tomographic volumetry: before surgery, on completion of adjuvant chemotherapy, and 1 year after completing adjuvant chemotherapy. RESULTS: SV on completing and 1 year after chemotherapy was significantly higher than that before surgery (P < 0.001). Oxaliplatin-induced SOS persisted for > 1 year after the completion of adjuvant chemotherapy in half of the patients. There was no difference in 3-year disease-free survival with respect to the presence or absence of increased SV. An increase in SV was observed in 72% of patients treated with mFOLFOX6 and 94% of patients treated with CAPOX (P = 0.13). CONCLUSION: This study can be verified the findings observed in our previous single-center study, oxaliplatin-based adjuvant chemotherapy was associated with an increase in SV. Furthermore, this increase can persist for > 1 year. The continuous presence of SOS may have a negative impact on prognosis in patients that develop recurrent disease.

[Advanced Gastric Cancer with Tumor Shrinkage Persisting after the Discontinuation of Nivolumab-A Case Report].

The patient was a 65-year-old man with advanced gastric cancer, cT4bN3aM1, cStage Ⅳ. The SOX therapy was administered as the primary treatment but discontinued after 9 courses because of disease progression. The PTX plus RAM therapy was then administered for 1 courses as the secondary treatment but discontinued because of the development of peritoneal dissemination, increased number of ascites, and increased number of lymph node metastases. The nivolumab(NIV)therapy was initiated as the tertiary treatment, but the patient complained of fatigue and diplopia after 2 courses. Ptosis was observed, and transaminase and creatine kinase levels were elevated. Electrocardiography showed complete right bundle branch block. The patient showed immune-related adverse events and was diagnosed with myocarditis and myasthenia gravis due to NIV. Consequently, systemic steroids were administered. Although 2 course of CPT-11 was administered as the fourth-line treatment, the treatment was discontinued upon the patient's request. Ten months after the discontinuation of chemotherapy, the disease showed no progression. The patient is being followed-up as an outpatient. Here, we reported a case of gastric cancer with tumor shrinkage after the discontinuation of NIV.

A Japanese multicenter phase II study of adjuvant chemotherapy with mFOLFOX6/CAPOX for stage III colon cancer treatment after D2/D3 lymphadenectomy.

PURPOSE: A phase II trial was conducted to investigate the benefit of oxaliplatin-based adjuvant chemotherapy in Japanese stage III colon cancer patients. METHODS: Eligible patients were scheduled to receive 12 cycles of mFOLFOX6 or 8 cycles of CAPOX in adjuvant settings. The primary endpoint was the 3-year disease-free survival (DFS). Cox proportional hazards regression was performed to identify risk factors for a worse DFS. RESULTS: A total of 130 patients, including 73 patients receiving mFOLFOX6 and 57 patients receiving CAPOX, were enrolled from 16 institutions between April 2010 and April 2014. The 3-year DFS was 82.2%, exceeding the expected primary endpoint of 81.7%. The 3-year DFS tended to be higher in patients receiving mFOLOFOX6 than in those receiving CAPOX (mFOLFOX6, 86.3%; CAPOX, 76.9%; P = 0.06). The 3-year DFS rates did not differ markedly based on the risk stratification (T1/T2/T3 N1 vs. T4 or N2) indicated by the IDEA COLLABORATION study (P = 0.22). In the multivariate analysis, stage IIIC (P = 0.046) and early discontinuation (P < 0.01) were identified as independent significant risk factors for a worse DFS. CONCLUSION: Our findings represent the first positive results in a Japanese phase II trial of adjuvant chemotherapy with mFOLFOX6/CAPOX. Early discontinuation within 2 months was an independent risk factor for a shorter DFS.

A New Technique for Posterior Distraction in Craniosynostosis: The Double-Door Technique.

BACKGROUND: Posterior cranial vault distraction osteogenesis is a common treatment for syndromal patients of brachycephaly and oxycephaly. Although posterior distraction can increase intracranial volume, the flattened head phenotype is difficult to correct. The authors examined a new posterior distraction technique termed double-door distraction for improvement of the flattened head phenotype. METHODS: From 2010 to 2013, 6 patients with flattened posterior craniums were operated on using the double-door distraction technique. The calvarial segment was cut at the midline and divided into 2 pieces. Distractors were then fixed in parallel to join the calvarial pieces. The distraction was initiated at a rate of 1.0 mm/day and continued until proper cranial form was confirmed by radiography and appearance. RESULTS: The average surgery time was 2 hours 47 minutes and the amount of distraction ranged from 15 to 22 mm. An improved head shape and expanded cranial vault was achieved in all patients without any complications. CONCLUSIONS: The double-door distraction technique is a useful technique not only for calvarial expansion, but also for correction of the flattened posterior cranium phenotype.

Twenty-five-years follow-up results of our total cranial reshaping "bamboo-ware method".

PURPOSE: For patients with craniosynostosis, there is no single procedure available for reconstructing a normal cranial shape, regardless of the type of deformity. To achieve ideal dynamic total skull remodeling for any type of craniosynostosis, we developed the bamboo-ware method. METHODS: Using two or three coronal bars as landmarks, the anterior-posterior length of the skull was determined using the sagittal bandeau, thereby creating the basic framework for reconstruction. Bone was then bridged to the remaining defects in a manner resembling woven bamboo. RESULTS: We treated 30 craniosynostosis patients (20 isolated cases and 10 cases of syndromic craniosynostosis) using the bamboo-ware method. Although intracranial infection was observed in three cases during the postoperative period, no deaths or serious complications were noted. In all patients, good cranial shape and adequate cranial volume were achieved. CONCLUSIONS: The bamboo-ware method enabled outstanding results for every type of synostosis. This method could not only treat the deformity, but also resulted in good cranial form with a single operation.

Le Fort IV + I distraction osteogenesis using an internal device for syndromic craniosynostosis.

Monobloc and Le Fort III distractions can improve midfacial hypoplasia, a characteristic feature of syndromic craniosynostosis. The purpose of treating midfacial hypoplasia is to improve exophthalmos and dental occlusion. Typically, in Le Fort III or monobloc distractions, the midface is mobilized en bloc, and the extent and direction of the mobilization is determined according to the preferred intermaxillary occlusion. However, to obtain the preferred functional and esthetic results while correcting midface hypoplasia, the most sensible approach is the use of different degrees of mobilization and vectors for the upper and lower halves of the midface. This report describes the case of an adolescent with Crouzon syndrome showing frontal recession exophthalmos and an anterior crossbite. His condition was treated with monobloc minus Le Fort I and Le Fort I distraction using only internal devices, which the authors have designated Le Fort IV plus I distraction.

Effects of fatty acid hydroperoxides produced by lipoxygenase in wheat cultivars during dough preparation on volatile compound formation.

The formation of volatile compounds affects the flavor of processed wheat flour products. Herein, the effects of the composition of fatty acid hydroperoxides and the differences in the antioxidant contents among wheat cultivars on the flavor of wheat flour products were clarified. For this purpose, the volatile compounds in wheat flour doughs, LOX activity, fatty acid hydroperoxide composition from fractionated LOX, and antioxidant content were analyzed. Norin61 exhibited a high LOX activity and 9-fatty acid hydroperoxide production. Unsaturated aldehydes derived from 9-fatty acid hydroperoxides contributed significantly to the volatile compound profile of Norin61. Moreover, the lowest lutein content was observed in Norin61 among the analyzed cultivars. The LOX activity and composition of the fatty acid hydroperoxides produced by LOX affected the production of volatile compounds, whereas carotenoids had a suppressive effect. This study provides useful information for product design with the desired flavor for developing various processed wheat flour products.

Outcome analysis of morcellation craniotomy with distraction osteogenesis for scaphocephaly.

BACKGROUND: Techniques for sagittal synostosis correction continue to evolve, thus resulting in improved outcomes and minimized morbidity. Spring-assisted cranioplasty and strip craniotomy with postoperative helmet usage are simple minimally invasive surgeries. However, these procedures are only useful in younger patients (generally up to 9 months of age); older children usually undergo total cranial remodeling, which is more stressful. We have developed a procedure combining morcellation craniotomy with distraction osteogenesis (MoD), which we have been performing since 2000. Here, we describe and evaluate this method of treatment. METHODS: Seven patients who underwent MoD for isolated sagittal synostosis were followed for 10 years postoperatively. The control group consisted of 7 patients who had undergone total cranial remodeling in the period immediately preceding the MoD operations. Cephalography, clinical examinations, medical record data and medical photographs were used to evaluate and compare the 2 groups. RESULTS: In comparison with total cranial remodeling, the MoD procedure resulted in a significantly shorter mean operation time and a significantly lower mean blood transfusion volume. The postoperative cephalic index was not significantly different between the MoD (75.8 ± 0.9) and the control groups (75.6 ± 1.4), and satisfactory cranial shape volumes were achieved without serious complications. CONCLUSION: The MoD procedure is a safe, effective and reliable technique for dynamic total skull remodeling with minimal morbidity. It can be used to improve upon previous surgical concepts for treating scaphocephaly, particularly in older patients.

Venous architecture of the glabellar to the forehead region.

The precise venous anatomy of the glabellar to the forehead region remains unknown. This study aimed to detail the venous architecture of the glabellar region to the forehead in conjunction with that of the supratrochlear artery to reduce the risk of venous congestion of flaps in this area. Fifteen fresh human cadavers were examined here. In five specimens, contrast medium was injected only into the venous system; in 10 specimens, two different types of contrast media were injected into the arterial and venous systems, respectively. A total of 30 hemifacial specimens were radiographed stereoscopically and observed microscopically. In all the cadavers, a distinct vein (termed as the "transverse nasal root vein") connected the bilateral angular veins. One or two large ascending veins branched from the transverse nasal root or angular vein, coursing toward the forehead skin. Numerous small veins branched out from the large ascending vein(s), forming a subdermal polygonal venous network. Small ascending veins arose from this network and coursed toward the dermis, draining venous flow from the dermis. Three different-sized valves prevented the reflux of blood in the venous pathway. The large ascending vein(s) and supratrochlear artery ran parallel only in the medial canthal area. Tiny venous vasa vasorum surrounded the adventitia of the supratrochlear artery and anastomosed with the polygonal venous network, while a few small veins from the vasa vasorum ascended toward the dermis. Understanding the venous architecture of this region is expected to facilitate the safe elevation of various flaps in the area.

Role of solid model simulation surgery for hemifacial microsomia.

Distraction osteogenesis is now a standard procedure for hemifacial microsomia, and various methods have been described. However, it is sometimes difficult to obtain the horizontal occlusal plane and facial symmetry. This brief communication describes and discusses the usefulness of solid model simulation surgery for hemifacial microsomia.

Deactivation of glycogen synthase kinase-3ß by heat shock­inducible tumor small protein attenuates hyperthermia­induced pro­migratory activity in colorectal cancer cells.

Hyperthermia is a promising approach for improving cancer treatment in combination with chemotherapy, radiotherapy and/or immunotherapy; however, its molecular mechanisms remain unclear. Although heat shock proteins (HSPs) are involved in hyperthermia via antigen presentation and immune activation, major HSPs including HSP90 are associated with cancer progression via tumor cell migration and metastasis. The present study showed that heat shock­inducible tumor small protein (HITS) could counteract the pro­migratory effects of HSPs in colorectal cancer (CRC) cells, which represents a novel function. Western blotting analysis revealed that overexpression of HITS increased the protein level of glycogen synthase kinase­3ß (GSK3ß) phosphorylated (p) at the serine 9 (pGSK3ßS9; inactive form) in HCT 116, RKO and SW480 CRC cells. GSK3ßS9 phosphorylation was reported to suppress migration in some cancer types; therefore, by using the wound healing assay, the present study revealed that HITS overexpression decreased the migration activity of CRC cells. Induction of HITS transcription was observed at 12 and 18 h after heat shock (HS) by using semi­quantitative reverse transcription­PCR analysis, followed by increased levels of pGSK3ßS9 protein at 24 and 30 h in CRC cells in western blotting. Thus, HS induced not only HSPs to promote cell migration, but also HITS to counteract the migratory activity of these HSPs in CRC cells. HITS knockdown in CRC cells subject to HS showed increased cell migration in wound healing assay, which was decreased by the GSK3ß inhibitor AR­A014418, confirming the anti­migratory effect of HITS via the deactivation of GSK3ß. The present findings indicated that the deactivation of GSK3ß sufficiently offset the pro­migratory effect of hyperthermia via major HSPs in CRC.

Cell death and wing reduction during the metamorphosis of sex-specific flightless morphs in winter geometrid moths.

Winter geometrid moths show striking sexual dimorphism by having female-specific flightless morphs. The evolutionary grades of wing reduction in winter geometrid moths vary and range from having short wings, vestigial wings, to being wingless. Although the ontogenetic processes underlying the development of the wingless or short-wing morphs in Lepidoptera has been well studied, the mechanisms underlying the development of vestigial wing morphs in winter geometrid moths during metamorphosis are poorly understood. In the winter geometrid moth Sebastosema bubonaria Warren, 1896, the males have functional wings, but the females have vestigial wings. Here, we studied the ontogenetic processes affecting wing reduction in the winter geometrid moth S. bubonaria using light microscopy and transmission electron microscopy, and compared the ontogenetic process of wing reduction in this species with that in another species of the wingless-female winter moth that we investigated previously. Our results showed that, in the vestigial-wing morphs, the loss of pupal wing epithelium was terminated in the middle of the wing degeneration process, whereas in the wingless morph, the pupal wing epithelium disappeared almost completely and the final appearance of the wings differed slightly among flightless morphs. We propose that the extent and location of cell death in the pupal wing play an important role in the various patterns of reduced wings that are observed in flightless moths.

Transverse rectus abdominis myocutaneous flap combined with vascularized costal cartilages in cranial reconstruction.

Exposing the alloplastic materials after skull reconstruction is very difficult because of the risk of infection and the choice of reconstruction procedures. Conventional procedures were divided into two-step or multi-step surgery.To perform one-stage surgery, a transverse rectus abdominis myocutaneous flap combined with vascularized costal cartilages has been used for head reconstruction after exposing the alloplastic materials in two patients. This is the first report using the flap for skull reconstruction.In this article, we describe the usefulness and the disadvantages of the transverse rectus abdominis myocutaneous flap combined with vascularized costal cartilages.

Involvement of the sphenosquamosal suture for unilateral coronal synostosis.

The etiology of the clinical entity commonly known as unilateral coronal synostosis is often described as the unilateral fusion of the coronal ring. However, recent theories have poorly explained the basis of the deformities associated with unilateral coronal synostosis. We retrospectively analyzed computed tomographic data sets from 18 patients who presented with unilateral coronal synostosis and arrived at our hospital between 1985 and 2010. Using three-dimensional reconstructions of the computed tomographic images, analyses of the cranial base and measurements of each cranial bone were performed. As a result, the ipsilateral and contralateral basion-clinoid-pterion angles did not differ significantly (P = 0.49) and were almost identical in each case. However, the ipsilateral basion-partis-petrosae angle was wider than the corresponding contralateral angle (P < 0.001). In addition, the ipsilateral nasion-clinoid-pterion angle and the sphenoid, zygomatic, and temporal bones on the ipsilateral side were significantly shorter than those on the contralateral side (P < 0.001). Based on a shortening ratio, the sphenoid bone was smaller (42.0% ± 10.9%) than the temporal (68.9% ± 7.58%) and zygomatic bones (71.1% ± 8.38%). This difference was significant (P < 0.001). In conclusion, restricted growth potential of the central portion of the ipsilateral sphenoid bone was identified. We propose that the coronal ring, which includes the frontoparietal and frontosphenoidal sutures, and the sphenosquamosal suture are involved in unilateral coronal synostosis. Using our findings and the theory of Delashaw et al, the deformity observed in unilateral coronal synostosis can be explained more adequately and/or completely.

Maxillomandibular tandem osteotomy with distraction osteogenesis for hemifacial microsomia.

Currently, simultaneous maxillomandibular distraction osteogenesis is a standard procedure for the correction of hemifacial microsomia. Many variations of the procedure have been reported. However, a common problem has been the extended duration of the procedure. In particular, the lengthy intermaxillary fixation period includes a prolonged distraction series that requires the restriction of oral food intake and creates significant stress for the patient, which has a profound effect on patient satisfaction. To avoid this stress, we have developed tandem osteotomy with distraction osteogenesis, termed the TODO procedure. The TODO procedure not only shortens the intermaxillary fixation period and the duration of therapy but also creates the ideal skeletal proportions, with horizontalization of the occlusal plane. The TODO procedure has the added benefit of producing a marked aesthetic improvement. The patient was extremely satisfied by the result and endured minimal stress.