Long-Term Outcomes of S-1 Combined With Low-Dose Docetaxel as Neoadjuvant Chemotherapy (N-1 Study, Phase II Trial) in Patients With Operable Breast Cancer.

BACKGROUND: We previously reported that S-1 and low-dose docetaxel (DOC) (N-1 study, phase II trial) could be a well-tolerated and effective neoadjuvant chemotherapies (NACs) for patients with operable breast cancer. Herein, we analyzed the long-term outcomes and developed clinicopathological and molecular predictors of pathological complete response (pCR). PATIENTS AND METHODS: Eighty-three patients received S-1 (40 mg/m2 orally on days 1-14) and DOC (40 mg/m2 intravenously on day 1) every 3 weeks for 4 to 8 cycles. Disease-free survival (DFS) and overall survival (OS) were analyzed for each population with a pCR status. To assess the relationship between pCR and clinicopathological factors such as tumor-infiltrating lymphocytes (TILs, 1+ <10%, 2+ 10%-50%, and 3+ >50%) and nuclear grade (NG), microarray was used to compare the microRNA profiles of the pCR and non-pCR groups using core needle biopsy specimens. RESULTS: With a median follow-up duration of 99.0 (range, 9.0-129.0) months, the 5-year DFS and OS rates were 80.7% and 90.9%, respectively. The 5-year OS rate of the pCR group was significantly better than that of the non-pCR group (100% vs. 86.2%, p = .0176). Specifically, in triple-negative patients, the difference was significant (100% vs. 60.0%, p = .0224). Multivariate analysis revealed that high TILs (≥2-3+) and NG 2-3 independently predicted pCR. Microarray data revealed that 3 miRNAs (miR-215-5p, miR-196a-5p, and miR-196b-5p) were significantly upregulated in the pCR group. CONCLUSION: Our NAC regimen achieved favorable long-term outcomes and significantly improved OS in the pCR group. High TILs, NG 2-3, and some miRNAs may be predictors of pCR.

Absolute Lymphocyte Count Changes During Neoadjuvant Chemotherapy are Associated With Prognosis of Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Patients.

NTRODUCTION/BACKGROUND: Some reports have shown that absolute lymphocyte count (ALC) is associated with prognosis in breast cancer; however, the impact of ALC changes remains unclear. This study aimed to investigate the relationship between ALC changes during neoadjuvant chemotherapy for human epidermal growth factor receptor-2 (HER2)-positive breast cancer patients and disease prognosis. PATIENTS AND METHODS: This retrospective cohort study January 2010 to September 2020) included patients diagnosed with HER2-positive breast cancer and treated with trastuzumab-based neoadjuvant chemotherapy. The ALC ratio was defined as the ALC value after administration of the anti-HER2 drug divided by the ALC value before administration. The optimal ALC ratio cut-off value was identified using the receiver operating characteristic curve analysis and Youden's index. The relationship between the ALC ratio and disease-free survival was assessed using the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazards model. RESULTS: Data from a total of 100 HER2-positive breast cancer patients were analyzed. The cut-off value of the ALC ratio was set as 1.142. The median follow-up period was 52.0 (range: 5.1-123.7) months. The 5-year disease-free survival rates were 88.4% and 60.9% in the high-and low-ALC ratio groups, respectively, and were significantly higher in the high-ALC ratio group (p = .0031). The ALC ratio was an independent prognostic factor in multivariate Cox proportional hazards analysis (p = .0032). CONCLUSION: HER2-positive breast cancer patients with a higher ALC ratio during trastuzumab-based neoadjuvant chemotherapy may have a better prognosis than their counterparts.

Drug-induced interstitial pneumonia during perioperative chemotherapy for breast cancer.

PURPOSE: Drug-induced interstitial pneumonia (DIP) that occurs during chemotherapy for breast cancer is a rare but a serious adverse event. Treatments of DIP requires interruption of breast cancer treatment, which may affect the patient's prognosis. However, there are few reports which discuss DIP during breast cancer treatments. Purpose of this report is to make clear how DIP occurred and influenced breast cancer treatment in our hospital. PATIENTS AND METHODS: A total of 74 patients who started perioperative chemotherapy in Tokushima Municipal Hospital for breast cancer from January 2019 to December 2020 were evaluated for DIP. Patients' and tumors' characteristics, and regimens which caused DIP were investigated. The clinical courses of the DIP patients were also followed up. RESULTS: Twelve of the 74 patients developed DIP. All 12 patients had histories of cyclophosphamide administration;however, the causative drug could not be determined. Ten of the 12 patients were treated with steroids, and all the patients recovered ultimately from the interstitial pneumonia. While chemotherapy was administered in six patients after mild DIP, no relapse of pneumonia was observed. CONCLUSION: DIP during perioperative chemotherapy for breast cancer was resolved with appropriate treatment. Patients were able to resume breast cancer treatment with minimal interruption. J. Med. Invest. 69 : 107-111, February, 2022.

Phase II Study of S-1 Combined With Low-Dose Docetaxel as Neoadjuvant Chemotherapy for Operable Breast Cancer Patients (N-1 Study).

BACKGROUND: To improve the pathological complete response (pCR) rate, we devised new neoadjuvant chemotherapy. Efficacy and safety of the oral fluoropyrimidine derivative S-1 (Taiho Pharmaceutical Co, Tokyo, Japan) combined with low-dose docetaxel (S-1+DOC) were evaluated. PATIENTS AND METHODS: Patients were treated with docetaxel (40 mg/m2 intravenously on day 1) and S-1 (40 mg/m2 orally twice per day on days 1-14) every 3 weeks for 4 cycles. In accord with the Response Evaluation Criteria In Solid Tumors version 1.1 criteria, the patients who showed a complete response (CR) underwent surgery, and those who achieved a partial response (PR) underwent 4 more cycles of S-1+DOC. Patients who achieved stable disease (SD) or progressive disease (PD) received EC (epirubicin and cyclophosphamide) or HT (trastuzumab and paclitaxel) according to their HER2 status. The primary end point was the pCR rate. RESULTS: Ninety-four patients entered the study. After 4 cycles of S-1+DOC, CR was noted in 5 patients, PR in 57, SD in 18, and PD in 3. Of the patients who achieved SD and PD, 12 received EC, and 9 received HT. Among the 83 assessable patients, the pCR rate was 34.9%, and the response rate was 80.7%. The pCR rates were 19.5% in the luminal type group, 53.8% in the luminal HER2 group, 46.1% in the HER2 group, and 50.0% in the triple-negative group. CONCLUSION: The S-1+DOC regimen in this study could be well tolerated and a new candidate neoadjuvant chemotherapy in operable breast cancer patients. It is also expected to be effective even in patients with luminal type disease. However, further randomized control trials are needed to ascertain whether pCR can contribute to favorable outcomes.

Overexpression of IGF2 and IGF2 receptor in malignant solitary fibrous tumor with hypoglycemia: a case report.

BACKGROUND: Solitary fibrous tumor (SFT) is a prototypical mesenchymal neoplasm that induces non-islet cell tumor hypoglycemia (NICTH) due to overproduction of insulin-like growth factor 2 (IGF2). We here report the case of a malignant SFT associated with a hypoglycemia attack. CASE PRESENTATION: An 81-year-old man with a large subphrenic mass presented with hypoglycemia and loss of consciousness. His serum insulin and IGF1 levels were relatively low, suggesting an excessively high serum IGF2 levels. Preoperative Western blotting of serum confirmed the overproduction of high-molecular-weight IGF2. After total tumor resection, the patient recovered from hypoglycemia without the need for further treatment. Histological examination revealed proliferation of spindle cells and frequent nuclear mitoses with STAT6 and CD34 immunoreactivity, which led to the diagnosis of malignant SFT. IGF2 was strongly upregulated in the tumor upon immunohistochemistry, consistent with the report of NICTH. In addition, the tumor expressed IGF2 receptor (IGF2R) but not IGF1R. CONCLUSIONS: The present results indicate that the tumor co-expressed IGF2 and IGF2R. IGF2R has not previously been recognized as a tyrosine kinase receptor participating in cell signal transduction. Thus, further case series are required to determine whether IGF2R overexpression reflects the action of an unknown autocrine/paracrine system involving IGF2 for cell proliferation or for the scavenging and degradation of IGF2.

Low sense of coherence is associated with anxiety among adults: Results based on data from all 47 prefectures of Japan.

BACKGROUND: Anxiety disorder is a major societal, economic, and healthcare burden, so it is essential to identify underlying risk factors. Sense of coherence (SOC), defined as an individual's perceived ability to control events and cope with challenges, is strongly associated with healthcare outcomes. METHODS: This study investigated the association between SOC and anxiety among adults in all 47 prefectures of Japan using a cross-sectional online panel survey. SOC was assessed using the University of Tokyo Health Sociology version of the SOC Scale and anxiety was assessed using the Generalized Anxiety Disorder-7 (GAD-7) scale. RESULTS: Among 2100 participants (1051 males and 1049 females), 475 (22.6%) were identified with anxiety (scoring 8 points or higher on the GAD-7 scale). Before adjustment for potential confounders, there was a significant negative association between SOC and presence of anxiety. Even after adjustment, the presence of anxiety was significantly higher among the lower SOC subgroup than the higher SOC subgroup. CONCLUSIONS: These results indicate that approximately one-fifth of adults in Japan suffer from anxiety and that low SOC is a significant risk factor.

Efficacy of erlotinib and imatinib in a patient with a rectal gastrointestinal stromal tumor and synchronous pulmonary adenocarcinoma: A case report.

The synchronous existence of lung cancer and gastrointestinal stromal tumors (GIST) is considered to be extremely rare. To the best of our knowledge, this is the first report about the treatment of lung cancer and GIST with two kinds of molecular targeting drugs. An 83-year-old woman with a rectal GIST, which carried a c-kit mutation, and pulmonary adenocarcinoma, which exhibited an epidermal growth factor receptor (EGFR) mutation, was treated alternately with imatinib and erlotinib. Good control over both diseases was achieved for two years. The present case is not only of interest due to the rare co-occurrence of GIST and lung cancer, but also because it involved two tumors carrying different gene mutations, and both tumors were brought under control using different molecular targeting drugs.

A case of thoracic esophageal cancer undergone esophagectomy after induction chemotherapy in a Jehovah's Witness.

We report the case of a 50-year-old female Jehovah's Witness with advanced esophageal cancer who underwent esophagectomy following induction chemotherapy. She visited our hospital complaining of dysphagia and was diagnosed of advanced esophageal cancer by upper endoscopy. She refused allogeneic transfusion. Induction chemotherapy was performed. Severe anemia occurred as an adverse event. A subtotal esophagectomy was performed after her anemia improved. During the surgery, a large volume of replacement fluid was injected, the blood was diluted, and intraoperative bleeding was relatively reduced. Intraoperative blood salvage was made using Cell Saver. The postoperative course were stable by using autologous blood and albumin infusion. The patient was discharged on postoperative day 27. Jehovah's Witnesses with gastrointestinal malignancies can be treated safely by performing surgical therapy based on blood replacement therapy and autologous blood transfusion.

[Small size lung adenocarcinoma with rocal recurrence and port site recurrence 56 months after partial resection].

A lobectomy with systemic lymphadenectomy is a standard surgical procedure for a resectable lung cancer. However there is not a consensus on the limited surgery. A 60-year-old man underwent left upper lobe partial resection for small size lung adenocarcinoma under video assisted thoracic surgery (VATS). Fifty-six months after the operation, a computed tomography (CT) scan showed a local recurrence on the staple-line. A positron emission tomography (PET) scan showed an additional port site recurrence, which wasn't showed by a CT scan. He underwent left upper lobectomy and port site resection.

[Two elderly patients with advanced breast cancer successfully treated by tri-weekly docetaxel].

Case 1: An 86-year-old woman had an invasive breast cancer with dermal infiltration. Bone metastases were found in the femur and lumbar vertebrae. She was treated with 2 courses of 70 mg docetaxel (DOC) chemotherapy every 3 weeks, after which the tumor dramatically decreased in size. Following this treatment, she underwent a radical mastectomy. Case 2: An 80-year-old woman had a 10 cm tumor in the right breast. Lung and bone metastases were also found. Two 80 mg courses of DOC reduced the lung and bone metastases, and the size of the breast tumor. She underwent a local excision. Hormonal therapy is a standard treatment for hormone-sensitive breast cancer in elderly patients. It is suitable for patients who have a declining quality of life (QOL), although chemotherapy shows a higher response rate and takes less time than hormonal therapy. However, it is difficult to continue chemotherapy until pCR is achieved, even for chemotherapy-effective patients because the side effects of chemotherapy are severe. Therefore, local excision after chemotherapy is necessary for breast cancer patients to improve their QOL, even if there are distant metastatic lesions.

A case of a giant phyllodes tumor of the breast with hypoglycemia caused by high-molecular-weight insulin-like growth factor II.

We report the case of a patient who presented with hypoglycemia associated with a giant breast mass and presence of serum high-molecular-weight insulin-like growth factor II (big IGF-II). In July 2005, a 49-year-old woman was admitted because of delirium, transient loss of consciousness, and a giant mass of about 28 cm in diameter on the right breast. She had noticed the mass for more than 2 years, but had refused medical attention at that time. A blood examination indicated hypoglycemia (21 mg/dl) and decreased levels of endogenous insulin. Furthermore, a western blot analysis revealed that big IGF-II (20 kDa) was the predominant serum IGF-II peptide (mature IGF-II is 7.5 kDa). Because we suspected that the big IGF-II was produced by the breast tumor and was likely the cause of the hypoglycemia, a mastectomy was performed. A histological examination determined that the mass was a benign phyllodes tumor. After surgery, the hypoglycemia resolved, and endogenous insulin levels improved. We suspected that the patient had non-islet cell tumor hypoglycemia (NICTH), but the behavioral symptoms of the hypoglycemia caused by NICTH were similar to some mental diseases, which made diagnosis based on the behavior alone difficult. We suggest that co-occurrence of symptoms such as recent appearance of mental disease-like behavior, hypoglycemia, and giant breast tumor may help diagnose NICTH caused by big IGF-II.

[A case of occult breast cancer successfully treated by capecitabine in combination with weekly paclitaxel followed by FEC (75)].

A 78-year-old woman was referred to our hospital complaining of a hard nodule on the left side of her neck. Histological examination of this nodule showed metastatic carcinoma from breast cancer. Further examination revealed paraaortic lymph node swelling and no breast tumors. We diagnosed her tumors as occult breast cancer and its metastasis to lymph nodes (cT0N3cM1, Stage IV). We used weekly paclitaxel followed by a FEC75 regimen. The neck nodule size did not change after administration twice. We added capecitabine to the weekly paclitaxel, which had decreased the size of the nodule immediately. After this chemotherapy, PET-CT revealed that the lymph node metastasis had disappeared completely. It was considered that the addition of capecitabine in the early phase of the regimen was useful for this case.

Adult case of accessory cardiac bronchus presenting with bloody sputum.

We report an adult case of accessory cardiac bronchus (ACB) which extended from the carina to the diaphragm. A 32-year-old woman, with a history of frequent respiratory infections since childhood, recently presented with bloody sputum, and was admitted to our hospital. The ACB was detected as a supernumerary bronchus diverging from tracheal bifurcation. Complete resection of the ACB was performed by video-assisted thoracic surgery via minithoracotomy, approaching from the 5th intercostal space. The bloody sputum was caused by chronic inflammation of the ACB. She has been asymptomatic since surgery.

Intracellular calcium translocation during the contraction-relaxation cycle in scorpionfish swimbladder muscle.

To examine intracellular Ca(2+) translocation during the contraction-relaxation cycle in vertebrate striated muscle, electron probe X-ray microanalysis was performed on the swimbladder muscle (SBM) fibres of a scorpionfish Sebastiscus marmoratus. The SBM fibres were rapidly frozen at rest, during contraction and at various times after the onset of relaxation. Changes in calcium distribution in the components of the sarcoplasmic reticulum (SR) were examined on the SBM fibre cryosections. In resting fibres, the calcium concentration was highest around the boundary between the A and I bands (A-I boundary), where the terminal cisternae (TC) were located. In contracting fibres, the calcium concentration decreased around the A-I boundary, while it increased in all other regions of the sarcomere, indicating Ca(2+) release from the TC into the myoplasm. During relaxation, the calcium concentration first increased around the regions, where the fenestrated collars (FC) and the longitudinal tubules (LT) were located, and then gradually returned to the levels seen in resting fibres. These results support the view that, after the onset of relaxation in the SBM fibres, Ca(2+) in the myoplasm is first taken up by the FC and the LT, and then gradually returns to the TC.

Ultrastructural organization of the transverse tubules and the sarcoplasmic reticulum in a fish sound-producing muscle.

The ultrastructural basis for the extremely rapid contraction-relaxation cycle (up to 300 s(-1)) in the swim-bladder muscle (SBM) of a scorpionfish (Sebastiscus marmoratus), producing characteristic sounds for communication, was investigated by electron microscopy. The SBM fibres contained well-developed sarcoplasmic reticulum (SR) showing triadic contacts with well-organized transverse tubules (T tubules). It was newly found that different types of triadic contacts were present within the single SBM fibre. In the middle region of the fibre (approximately 54% of the fibre length), the triadic contacts were located around the level of boundary between the A- and I-bands (AI-type triad). However in the two end regions of the fibre (approximately 21% and approximately 12% of the fibre length), the triadic contacts were seen around the level of the Z-band (Z-type triad). Between the middle and end regions of the fibre, T tubule-SR contacts exhibited the form of pentads composed of a pair of T tubules and three SR elements, and newly found heptads composed of three T tubules and four SR elements. The fractional volume of SR relative to the fibre volume was estimated to be approximately 26% in the middle region of the fibre with the AI-type triads and approximately 15% in the fibre ends with the Z-type triads. These results are discussed in connection with the mechanism, by which the mechanical activity of the SBM muscle is neurally controlled.

Modulation of manganese currents by 1, 4-dihydropyridines, isoproterenol and forskolin in rabbit ventricular cells.

Although often used as a Ca(2+) channel blocker, Mn(2+), in fact, permeates through Ca(2+) channels. Under Na(+)-free conditions, depolarizing pulses evoked slowly-decaying Mn(2+) currents ( I(Mn)). Maximal I(Mn) densities in the presence of 5 and 20 mM Mn(2+) were 0.42+/-0.12 pA/pF (mean+/-SEM, n=17) and 1.23+/-0.10 pA/pF ( n=40), respectively. At 5 mM, the ratio of maximal amplitude of I(Mn) to that of the Ca(2+) current ( I(Ca)) was 0.079+/-0.009 ( n=8). I(Mn) elicited from a holding potential of -50 mV was depressed by nitrendipine (1 microM) by approximately 70%. Nitrendipine (0.3 microM) shifted the steady-state inactivation curve to more negative potentials and shifted the potential for half-maximal inactivation ( E(0.5)) from 1.3 to -8.8 mV and also decreased the time constant of decay of I(Mn) at 20 mV from 986.2 to 167.9 ms. BAY K 8644 (1 microM), isoproterenol (10 microM) and forskolin (10 microM) all increased I(Mn) and shifted the current/voltage ( I/ V) relationship to more negative potentials. The small, slowly-inactivating I(Mn) is thus modulated by dihydropyridine Ca(2+) channel modulators and cyclic AMP-mediated phosphorylation in a manner similar to other L-type Ca(2+) channel currents. L-type Ca(2+) channels are involved in the regulation of intracellular [Mn] in ventricular myocytes.

Diltiazem facilitates inactivation of single L-type calcium channels in guinea pig ventricular myocytes.

Diltiazem is a benzothiazepine Ca2+ channel blocker used clinically for its antihypertensive and antiarrhythmic effects. We studied the mechanism of diltiazem blockade by recording L-type Ca2+ channel currents from cell-attached patches in isolated guinea pig ventricular myocytes using Ba2+ as the charge carrier. With diltiazem (200 microM) in the superfusate, multichannel currents showed a use-dependent decline in amplitude reflecting reductions in the numbers of superpositions of channel openings. Analysis of single-channel currents revealed that both open and closed times were little affected by diltiazem (50 and 100 microM). However, the rate of decay of the averaged current during 150-ms depolarization steps was significantly accelerated and the open state probability in current containing-sweeps was significantly decreased by diltiazem, suggesting that the drug accelerates transition from the activated state to the inactivated state. The effect of diltiazem on the slow gating process was studied by repetitively applying 500-1000 step pulses at selected holding potentials. Decreased channel availability by diltiazem was reflected by the increasing number of blank sweeps per run at depolarized holding potentials. These results suggest that diltiazem reduces Ca2+ influx by accelerating inactivation during action potentials, and that the use-dependent blockade is due to increases in the number of channels in a sustained closed state.

KV2.1 K+ channels underlie major voltage-gated K+ outward current in H9c2 myoblasts.

The H9c2 clonal cell line derived from embryonic rat ventricle is an in vitro model system for cardiac and skeletal myocytes. We used the whole-cell patch clamp technique to characterize the electrophysiological and pharmacological properties of an outward K+ current (IK(V)) and determined its molecular correlate in H9c2 myoblasts. IK(V) was activated by threshold depolarization to -30 mV, and its current amplitude and rate of activation increased with further depolarizations. IK(V) inactivated slowly with a time constant of 1-2 s, and the V(0.5) for steady-state inactivation was -37.9 +/- 4.6 mV (n = 10). Tetraethylammonium and quinidine suppressed IK(V) with IC(50)'s of 3.7 mM and 11.6 microM, respectively. Using RT-PCR analysis we found that the K(V )2.1 gene is the most abundantly expressed among genes for K(V)1.2, 1.4, 1.5, 2.1, 4.2, and 4.3, and by Western blotting we confirmed the synthesis of the K(V)2.1 alpha-subunit protein. We conclude that IK(V), the predominant voltage-gated outward current in H9c2 myoblasts, flows through the channels comprised of the K(V)2.1-subunit gene product.