[A Case of Drug-Induced Pneumomediastinum Preceding Interstitial Pneumonitis Onset during Treatment with a First-Line Regimen of GnP in a Patient with Unresectable Pancreatic Cancer].

BACKGROUND: The highest prevalence of drug-induced interstitial pneumonitis(IP)occurs in patients receiving antineoplastic agents, such as cytotoxic chemotherapeutic drugs, molecular targeted drugs, and immune checkpoint inhibitors. A certain period of the treatment for IP requires discontinuation of the anticancer therapy, resulting in progression of the malignant status. CASE: A 70-year-old man was incidentally diagnosed with locally advanced unresectable pancreatic cancer in the course of his treatment for ventricular dysrhythmia. After the insertion of a pacing instrument, he was ensured to be eligible to receive combination chemotherapy with gemcitabine and nab-paclitaxel(GnP)as the primary regimen. Shortly after the second course of GnP, the patient had high fever and developed pneumomediastinum 3 days prior to the onset of IP. The GnP treatment was suspended, and the IP was treated with pulse steroid therapy. The respiratory disorder took approximately 3 months to resolve; however, this concomitantly led to aggravation of the malignancy, which developed multiple metastases to the liver. The patient was no longer allowed to receive antineoplastic treatment. CONCLUSION: Although GnP may be a key regimen for the treatment of unresectable pancreatic cancer, patients should be closely monitored to ensure early detection of adverse events, such as interstitial pneumonia. Furthermore, drug-induced pneumomediastinum may be a precursor to the onset of interstitial pneumonia.

[A Case of Advanced Late Recurrence of Hormone Receptor Positive Breast Cancer Successfully Treated with Abemaciclib and Anastrozole].

BACKGROUND: In step with the aging of the Japanese population, late recurrence of hormone receptor positive (HR+) breast cancer occurring especially beyond 20 years after the initial diagnosis has been recognized as not rare anymore, as it has been occurring at a constant rate lately. The administration of an aromatase inhibitor with a CDK4/6 inhibitor has become the gold standard in Japan for cases of recurring HR+ breast cancer without severe visceral metastasis. CASE: A 73- year-old woman was diagnosed by chance with late recurrence of HR+ breast cancer 21 years after undergoing radical resection followed by adjuvant anastrozole for 5 years for stage Ⅲb right breast cancer. Asymptomatic multiple bone metastases on her ribs and sternum with bilateral lung metastasis and malignant effusion all disappeared while she was on a year- long administration of anastrozole and an optimal dose of abemaciclib(100 mg bid). However, because of the Grade 3 digestive adverse event that occurred at approximately 1 year of treatment, she could only maintain the treatment for up to 13 months. After then, no recurrence has been detectable for 6 months so far. CONCLUSION: CDK4/6 inhibitors, in combination with anastrozole, will play a pivotal role in the initial approach to elderly patients with HR+ late recurrence as a chemotherapy- free strategy.

A Case of Portal Venous Stenting for Metastatic Hilar Stricture After the Radical Resection of Colon Cancer.

Like standard stenting in an unresectable malignant stricture of the biliary or digestive tract, minimally invasive modality for portal stenosis is indispensable for palliation. We describe here a safe and practical procedure of portal stenting in a case of metastatic hilar strictures developed nine years after the radical resection of sigmoid colon cancer. After urgent delivery of the biliary tract stenting for the relief of jaundice, the patient received palliative stenting for the stricture of the portal trunk. Transhepatic approach, via the anterior branch, of the portal vein intervention may fit into the standard aspects for portal stenting.

[A case of S-1-resistant resected advanced gastric cancer with para-aortic lymph node recurrence responding to bi-weekly CPT-11 and CDDP].

A 64-year-old man with advanced gastric cancer who underwent a curative total gastrectomy(LM, Less, Type 3, 70×55 mm, por1>tub2>sig, pT3(ss), med, INF b, ly3, v3, pN3b(41/61), pPM0, pDM0, pT3N3bM0, Stage III B)followed by adjuvant chemotherapy(paclitaxel+S-1)a year ago, revealed an increasing level of serum CEA and para-aortic lymphnode (#16b1)recurrence on abdominal CT. He was given chemotherapy with low-dose weekday CDDP+S-1 for the recurrence, after which he failed to respond. Thereafter, he received 2nd-line chemotherapy with bi-weekly CPT-11+CDDP as a S-1- refractory regimen. 3 courses of the regimen reduced the serum CEA level accompanied by grade 3 of anemia. After recovery from the adverse event, another 4 courses at a 20% lower dosage for safety were administered. Complete response to the lymphnode was ensured on the abdominal CT with a reduced serum CEA level into the normal range. The patient has no signs of recurrence and has survived in fair condition for more than 5 years after the surgery. The combination treatment of biweekly CPT-11+CDDP can be a worthwhile regimen for patient with S-1-refractory recurrence of the resected advanced gastric cancer.

[A case of advanced breast cancer with multiple bone metastases responding to docetaxel and high-dose toremifene as fourth-line chemo-endocrine therapy].

A 55-year old woman, who underwent left mastectomy (Bt+Ax), was revealed to have sternum metastasis by postoperative 99mTc bone scanning(T1bN1M1). She received daily aromatase inhibitor (anastrozole), as a primary systemic endocrine therapy, and biweekly pamidronate for metastatic breast cancer. However, she depended on folk medicine a year later, at which time the primary treatment was discontinued. Another year later, the bone metastases developed with increased serum levels of tumor markers (CEA, CA19-9, and NCC-ST-439). Then, she underwent three different regimens of systemic chemo-endocrine therapy over the following three years, including CAF+MPA as the first-line, paclitaxel (PTX) + anastrozole as the second-line, and S-1+anastrozole as the third-line regimen. She recently completed 10 courses of the fourth-line regimen[tri-weekly docetaxel (DOC) and high-dose toremifene (TOR 120 mg/day)], which reduced levels of 99mTc accumulation in the multiple bone metastases and levels of the serum tumor markers to the normal range. No severe adverse events occurred except peripheral thrombovasculitis (grade 2) in her left anterior arm during the fourth regimen. She recently maintains the current status by taking a regular dose (40 mg/day) of toremifene for 5 months. Combination treatment with DOC and high-dose TOR can be one of the worthwhile regimens as systemic chemo-endocrine therapy for patients with advanced breast cancer who develop bone metastases.

Successful thoracoscopic lobectomy for lung cancer in a patient with anatomic variation of the left inferior pulmonary vein.

We present a case of primary lung cancer with a rare distribution pattern of left inferior pulmonary vein (PV), encountered in the thoracoscopic left lower lobectomy. Thoracoscopic observation revealed 2 trunks of inferior PV (ventral and dorsal branch) at the stem level. The ventral trunk consisted of a branch of vein (V(5)) from the lingular segment and venous ramifications (V(8)a, V(9) and V(10)a) from the basal segment. On the other hand, a branch of vein (V(6)) from the superior segment in the lower lobe and other veins (V(8)b and V(10)b + c) from the basal segment emptied together into the dorsal trunk. We successfully carried out a thoracoscopic left lower lobectomy without excision of the aberrant vein (V(5)). Retrospective review of the preoperative chest CT demonstrates the double trunk inferior PV and the aberrant lingular branch emptying with V(8)a into the ventral trunk. Knowledge of the branching variations of PV from preoperative evaluations leads to appropriate thoracoscopic procedures for lung cancer.

Carbon monoxide rescues ischemic lungs by interrupting MAPK-driven expression of early growth response 1 gene and its downstream target genes.

Carbon monoxide (CO), an endogenous cytoprotective product of heme oxygenase type-1 regulates target thrombotic and inflammatory genes in ischemic stress. Regulation of the gene encoding early growth response 1 (Egr-1), a potent transcriptional activator of deleterious thrombotic and inflammatory cascades, may govern CO-mediated ischemic lung protection. The exact signaling mechanisms underlying CO-mediated cytoprotection are not well understood. In this study we tested the hypothesis that inhibition of mitogen-activated protein kinase-dependent Egr-1 expression may be pivotal in CO-mediated ischemic protection. In an in vivo isogeneic rat lung ischemic injury model, inhaled CO not only diminished fibrin accumulation and leukostasis and improved gas exchange and survival but also suppressed extracellular signal-regulated kinase (ERK) activation, Egr-1 expression, and Erg DNA-binding activity in lung tissue. Additionally, CO-mediated inhibition of Egr-1 reduced expression of target genes, such as tissue factor, serpine-1, interleukin-1, and TNF-alpha. However, CO failed to inhibit serpine-1 expression after unilateral lung ischemia in mice null for the Egr-1 gene. In RAW macrophages in vitro, hypoxia-induced Egr-1 mRNA expression was ERK-dependent, and CO-mediated suppression of ERK activation resulted in Egr-1 inhibition. Furthermore, CO suppression of ERK phosphorylation was reversed by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one but was insensitive to cAMP-dependent protein kinase A inhibition with H89 and NO synthase inhibition with l-nitroarginine methyl ester. This finding indicates that CO suppresses ERK in a cGMP-dependent but cAMP/protein kinase A- and NO-independent manner. Together, these data identify a unifying molecular mechanism by which CO interrupts proinflammatory and prothrombotic mediators of ischemic injury.

A thoracoscopically resected case of mediastinal parathyroid cyst.

A 67-year-old male visited his physician because of a 2-month history of cough and sputum. An abnormal shadow at the left upper mediastinum on chest x-ray film was detected, and the patient was referred to our department for further examination. Chest x-ray film revealed a round shadow at the left upper posterior mediastinum. Computed tomography(CT)revealed a uniform iso density mass about 4 cm in diameter, with a well-defined border. After the intravenous contrast administration, a slight peripheral enhancement was seen around the mass. On magnetic resonance imaging, the mass was hypointense in T1-weighting and hyperintense in T2-weighting. The contrast pattern was the same as that observed in the CT scan. On sagittal and coronal sections, the mass was adjacent to the aortic arch. Although a benign tumor was mostly suspected based on imaging findings, a malignant tumor was also possible. Accordingly, we resected this mass with video-assisted thoracoscopy. Findings at operation were a cystic mass. The pathological findings were compatible with benign parathyroid cyst, which was suspected to be the cystic degeneration of a parathyroid adenoma.

Reciprocal regulation of airway rejection by the inducible gas-forming enzymes heme oxygenase and nitric oxide synthase.

Obliterative bronchiolitis (OB) develops insidiously in nearly half of all lung transplant recipients. Although typically preceded by a CD8(+) T cell-rich lymphocytic bronchitis, it remains unresponsive to conventional immunosuppression. Using an airflow permissive model to study the role of gases flowing over the transplanted airway, it is shown that prolonged inhalation of sublethal doses of carbon monoxide (CO), but not nitric oxide (NO), obliterate the appearance of the obstructive airway lesion. Induction of the enzyme responsible for the synthesis of CO, heme oxygenase (Hmox) 1, increased carboxyhemoglobin levels and suppressed lymphocytic bronchitis and airway luminal occlusion after transplantation. In contrast, zinc protoporphyrin IX, a competitive inhibitor of Hmox, increased airway luminal occlusion. Compared with wild-type allografts, expression of inducible NO synthase (iNOS), which promotes the influx of cytoeffector leukocytes and airway graft rejection, was strikingly reduced by either enhanced expression of Hmox-1 or exogenous CO. Hmox-1/CO decreased nuclear factor (NF)-kappaB binding activity to the iNOS promoter region and iNOS expression. Inhibition of soluble guanylate cyclase did not interfere with the ability of CO to suppress OB, implicating a cyclic guanosine 3',5'-monophosphate-independent mechanism through which CO suppresses NF-kappaB, iNOS transcription, and OB. Prolonged CO inhalation represents a new immunosuppresive strategy to prevent OB.

Effect of gravitation for detection of bronchioloalveolar carcinoma on computed tomography.

A 64-year-old female was found to have localized ground-glass opacity (GGO) in the middle lobe on a chest computed tomography (CT) for screening. Middle lobectomy with video-assisted thoracoscopic surgery (VATS) was undertaken, and pathological diagnosis was a bronchioloalveolar carcinoma (BAC) in stage IA. A follow-up CT a year following the surgery revealed localized GGO in area S6 of the left lung. However, it disappeared during the gravitation-dependent gradient in the observation period. The patient was scanned again under prone position to exclude the gravitational effect, resulting in definite detection of the GGO. Left extended S6 segmentectomy with VATS was performed, and pathological diagnosis was a BAC in stage IA. As GGO existing in a gravitation-dependent area may be masked by the gravitation-dependent density, a change of the scanning position may lead to a proper detection of the tumor for the diagnosis of BAC.

Recipient iNOS but not eNOS deficiency reduces luminal narrowing in tracheal allografts.

Chronic airway rejection is characterized by prolonged inflammation, epithelial damage, and eventual luminal obliterative bronchiolitis (OB). In cardiac allografts, the inducible nitric oxide synthase (iNOS) promotes acute rejection but paradoxically reduces neointimal formation, the hallmark of chronic rejection. The specific roles of NOS isoforms in modulating lymphocyte traffic and airway rejection are not known. Using a double lumen mouse tracheal transplant model, tracheal grafts from B10.A (allo) or C57BL/6J (iso) mice were transplanted into cyclosporine-treated wild-type (WT) iNOS(-/-) or endothelial NOS (eNOS)(-/-) recipients. OB was observed in WT tracheal allografts at 3 weeks (53 +/- 2% luminal occlusion vs. 17 +/- 1% for isografts, P < 0.05) with sites of obstructive lesion formation coinciding with areas of CD3(+) CD8(+) T cell-rich lymphocytic bronchitis. In contrast, allografts in iNOS(-/-) recipients exhibited reductions in local expression of proinflammatory chemokines and cytokines, graft T cell recruitment and apoptosis, and luminal obliteration (29 +/- 2%, P < 0.05 vs. WT allografts). Recipient eNOS deficiency, however, suppressed neither chemokine expression, lymphocyte infiltration, nor airway occlusion (54 +/- 2%). These data demonstrate that iNOS exacerbates luminal obliteration of airway allografts in contrast with the known suppression by iNOS of cardiac allograft vasculopathy. Because iNOS(-/-) airways transplanted into WT allograft hosts are not protected from rejection, these data suggest that iNOS expressed by graft-infiltrating leukocytes exerts the dominant influence on airway rejection.

Transcriptional control of cardiac allograft vasculopathy by early growth response gene-1 (Egr-1).

Expression of the zinc finger transcription factor early growth response gene-1 (Egr-1) is triggered rapidly after mechanical vascular injury or after a precipitous drop in ambient oxygen, whereupon it induces the expression of diverse gene families to elicit a pathological response. Initially characterized as an early response transcriptional activator, the role of Egr-1 in more chronic forms of vascular injury remains to be defined. Studies were designed to examine whether Egr-1 induction may serve as a causal link between early preservation injury and delayed vascular consequences, such as coronary allograft vasculopathy (CAV). The preservation and transplantation of heterotopic murine cardiac allografts strongly induce Egr-1 expression, leading to increased expression of its downstream target genes, such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and platelet-derived growth factor A chain. Expression of these Egr-1-inducible gene targets is virtually obliterated in homozygous Egr-1-null donor allografts, which also exhibit attenuated parenchymal rejection and reduced CAV as long as 60 days. Congruous data are observed by treating donor hearts with a phosphorothioate antisense oligodeoxyribonucleotide directed against Egr-1 before organ harvest, which blocks subsequent expression of Egr-1 mRNA and protein and suppresses the late development of CAV. These data indicate that Egr-1 induction represents a central effector mechanism in the development of chronic rejection characterized by CAV. Blocking the expression of this proximal transcription factor solely at the time of organ harvest elicits beneficial delayed consequences for the cardiac allograft.

Suppression of murine cardiac allograft arteriopathy by long-term blockade of CD40-CD154 interactions.

BACKGROUND: The interaction between CD40 on antigen-presenting cells and CD40L on T cells is critical in allograft rejection. CD154 blockade suppresses allograft rejection, but the role of this pathway in allograft vasculopathy remains obscure. METHODS AND RESULTS: A vascularized murine heterotopic cardiac transplant model was used to test whether perioperative CD154 blockade suppresses allograft vasculopathy or whether long-term CD154 blockade is required to suppress allograft vasculopathy. Perioperative CD154 blockade consisted of MR1 given on days -1, 1, and 3; long-term blockade consisted of MR1 given on days -1, 1, and 3 and continued twice weekly for 8 weeks. Allografts treated with perioperative or long-term CD154 blockade survived indefinitely. Perioperative and long-term treatment with control antibody (Ha4/8) resulted in uniform early rejection. Perioperative CD154 blockade transiently reduced early T-cell and macrophage infiltration in parallel with a transient reduction in endothelial adhesion receptor expression. Although perioperative CD154 blockade prevented allograft failure, it did not reduce allograft vasculopathy; mean neointimal cross-sectional area in perioperative MR1-treated and Ha4/8-treated recipients was 43+/-7% and 50+/-12%, respectively (P=NS). In contrast, mean neointimal cross-sectional area in long-term, MR1-treated recipients was 19+/-3% (P<0.001 versus perioperative MR1). Long-term CD154 blockade also suppressed endothelial E-selectin, P-selectin, and intracellular adhesion molecule-1 expression and improved graft function 3.5-fold versus control (P<0.05). CONCLUSIONS: These data show that perioperative CD154 blockade mitigates acute rejection but long-term CD154 blockade may result in decreased allograft endothelial activation and is required to suppress allograft arteriopathy.

Timing of nitric oxide donor supplementation determines endothelin-1 regulation and quality of lung preservation for transplantation.

Nitroglycerin (NTG) given to donor lungs improves lung preservation for transplantation, but the mechanism(s) underlying this therapeutic benefit remain incompletely understood. Furthermore, it is not known whether the therapeutic window of opportunity for NTG administration is temporally-restricted. Because endothelin-1 (ET-1), a potent vasoconstrictor, and nitric oxide (NO) are reciprocally regulated in vitro, we hypothesized that early administration of the NO donor NTG may suppress ET-1 and thereby improve lung preservation. Using an isogeneic rat left lung transplantation model, four groups were studied (n = 12 transplant/group): (1) NTG given during flush/ preservation (Early NTG); (2) NTG given in the ex vivo flush (Late NTG); (3) No NTG; and (4) a nonselective ET-receptor antagonist (PD156252) given during flush/preservation. Early NTG decreased vascular tone in lung grafts measured ex vivo as well as in vivo following lung transplantation, and resulted in improved survival (100%) and gas exchange (pO2 209 +/- 19 mm Hg) compared with Late (17%, 62 +/- 16 mm Hg) or No NTG (25%, 59 +/- 9 mm Hg) (P < 0.05 for Early NTG versus all other groups for both survival and pO2). PD156252 was associated with an intermediate level of survival (50%) and function (104 +/- 23 mm Hg). Transplanted lung graft ET-1 mRNA, measured by Northern blotting and in situ hybridization, and protein, measured by Western blotting and immunohistochemistry, were suppressed only with Early NTG (P < 0.05 versus all other groups). Post-transplantation benefits of NTG are restricted to lung grafts which received NTG during the early harvest and immersion periods, and are coincident with suppression of graft ET-1 expression. When viewed in the context of improved graft survival and function with ET-1 receptor blockade, these data suggest that early administration of NTG to donor lungs improves primary graft function, in part, by suppressing graft ET-1 expression.