Perioperative FLOT plus ramucirumab for resectable esophagogastric adenocarcinoma: A randomized phase II/III trial of the German AIO and Italian GOIM

This multicenter, randomized phase II/III study evaluated the addition of the vascular endothelial growth factor receptor-2 inhibitor ramucirumab to FLOT as perioperative treatment for resectable esophagogastric adenocarcinoma. Patients received either FLOT alone (Arm A) or combined with ramucirumab followed by ramucirumab monotherapy (Arm B). The primary endpoint for the phase II portion was the pathological complete or subtotal response (pCR/pSR) rate. Baseline characteristics were comparable between both arms with a high rate of tumors signet-ring cell component (A:47% B:43%). No between-arm difference in pCR/pSR rate was seen (A:29% B:26%), therefore the transition to phase III was not pursued. Nevertheless, the combination was associated with a significantly increased R0-resection rate compared with FLOT alone (A:82% B:96%; P = .009). In addition, the median disease-free survival was numerically improved in Arm B (A:21 months B:32 months, HR 0.75, P = 0.218), while the median overall survival was similar in both treatment arms (A:45 months B:46 months, HR 0.94, P = 0.803). Patients with Siewert type I tumors receiving transthoracic esophagectomy with intrathoracic anastomosis showed an increased risk of serious postoperative complications after ramucirumab treatment, therefore recruitment of those patients was stopped after the first-third of the study. Overall, surgical morbidity and mortality was comparable, whereas more non-surgical grade ≥ 3 adverse events were observed with the combination, especially anorexia (A:1% B:11%), hypertension (A:4% B:13%) and infections (A:19% B:33%). The combination of ramucirumab and FLOT as perioperative treatment shows efficacy signals, particularly in terms of R0 resection rates, for a study population with a high proportion of prognostically poor histological subtypes, and further evaluation in this subgroup seems warranted.     

A novel technique to diagnose non‐melanoma skin cancer by thermal conductivity measurements: Correlations with cancer stromal factors

The skin surface temperature reflects the physiological state of the human body. Quantitative methods of identification of skin cancers based on accurate measurement of effective thermal conductivity (ETC) are among the promising diagnostic tools for differentiating non‐invasive and invasive melanomas before surgical treatment. To validate these findings, in this report, the diagnostic methods for invasive and non‐invasive extramammary Paget’s disease (EMPD) and squamous cell carcinoma (SCC) were further tested by measuring the absolute value of skin surface temperature and the ETC of the skin. In addition, to investigate the stromal factors that might affect ETC, immunohistochemical staining for LL37, periostin (POSTN), MMP12, and MMP28 was performed. The invasive SCC and EMPD group showed a relatively higher skin surface temperature compared to the in situ SCC group. The non‐invasive EMPD and SCC group showed significantly lower values of ETC at lesions, whereas the invasive EMPD group showed significantly higher ETC values at lesions compared to healthy skin. Immunohistochemical staining showed that the percentage of LL37‐producing cells was significantly increased in invasive EMPD and SCC compared to that in non‐invasive EMPD and SCC. Moreover, Spearman's rank correlation test showed a significant inverse correlation between the percentage of MMP12‐positive cells and increased levels of ETC‐expressing areas in EMPD and SCC (r = ?.5997). The present study suggested that differences in ETC could be a novel high‐accuracy diagnostic technique for non‐melanoma skin cancer, especially for detecting dermal invasion of SCC and EMPD.     

A fatal case of pemphigus vulgaris with interstitial pneumonia occurring during gold therapy

We report a case of a 52-year-old female with therapy-resistant pemphigus vulgaris. She was treated with prednisone, azathioprine and gold sodium thiomalate. After administration of a total dose of 110 mg gold sodium thiomalate, she suddenly developed pityriasis rose-like drug eruptions and interstitial pneumonia and died despite intensive care including pulse therapy. In Japan, there have been 8 reported cases of pemphigus or bullous pemphigoid that developed interstitial pneumonia during gold therapy. In these 7 cases, interstitial pneumonia occurred after administration of 110 to 430 mg gold sodium thiomalate, and 4 cases died. This rate of death is higher than those with other diseases: i.e., 9 dead cases among 99 cases of interstitial pneumonia developing in patients with rheumatoid arthritis or asthma under treatment with gold sodium thiomalate. We think that it is necessary to reevaluate the combined treatment of sodium thiomalate and other immunosuppressive drugs such as azathioprine in pemphigus, because we also found 2 other fatal cases among the 4 reported ones with interstitial pneumonia.     

Endothelial signal transduction system enhances neutrophil-induced pulmonary vascular permeability.

The mechanism by which stimulated polymorphonuclear leukocytes and neutrophils (PMNs) damage pulmonary vascular endothelium was investigated. The authors assessed the ability of unstimulated and mechanically stimulated PMNs to adhere to pulmonary endothelial cells and, thereby, alter pulmonary vascular permeability, measured as the pulmonary filtration coefficient (K) and haemodynamics. PMNs were stimulated by gentle agitation in a glass vial for 10 s. Perfusing lungs with the stimulated PMNs (n=6) resulted in significant accumulation of PMNs within the lungs, assessed by myeloperoxidase levels, and elicited a 4-fold increase in K and a 2-fold increase in pulmonary vascular resistance as compared to lungs perfused with unstimulated cells (n=6). The increases in K were completely blocked by GF109203X, a protein kinase C inhibitor (n=6); however, GF109203X only partially attenuated the increase in vascular resistance and had little effect on the accumulation of stimulated PMNs. An agonist of protein kinase C, phorbol myristate acetate, elicited dose dependent increases in both K and pulmonary vascular resistance even in the absence of PMNs (n=6). These findings indicate that the increases in pulmonary filtration coefficient and pulmonary vascular resistance induced by polymorphonuclear neutrophils result from endothelial cell injury mediated by activation of protein kinase C within the endothelial cells themselves.     

Time-course of the concentration of cefotiam in human extra-vascular pulmonary tissue

The concentration of cefotiam in the blood and in blood-free, extra-vascular pulmonary tissue (lung tissue) was determined and its transition into the lung tissue was observed. One gram of cefotiam was injected intravenously into 27 lobectomized cases of bronchogenic carcinoma at 30 (n = 8), 60 (n = 6), 120 (n = 7) and 180 minutes (n = 6) before thoracotomy. Informed consent was obtained from these patients before the study. Lung samples were collected from the resected lobe immediately after thoracotomy, and the blood samples were also collected. Drug concentrations of the lung and blood specimens were determined. The blood volume of the lung sample was determined according to the gravimetric method with hemoglobin as an index. The drug concentration in the lung tissue was determined by the difference of the concentration between blood and lung. The time-courses of lung tissue drug concentration and blood drug concentration were compared. The lung tissue drug concentration reached a peak at 30 minutes after intravenous injection and thereafter decreased gradually, reaching equilibrium at about 50% of the blood concentration. Thirty minutes after intravenous injection, the lung tissue drug concentration was higher than the blood concentration, suggesting a higher rate of transition of the drug from the blood to the lung tissue than vice versa.     

Radioaerosol inhalation and perfusion imaging studies in immediate postoperative phase after lobectomy]

In order to determine the changes in pulmonary ventilation-perfusion imaging after lobectomies, we examined 11 patients using radioaerosol inhalation and perfusion scintigraphies, before and after the operations. We employed 99mTc-labeled albumin aerosol generated by a jet nebulizer for the inhalation imaging, and 99mTc-labeled macroaggregated albumin for the perfusion imaging, respectively. Prior to the operations, there were no (major) defects of imagings on the lung fields. Immediately after the operations, however, we could not detect any abnormal findings on chest roentgenograms, we found detects of imagings on the lung fields in either inhalation or perfusion scintigraphy whose area were mismatching. It took more than 3 weeks for these defects of imagings to disappear. In conclusion, these findings suggest that postoperative hypoxemia might be occurred by these mismatchings.     

A case of hemangioma of the heart

A-74-year old woman who had suffered from anterior chest pain and palpitation was admitted to our hospital. The chest X-ray photograph showed that the heart was enlarged mildly. We found that the tumor lay in the mediastinum by the echocardiograph and was enhanced at the aortic phase of the radioisotope angiography. In order to obtain the histological specimen, she underwent exploratory thoracotomy. The tumor was diagnosed as a cavernous hemangioma. She has been asymptomatic over 1-year period. The RI angiography seemed to be useful to diagnose the hemangioma of the heart.     

A rapidly growing pigmented nail streak resulting in diffuse melanosis of the nail. A possible sign of subungual melanoma in situ

Subungual melanomas are one of the most common types of malignant melanoma among the Japanese population. Although most pigmented nail streaks are benign and remain unchanged in their color and shape for a long time, rarely are they precursor lesions of subungual melanomas i.e., a rapid growing pigmented nail streak resulting in diffuse melanosis of the nail is thought to be an early stage of subungual melanoma in situ. We found four patients with these changes: three of these patients were children. The lesions occurred on the right index finger, right thumb, left middle finger, and right great toe, respectively. A slightly haphazard combination of colors ranging from dark brown to black, the important characteristic of subungual melanoma in situ, was observed in two cases. In the remaining two cases, although the haphazard combination of colors was not distinctive, many fine, dark longitudinal lines were seen within diffuse, light-brownish pigmentation. Serial histologic examination of the excised tissue specimens showed great proliferation of vacuolated melanocytes with variable nuclear atypicality along the entire basal layer in all cases. These histologic changes were compatible with those of atypical melanocytic hyperplasia or intraepidermal melanoma (in situ melanoma), which is an early lesion of subungual melanoma. An adult case is thought to be a definite example of a subungual melanoma in situ. We also made the diagnosis of melanoma in situ in the remaining three cases of children with rapidly growing pigmented nail streaks because their histopathologic features were distinguishable from those of the adult case. However, there remains some hesitation about this because invasive subungual melanoma is rare in children.     

Intrapleural rupture of a pulmonary arteriovenous fistula occurring just beneath the pleura: Report of a case

We report herein a rare case of a 21-year-old man with Rendu-Osler-Weber disease, otherwise known as hemorrhagic teleangiectasia, in whom a spontaneous hemothorax occurred following the rupture of one of multiple pulmonary arteriovenous fistulae (PAVF). An emergency life-saving operation was performed which revealed the ruptured fistula lying just beneath the visceral pleura. This case demonstrates that patients in whom a pulmonary angiogram shows an arteriovenous fistula lying just beneath the visceral pleura should undergo prophylactic surgery to avoid a life-threatening emergency, whenever possible.     

Possible involvement of vascular endothelium-derived relaxing factor induced by platelet-activating factor (PAF) on human pulmonary artery after contraction in vitro

We studied the effects of platelet-activating factor (PAF) on human pulmonary vascular smooth muscle in vitro. 10(-6) M PAF elicited slight contractions in 2 of 7 endothelium-denuded arterial strips, but did not elicit distinct contractions or relaxations in the other strips. After incubation with PAF at 10(-7) M, the contractions of pulmonary vascular smooth muscle induced by histamine and prostaglandin F2 alpha were significantly decreased. Preincubation of 10(-3) M indomethacin did not affect the inhibitory effects of PAF, but these disappeared with removal of endothelium. These results suggest that the inhibitory effects of PAF on human pulmonary vascular smooth muscle contractions may appear not through the cyclooxygenase products but the endothelium-derived relaxing factor.