Nirmatrelvir Resistance in an Immunocompromised Patient with Persistent Coronavirus Disease 2019.

Although the coronavirus disease 2019 (COVID-19) pandemic is coming to an end, it still poses a threat to the immunocompromised and others with underlying diseases. Especially in cases of persistent COVID-19, new mutations conferring resistance to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) therapies have considerable clinical implications. We present a patient who independently acquired a T21I mutation in the 3CL protease after nirmatrelvir exposure. The T21I mutation in the 3CL protease is one of the most frequent mutations responsible for nirmatrelvir resistance. However, limited reports exist on actual cases of SARS-CoV-2 with T21I and other mutations in the 3CL protease. The patient, a 55 year-old male, had COVID-19 during chemotherapy for multiple myeloma. He was treated with nirmatrelvir early in the course of the disease but relapsed, and SARS-CoV-2 with a T21I mutation in the 3CL protease was detected in nasopharyngeal swab fluid. The patient had temporary respiratory failure but later recovered well. During treatment with remdesivir and dexamethasone, viruses with the T21I mutation in the 3CL protease showed a decreasing trend during disease progression while increasing during improvement. The impact of drug-resistant SARS-CoV-2 on the clinical course, including its severity, remains unknown. Our study is important for examining the clinical impact of nirmatrelvir resistance in COVID-19.

[Latent essential thrombocythemia becoming perceptible after splenectomy].

A 47-year-old male was admitted to our hospital because of left hypochondrium part pain and was diagnosed with splenomegaly with splenic infarctions in May 2016. His complete blood cell count was almost within normal limits, and a bone marrow biopsy revealed normal cellularity with no fibrosis. In addition, no abnormal uptake was noted on FDG PET/CT. In August 2016, he underwent splenectomy for splenomegaly. The histological examination revealed fibrotic stenosis of the blood vessels in the spleen. After splenectomy, his platelet count elevated and remained at >1,000×109/l 3 months later. Finally, he was diagnosed with latent essential thrombocythemia (ET) because the JAK2V617F mutation was positive. Accordingly, oral hydroxyurea was initiated. Thrombosis could be a complication in myeloproliferative neoplasms (MPN). In our case, ET was masked, perhaps, because of hypersplenism and splenomegaly because of splenic vein thrombosis. Hence, examination of the JAK2V617F mutation in patients with splanchnic vein thrombosis is recommended because of the possibility of latent MPN.

[Agranulocytosis during therapy of chronic myeloid leukemia lymphoid blast crisis with dasatinib].

A 61-year-old female was diagnosed with a lymphoid crisis of chronic myeloid leukemia (CML) in February 201X and started chemotherapy combined with dasatinib (DAS). After 1 month of initiating second consolidation therapy, the neutrophils decreased to 1%, bone marrow examination revealed large granular lymphocytes (LGL) at 13%, and complete cytogenetic remission was attained (CCyR). Suspecting DAS-induced agranulocytosis, DAS was discontinued. After 2 weeks, LGL disappeared and neutrophils recovered. In this case, CCyR was attained for the first time when LGL increased. We considered that the expansion of LGL correlated with the clinical efficacy, and agranulocytosis was an off-target effect of DAS.

A phase I study of capecitabine combined with CPT-11 in metastatic breast cancer pretreated with anthracyclines and taxanes.

OBJECTIVE: A dose escalation study of biweekly irinotecan (CPT-11) combined with capecitabine was performed to determine the maximum tolerated dose (MTD) and recommended dose (RD) for metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes. METHODS: Escalating doses of CPT-11 (80-120 mg/m(2)) were administered on days 1 and 15. Capecitabine was administered at a fixed dose of 1,657 mg/m(2)/day for 21 consecutive days, followed by 7 days of rest. We treated 3-6 patients at a particular dose level until the MTD was determined. RESULTS: Twenty patients were treated. The MTD was determined to be 100 mg/m(2), as 3 of 6 patients developed dose-limiting toxicities, grade 3 leukopenia, neutropenia, photophobia, fatigue and diarrhea. The RD for the phase II study was thus determined to be 90 mg/m(2). The response rate was 41.7%. CONCLUSIONS: Combination therapy with CPT-11 and capecitabine was well tolerated with a promising response rate for MBC that had been treated previously with anthracyclines and taxanes. A multi-center phase II study is warranted to evaluate the efficacy and safety of this combination therapy with pharmacokinetic assessment.

Long-term complete remission of metastatic breast cancer, induced by a steroidal aromatase inhibitor after failure of a non-steroidal aromatase inhibitor.

PATIENT: Female, 56 FINAL DIAGNOSIS: Breast cancer Symptoms: Solid mass in the right breast Medication: Exemestane Clinical Procedure: - Specialty: Oncology. OBJECTIVE: Unusual clinical course. BACKGROUND: The efficacy of third-generation aromatase inhibitors for hormone receptor-positive postmenopausal metastatic breast cancer is well established. Although several clinical trials have reported incomplete cross-resistance between different aromatase inhibitors, few cases of complete responses of recurrent metastatic breast cancer occurring after substituting a second aromatase inhibitor have been reported. We here present a rare case of non-steroidal aromatase inhibitor-tolerant metastatic breast cancer with long-term complete remission following substitution of a steroidal aromatase inhibitor. CASE REPORT: We present the case of a 56-year-old Japanese woman who underwent right breast-conserving surgery for breast cancer, TNM staging T1, N0, M0, Stage I. She received adjuvant chemotherapy with 6 cycles of FEC100 and radiation therapy, and then began hormonal therapy with anastrozole. Twelve months postoperatively, computed tomography (CT) revealed multiple lung metastases. Exemestane was substituted for anastrozole. After 3 months of exemestane, CT showed that all lung metastases had completely resolved. Her complete response was maintained for 5 years: she died during a tsunami 6 years after the initial surgery. CONCLUSIONS: Substitution of a steroidal for a non-steroidal aromatase inhibitor produced a sustained complete remission in a patient with hormonal receptor-positive postmenopausal recurrent breast cancer. Achieving complete response after switching from a non-steroidal to a steroidal aromatase inhibitor in a hormonal receptor-positive postmenopausal recurrent breast cancer contributed to a higher quality of life for the patient. Further investigation is needed to identify the predictors of long-term remission following such a switch.

Intraocular Invasion of Adult T-Cell Leukemia Cells without Systemic Symptoms after Cataract Surgery.

Adult T-cell leukemia (ATL) is an aggressive lymphoid proliferation associated with the human T-lymphotropic virus type I (HTLV-I). The intraocular invasion of ATL is a rare event. A 75-year-old man without any systemic disease underwent uneventful cataract surgery of the right eye. On postoperative day 6, the patient presented with blurred vision due to severe vitreous opacity in the right eye. Analysis of the vitreous fluid revealed a suspected ATL infection based on the flow cytometric analysis. Moreover, cytological examination of the vitreous specimen revealed flower cell infiltration, and HTLV-1 DNA was detected by PCR analysis of the vitreous sample. Monoclonal T-cell receptor chain rearrangement was also detected by PCR. Thorough analysis of a vitreous sample is essential for vitrectomy in vitreous opacity of unknown cause. Flow cytometric, cytological, and PCR analysis of vitreous samples is beneficial for determining the cause of this kind of severe illness.

Association of a novel in-frame deletion mutation of the MYH9 gene with end-stage renal failure: case report and review of the literature.

MYH9 disorders are autosomal dominant diseases characterized by giant platelets, thrombocytopenia, and granulocyte inclusion bodies. These diseases are caused by mutations in the MYH9 gene that encodes nonmuscle myosin heavy chain IIA. We describe the case of a 27-year-old male who presented with macrothrombocytopenia and leukocyte inclusion bodies. Chronic kidney disease, probably due to progressive glomerulosclerosis, and high-tone sensorineural deafness were evident. Although deterioration of renal function necessitated renal replacement therapy in the form of peritoneal dialysis, we reconsidered the etiology of the kidney disease due to the patient's clinical history. We identified an in-frame deletion mutation in exon 24 of the MYH9 gene that resulted in the removal of 21 nucleotides. The patient was diagnosed with an MYH9 disorder. We report this novel abnormality of the nucleotide sequence and compare it with previous cases and their associated phenotypes.

[The ideal follow-up after breast cancer operation].

With the increase in breast cancer patients in Japan, therapy for breast cancer has progressed with evidence-based medicine (EBM), and most of it has shifted to outpatient clinics (OPC) except for surgery. With the specialization of surgical techniques and pharmacological treatments, i. e. sentinel node biopsy and advanced medical treatment, many patients now visit specialized cancer clinics, and the congestion has resulted in difficulty in follow-up after surgery, and the reconsideration of how to follow-up is under way. Although the clinical guideline issued by the Japanese Breast Cancer Society recommends performing a careful history, physical examination and annual mammography, each clinic has its own follow-up program with additional modalities different approaches in EBM. Here we investigate the recommendations of the clinical guideline, how they discuss evidence, and we attempt to pinpoint the problems when used at the daily clinical level while considering the characteristics of current breast cancer practice. Then, we considered the specific characteristics of breast cancer revealed by meta-analyses, the effect of long-term adjuvant endocrine therapy after surgery, and reflecting the patient's intent in follow-up in order to conduct an ideal follow-up with a view to cooperation between cancer specialized hospitals and community clinics.

[Palliative chemotherapy for metastatic breast cancer with capecitabine].

We examined 51 patients treated with Capecitabine for metastatic breast cancer. 51 patients achieved a 30.8% response rate, 59.6% a clinical benefit rate(59.6%)and 7.2 M of time to disease progression, as previously reported. Capecitabine therapy, single agent or combination therapy, should be considered a treatment of choice for metastatic breast cancer with certain response and general tolerability.

Mohs chemosurgery for local control of giant recurrent papillary thyroid cancer.

BACKGROUND: Papillary thyroid carcinoma (PTC) generally has a good prognosis but may have an aggressive course, particularly in the elderly. Standard treatment consists of radioactive iodine and thyrotropin suppression with superphysiological doses of thyroid hormone. Other modalities are less commonly used. We report perhaps the first patient with PTC who was treated with Mohs chemosurgery. SUMMARY: The patient was a 94-year-old woman who was diagnosed at age 67 with PTC and underwent a near-total thyroidectomy. The PTC recurred in the cervical nodes and reached the size of 8 x 5.5 cm by age 89. The tumor had become exposed and was hemorrhaging. By age 92 it measured 10 cm, encompassed the right common carotid artery, and was invading the trachea and larynx. In order to implement local control, we applied Mohs ointment. She also required blood transfusions. After approximately 1 month, the tumor had flattened, and the hemorrhaging stopped, and the patient was able to be discharged from the hospital to home nursing. CONCLUSION: Treatment with Mohs chemosurgery should be considered in the rare patient with exposed locally aggressive PTC for palliation and improved quality of life.

Development of parallel density functional program using distributed matrix to calculate all-electron canonical wavefunction of large molecules.

We developed a new parallel density-functional canonical molecular-orbital program for large molecules based on the resolution of the identity method. In this study, all huge matrices were decomposed and saved to the distributed local memory. The routines of the analytical molecular integrals and numerical integrals of the exchange-correlation terms were parallelized using the single program multiple data method. A conventional linear algebra matrix library, ScaLAPACK, was used for matrix operations, such as diagonalization, multiplication, and inversion. Anderson's mixing method was adopted to accelerate the self-consistent field (SCF) convergence. Using this program, we calculated the canonical wavefunctions of a 306-residue protein, insulin hexamer (26,790 orbitals), and a 133-residue protein, interleukin (11,909 orbitals) by the direct-SCF method. In regard to insulin hexamer, the total parallelization efficiency of the first SCF iteration was estimated to be 82% using 64 Itanium 2 processors connected at 3.2 GB/s (SGI Altix3700), and the calculation successfully converged at the 17-th SCF iteration. By adopting the update method, the computational time of the first and the final SCF loops was 229 min and 156 min, respectively. The whole computational time including the calculation before the SCF loop was 2 days and 17 h. This study put the calculations of the canonical wavefunction of 30,000 orbitals to practical use.

All-electron density functional calculation on insulin with quasi-canonical localized orbitals.

An all-electron density functional (DF) calculation on insulin was performed by the Gaussian-based DF program, ProteinDF. Quasi-canonical localized orbitals (QCLOs) were used to improve the initial guess for the self-consistent field (SCF) calculation. All calculations were carried out by parallel computing on eight processors of an Itanium2 cluster (SGI Altix3700) with a theoretical peak performance of 41.6 GFlops. It took 35 h for the whole calculation. Insulin is a protein hormone consisting of two peptide chains linked by three disulfide bonds. The numbers of residues, atoms, electrons, orbitals, and auxiliary functions are 51, 790, 3078, 4439, and 8060, respectively. An all-electron DF calculation on insulin was successfully carried out, starting from connected QCLOs. Regardless of a large molecule with complicated topology, the differences in the total energy and the Mulliken atomic charge between initial and converged wavefunctions were very small. The calculation proceeded smoothly without any trial and error, suggesting that this is a promising method to obtain SCF convergence on large molecules such as proteins.

Idiopathic thrombocytopenic purpura and mononeuropathy multiplex.

Peripheral neuropathy is an uncommon complication of idiopathic thrombocytopenic purpura (ITP). We report a 61-year-old man with ITP who developed acute-onset mononeuropathy multiplex. An electrophysiologic study revealed active axonal degenerative alteration, and a sural nerve biopsy showed axonal degeneration. Intraneural hemorrhage was suggested to be the most likely cause.

[A case of advanced gastric cancer which became operable after chemotherapy with combination of TS-1/CDDP and in which complete disappearance of liver metastasis was histopathologically confirmed].

We encountered a patient in whom TS-1/cisplatin (CDDP) combination chemotherapy was effective. The cancer became operable, and complete disappearance of liver metastasis was histopathologically confirmed. The patient was a 65-year-old man who presented with complaints of epigastric discomfort and anorexia. Based on upper GI endoscopy and abdominal CT, type 1 gastric cancer associated with liver and abdominal lymph node metastases was diagnosed. The cancer was judged to be inoperable, and chemotherapy with a combination of TS-1 and CDDP was initiated. One course of treatment consisted of administration of 120 mg/day of TS-1 for 21 days followed by 14 days of withdrawal, and administration of 100 mg/body/day of CDDP on day 8 (80 mg/body/day in the second course). After two courses of treatment, the primary lesion and the liver and lymph node metastatic lesions decreased in size (reduction ratios were 42.3%, 90.5% and 85.2%, respectively). The tumor marker values became normal. Subsequently, the cancer was judged to have become operable. After consultation with the patient, total gastrectomy, splenectomy, partial hepatectomy, and D3 dissection were performed, and curability B was achieved. The only adverse event of Grade 2 or more severity observed during drug administration was anorexia. Liver metastasis was judged from pathological findings to have disappeared. The postoperative course was uneventful and the patient was discharged from the hospital. To date, there have been no signs of recurrence. TS-1/CDDP therapy is believed to provide effective treatment against liver metastasis and lymph node metastasis of gastric cancer.

A rapid biosensor chip assay for measuring of telomerase activity using surface plasmon resonance.

Considerable interest has been focused on telomerase because of its potential use in assays for cancer diagnosis, and for anti-telomerase drugs as a strategy for cancer chemotherapy. A number of assays based on the polymerase chain reaction (PCR) have been developed for evaluation of telomerase activity. To overcome the disadvantages of the conventional telomerase assay [telomeric repeat amplification protocol (TRAP)] related to PCR artifacts and troublesome post-PCR procedures, we have developed a telomeric repeat elongation (TRE) assay which directly measures telomerase activity as the telomeric elongation rate by biosensor technology using surface plasmon resonance (SPR). 5'-Biotinylated oligomers containing telomeric repeats were immobilized on streptavidin-pretreated dextran sensor surfaces in situ using the BIACORE apparatus. Subsequently, the oligomers associated with the telomerase extracts were elongated in the BIACORE apparatus. The rate of TRE was calculated by measuring the SPR signals. We examined elongation rates by the TRE assay in 18 cancer and three normal human fibroblast cell lines, and 12 human primary carcinomas and matching normal tissues. The elongation rates increased in a concentration- and time-dependent manner. Those of cancer cells were two to 10 times higher than fibroblast cell lines and normal tissues. Telomerase activities and its inhibitory effects of anti-telomerase agents as measured by both the TRE and TRAP assays showed a good correlation. Our assay allows precise quantitative comparison of a wide range of human cells from somatic cells to carcinoma cells. TRE assay is suitable for practical use in the assessment of telomerase activity in preclinical and clinical trials of telomerase-based therapies, because of its reproducibility, rapidity and simplicity.

Gastrointestinal stromal tumour of the oesophagus: significance of immunohistochemical and genetic analyses of the c-kit gene.

Oesophageal gastrointestinal stromal tumours (GISTs) are rare in comparison to those of the stomach and intestines. Recently, it has been clarified that mutations of the c-kit gene resulting in gain of function might be associated with histogenesis of this type of tumour arising in the stomach and intestines. We describe an oesophageal GIST on immunohistochemical and genetic analyses of the gene. A 71-year-old man had an intramural tumour of the middle third of the oesophagus. Tumour cells were composed predominantly of spindle-shaped and partially epithelioid cells. They were diffusely positive for CD117. Six base deletion resulting in in-frame mutation of the c-kit gene was confirmed at codon 556-558 (cag tgg aag to cag) of exon 11. Patients with mutations of the c-kit gene revealed worse prognoses in GISTs arising from other locations. A long-term follow-up observation is needed for the case.

Evaluation of the ratio of lymph node metastasis as a prognostic factor in patients with gastric cancer.

BACKGROUND: Lymph node metastasis in patients with gastric cancer is one of the important prognostic factors. However, there is no consensus concerning the best classification for lymph node metastasis as a prognostic factor. So, to evaluate the ratio of the number of metastatic lymph nodes to the total number of dissected lymph nodes (the ratio of LN meta) as a prognostic factor, we compared the ratio of LN meta with lymph node status according to the Japan Classification of Gastric Carcinoma and the total number of metastatic lymph nodes with multivariate analysis.METHODS: Between 1991 and 1997, a total of 360 patients with primary gastric cancer who underwent gastrectomy with D2 or more extended lymph node dissection were included in this study. Ten kinds of prognostic factors and three types of different classifications for lymph node metastasis were analyzed by multivariate analysis using the Cox regression.RESULTS: The average number of dissected lymph nodes and metastatic lymph nodes were 55.0 (range, 11-184) and 2.6 (range, 0-86), respectively. There were significant differences of the 5-year cumulative survival rates among each group of the ratio of LN meta (0%, 1%-9%, 10%-24%, and more than 25%). Age, tumor size, curability, and the ratio of LN meta were selected as independent prognostic factors by forward stepwise selection. The ratio of LN meta showed the highest hazard ratio by Cox regression.CONCLUSION: The ratio of LN meta appears to be an important prognostic factor and the best classification factor for lymph node metastasis.