Successful conservative management of an anastomotic airway dehiscence at the left main bronchus following bilateral cadaveric lung transplantation

There is a dearth of data on management of anastomotic airway dehiscence following lung transplantation. Herein we report a case of successful conservative management of an anastomotic airway dehiscence after cadaveric donor lung transplantation. A 41-year-old woman with primary ciliary dyskinesia underwent cadaveric bilateral lung transplantation without cardiopulmonary bypass. On the postoperative day 25, left pneumothorax developed and bronchoscopy demonstrated a localized anastomotic dehiscence at the left main bronchus. The dehiscence was managed with 2 weeks of pleural drainage and was completely covered with regenerated bronchial epithelium at 4 months after transplantation. There is no finding suggestive of significant stenosis at 4 years of follow-up. Our case suggested asymptomatic and localized anastomotic dehiscence does not always require endobronchial stent placement or re-operation. Multiple factors that may contribute to the successful conservative management were discussed in this article.     

Clinical application of postoperative non-invasive positive pressure ventilation after lung cancer surgery

Objective

The purpose of this study was to clarify the clinical efficacy of postoperative non-invasive positive pressure ventilation (PONIV) after pulmonary lobectomy in patients with lung cancer.

Methods

From August 2010 and July 2015, 143 patients with lung cancer who underwent pulmonary lobectomy were retrospectively reviewed. PONIV was used immediately after surgery until the morning of postoperative day (POD) 1. Arterial blood gas was analyzed before and just after surgery (POD0) and on POD1. Oxygenation ability was perioperatively assessed by PaO₂/FiO₂ ratio, alveolar–arterial oxygen difference (A-aDO₂), and respiratory index (A-aDO₂/PaO₂).

Results

112 patients received PONIV. From POD0 to POD1, the PaO₂/FiO₂ ratio significantly improved in all patients who received PONIV (333?±?83 to 359?±?47 mmHg, p?=?0.004). Moreover, A-aDO₂ and respiratory index significantly decreased following PONIV. PONIV significantly improved the PaO₂/FiO₂ ratio in patients with PaO₂/FiO₂ ratio of ≤?300 on POD0, older age (≥?70 years), higher body mass index (≥?25 kg/m²), and longer one-lung ventilation time (≥?180 min). There was no respiratory failure requiring mechanical ventilation and no mortality.

Conclusions

PONIV effectively improved oxygenation in patients undergoing pulmonary lobectomy in patients with poor status, especially in patients with PaO₂/FiO₂ ratio of ≤?300 on POD0. PONIV could be an option of perioperative management for major thoracic surgery.

     

A novel phosphodiesterase type 4 inhibitor, YM976 (4-(3-chlorophenyl)-1,7-diethylpyrido[2,3-d]pyrimidin-2(1H)-one), with little emetogenic activity

We synthesized a novel phosphodiesterase type 4 (PDE4) inhibitor, YM976, that is structurally different from the other PDE4 inhibitors like rolipram. In the present study, the pharmacological profile of YM976 was investigated. YM976 exhibited a strong and competitive inhibition against PDE4 purified from human peripheral leukocytes with an IC(50) of 2.2 nM. IC(50) values of rolipram and RP73401 were 820 and 0.43 nM, respectively. Test compounds had no effects on the other PDE isozymes, PDE1, -2, -3, and -5. YM976 potentiated prostaglandin E(2)-induced cAMP accumulation in a human mononuclear cell line, U937, and inhibited tumor necrosis factor-alpha production from human peripheral blood mononuclear cells stimulated by lipopolysaccharide. Anti-inflammatory activities of PDE4 inhibitors were compared in rat carrageenan-induced pleurisy models. YM976, rolipram, and RP73401 inhibited the cell infiltration into the pleural cavity with oral ED(30) values of 9.1, 10, and 7.4 mg/kg, respectively. YM976 produced no emesis up to 10 mg/kg, whereas rolipram and RP73401 induced emesis at oral doses of 3 mg/kg. To evidence the dissociation of anti-inflammatory activity from emesis, the anti-inflammatory effect of YM976 was examined in ferrets. YM976 dose dependently reduced carrageenan-induced leukocyte infiltration at the doses of 1, 3, and 10 mg/kg, p.o. On the other hand, rolipram failed to show obvious inhibition at doses that do not induce emesis. In conclusion, YM976 is a novel and orally active PDE4 inhibitor and possesses a good separation of emetogenicity from anti-inflammatory activity.     

Phase I/II Study of Erlotinib to Determine the Optimal Dose in Patients With Non‐Small Cell Lung Cancer Harboring Only EGFR Mutations

The recommended daily dose of erlotinib was determined for patients with all types of non‐small cell lung cancer (NSCLC). We determined the optimal dose (OD) in patients with NSCLC harboring only epidermal growth factor receptor (EGFR) sensitizing mutations. EGFR‐tyrosine kinase inhibitor‐naïve patients with sensitizing mutations were eligible. Clinical OD was determined in a phase I/II study based on the continual re‐assessment method (CRM) of both disease control and dose‐limiting toxicity, defined as any toxicity of grade 2 (G2) or higher within 8 weeks. We also determined the pharmacologic OD via a pharmacokinetic (PK) study. Thirty‐eight patients were enrolled. Clinical OD was 25 mg/day by the CRM. Median progression‐free survival (mPFS) was 9.3 months. In receiver operating characteristic (ROC) analysis of mPFS, the trough concentration ( Cminss) was ≥ 0.30 μg/mL. The area under the curve (AUC) and Cminss were predicted via population PK (PopPK) or a bootstrap of 100 iterations (PopPK₁₀₀). TOX20 was defined as < 20% duration of any toxicity ≥ G2 during the PFS period. In ROC analysis of mPFS and TOX20 in the PopPK₁₀₀ study, Cminss was ≥ 0.17 and < 0.32 μg/mL, respectively. In ROC analysis of mPFS and TOX20 in the PopPK₁₀₀ study, Cminss was ≥ 0.15 and < 0.31 μg/mL, AUC was ≥ 14.4 and < 14.5 μg/mL•hour, and the dosage was ≥ 58.4 and < 58.8 mg/day, respectively. Clinical and pharmacologic ODs were 25 by CRM and 50–60 mg/day by PK, respectively. The proposed starting OD is 50–60 mg/day, with personalized adjustment of 0.15–0.31 μg/mL based on Cminss as determined by PopPK monitoring.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ The recommended daily dose of erlotinib was determined for patients with all types of non‐small cell lung cancer (NSCLC). Many patients suffer severe and long‐term adverse events related to treatment despite tumors harboring sensitizing mutations.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ What is the optimal dose of erlotinib for patients with NSCLC harboring sensitizing mutations?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ In terms of therapy with a reduced dose of erlotinib, modest benefit was achieved when all patients received the same reduced dose, but greater benefit is obtained if each patient receives a personalized optimal dose via population pharmacokinetic monitoring based on interpatient variations.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ The method can be adapted to determine the optimal dose of molecular targeting agents other than erlotinib. The most benefit for patients is realized if their tumors are treated with a personalized optimal dose of molecular targeting agent, balancing toxicity and efficacy to adjust to interpatient differences.

Five epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) are currently available for use in clinical practice. ¹ All of these EGFR‐TKIs improve progression‐free survival (PFS) compared with standard chemotherapy as first‐line treatment for patients with non‐small cell lung cancer (NSCLC) harboring sensitizing EGFR mutations. ² , ³ Erlotinib is a first‐generation EGFR‐TKI with a recommended once‐daily oral dose of 150 mg. This dose was intended to target all types of EGFR (i.e., wild type and any EGFR mutations) based on dose‐escalation experiments in a phase I study of cytotoxic agents ⁴ and is the maximum tolerated dose. EGFR‐tyrosine kinase sensitizing mutations include exon 19 deletions (E19DEL) and a point mutation in exon 21 (L858R); thus, erlotinib exhibits excellent efficacy in patients with NSCLC harboring these sensitizing mutations. ⁵ At a 150 mg/day dose, the mean trough steady‐state concentration ( Cminss) of erlotinib is > 2.5 µM. ⁴ However, several basic research studies reported a 50% growth inhibitory concentration in NSCLC cell lines harboring sensitizing mutations of < 0.1 µM. ⁶ , ⁷ , ⁸ It is, therefore, likely that erlotinib can be given at doses < 150 mg/day while maintaining clinical efficacy.A postmarketing surveillance study of erlotinib in Japan involving 3,488 patients ⁹ reported the following rates of adverse events (AEs) of grade 2 (G2) or higher; eruptions = 38.8%, paronychia = 3.4%, diarrhea = 7.1%, hepatic disorders = 5.4%, and interstitial lung disease = 3.7%. About 90% of the patients were given 150 mg/day of erlotinib during treatment in this surveillance study. Because 55.1% of the patients had a history of gefitinib treatment and patients with all types of EGFR were eligible for this study, median PFS was only 64 days (95% confidence interval (CI) 60–68 days). Several AEs induced by erlotinib persisted during treatment. Long‐term, persistent AEs, even of low grade, can restrict patients’ normal activities and adversely affect their quality of life (QOL). ¹⁰ In interpatient dose escalation, the degree of AEs became more and more severe depending on increasing the daily dose of erlotinib from 25 to 200 mg/day. ⁴ During long‐term treatment, reduced toxicity can lead to improved QOL. It is, therefore, likely that reducing the required dose of erlotinib would have beneficial toxicity and QOL effects.The purpose of the present two‐phase study was to determine the optimal dose (OD) of erlotinib in patients with NSCLC harboring only sensitizing mutations. The first phase determined the minimum effective dose (MED) and OD of erlotinib in the target patient population, and the second phase determined the clinical and pharmacologic ODs. The study’s overall goal was to facilitate personalized dosing of erlotinib with the objective of balancing toxicity and efficacy.     

Specific Action of 4-Nitropyridine 1-Oxide on Escherichia coli K-12 Pro+ Strains Leading to the Isolation of Proline-Requiring Mutants: Isolation and Characterization of Pro− Mutants

A specific action of 4-nitropyridine 1-oxide on Escherichia coli K-12 Pro⁺ strains leading to highly efficient, selective isolation of Pro⁻ mutants is described. Incubation of Pro⁺ cells with a sublethal concentration of 4-nitropyridine 1-oxide in Penassay broth gave Pro⁻ mutants, which lacked either the biosynthetic pathway of proline from glutamic acid to glutamyl γ-phosphate (proB⁻) or the pathway from glutamyl γ-phosphate to glutamic γ-semialdehyde (proA⁻) or both. Pro⁻ mutants, which have the metabolic block between Δ¹ pyrroline-5-carboxylate (the cyclized dehydration product of glutamic γ-semialdehyde) and proline (proC⁻) were not found among survivors. Treatment of Pro⁺ cells with N-methyl-N′-nitro-N-nitrosoguanidine led to isolation of all three types of Pro⁻ mutants, suggesting that the action of 4-nitropyridine 1-oxide on Pro⁺ cells is apparently distinct from the action of N-methyl-N′-nitro-N-nitrosoguanidine. F-duction and interrupted mating experiments led to determination of the correlation between proline loci and the biosynthetic pathway of proline from glutamic acid.     

Expression of Human Tumor-Associated Antigen RCAS1 in Adult T-Cell Leukemia/Lymphoma

In human cancer, RCAS1 (the receptor-binding cancer antigen expressed on SiSo cells) on the surface of various kinds of tumor cells reportedly induces the apoptosis of T-cells and natural killer cells, resulting in evasion of the immune system. In the present study, an immunohistochemical analysis of RCAS1 expression was performed with lymph node specimens obtained from patients with adult T-cell leukemia/lymphoma (ATLL). Positive staining was seen in 15 (75%) of 20 cases and in all cases of patients with short survival times. In the cases of B-cell lymphomas, positive staining was seen in only 1 (13%) of 8 cases. These findings indicate that expression of RCAS1 may be associated with the evasion from immune surveillance of cells infected with human T-lymphotropic virus type I, resulting in the development of overt leukemia/lymphoma. Determination of RCAS1 expression may be useful for predicting the prognosis of patients with ATLL.     

Cytosolic Ca2+ concentration and pH of diabetic rat myocytes during metabolic inhibition.

To investigate the role of Ca2+ metabolism and pH in diabetic cardiomyopathy, intracellular Ca2+ concentration ([Ca2+]i) and intracellular pH (pHi) of isolated myocytes were measured simultaneously using fura-2 and BCECF. We used diabetic (D.M.) rats at 8 weeks after the injection of streptozotocin (45 mg/kg, i.v.). (1) [Ca2+]i of D.M. myocytes was lower than that of controls (53 +/- 3 and 75 +/- 5 nM, mean +/- S.E., P less than 0.01). There was no difference in pHi (7.06 +/- 0.02 in D. M., 7.07 +/- 0.02 in control). There was no difference in the percentage of non-rounded cells at 30 min after the perfusion of glucose-free solution which contained 2 mM sodium cyanide (NaCN) between D.M. and controls (53% and 52%). When cells were rounded, the value of [Ca2+]i was significantly lower in D.M. myocytes than that in controls (172 +/- 21 and 421 +/- 106 nM, P less than 0.05). (2) When the cells were shortened or rounded in the high [Ca2+]o solution (24.5 mM), [Ca2+]i of D.M. rats was significantly lower than that of control rats. (3) The percentage of non-rounded cells at 30 min after the perfusion of NaCN increased in controls by 50 mM glucose (95%, P less than 0.01), but not in D.M. (47%). Insulin (25 mU/ml) and glucose (15 mM) increased the percentage of non-rounded cells in D.M. after 30 min perfusion with NaCN (88%, P less than 0.01 v.s. 53% without glucose nor insulin). It is suggested that there are disturbances of Ca2+ metabolism in D.M. myocytes, and that there is a close relation between cell injury and glucose utilization during metabolic inhibition.