Morphological lymphocytic reaction, patient prognosis and PD-1 expression after surgical resection for oesophageal cancer.

BACKGROUND: Immune checkpoint inhibitors, such as antibody against programmed cell death protein (PD-1), have demonstrated antitumour effects in patients with malignancies, including oesophageal cancer. A lymphocytic reaction observed by pathological examination is a manifestation of the host immune response to tumour cells. It was hypothesized that a stronger lymphocytic reaction to tumours might be associated with favourable prognosis in oesophageal cancer. METHODS: Using a database of resected oesophageal cancers, four morphological components of lymphocytic reactions (peritumoral, intranest, lymphoid and stromal) to tumours were evaluated in relation to clinical outcome, PD-1 expression by immunohistochemistry and total lymphocyte count in blood. RESULTS: Resected oesophageal cancer specimens from 436 patients were included in the study. Among the four morphological components, only peritumoral reaction was associated with patient prognosis (multivariable P for trend <0·001); patients with a higher peritumoral reaction had significantly longer overall survival than those with a lower reaction (multivariable hazard ratio 0·48, 95 per cent c.i. 0·34 to 0·67). The prognostic effect of peritumoral reaction was not significantly modified by other clinical variables (all P for interaction >0·050). Peritumoral reaction was associated with total lymphocyte count in the blood (P < 0·001), supporting the relationship between local immune response and systemic immune competence. In addition, higher morphological peritumoral reaction was associated with high PD-1 expression on lymphocytes in tumours (P = 0·034). CONCLUSION: These findings should help to improve risk-adapted therapeutic strategies and help stratify patients in the future clinical setting of immunotherapy for oesophageal cancer.

ANTECEDENTES: Los inhibidores de los puntos de control inmunitario (checkpoints) (p.ej. los anticuerpos anti-PD-1) han demostrado efectos antitumorales en pacientes con tumores malignos, incluido el cáncer de esófago. La reacción linfocítica detectada en estudios anatomopatológicos es una manifestación de la respuesta inmune del huésped a las células tumorales. Se estableció la hipótesis de que una mayor reacción linfocítica a los tumores podría asociarse con un mejor pronóstico en el cáncer de esófago. MÉTODOS: Usando una base de datos de 436 cánceres de esófago resecados, se evaluaron cuatro componentes morfológicos (peritumoral, intra-epitelial, linfoide y estromal) de las reacciones linfocíticas a tumores en relación con los resultados clínicos, la expresión inmunohistoquímica de PD-1 y el recuento total de linfocitos en sangre. RESULTADOS: De los cuatro componentes, solamente la reacción peritumoral se asoció con el pronóstico del paciente (P multivariable para tendencia < 0,001): los pacientes con mayor reacción peritumoral presentaron una supervivencia global significativamente más prolongada que aquellos pacientes con menor reacción peritumoral (cociente de riesgos instantáneos multivariable, hazard ratio, HR: 0,48; i.c. del 95%: 0,34 -0,67; P <0,001). El efecto pronóstico de la reacción peritumoral no se modificó significativamente por otras variables clínicas (todas las P para la interacción > 0,05). La reacción peritumoral se asoció con el recuento total de linfocitos en la sangre (P < 0,001), lo que respalda la relación entre la respuesta inmune local y la competencia inmune sistémica. Además, una elevada reacción morfológica peritumoral se asoció con una alta expresión de PD-1 en linfocitos tumorales (P = 0,034). CONCLUSIÓN: Estos hallazgos deberían ayudar a mejorar las estrategias terapéuticas adaptadas al riesgo y contribuir a estratificar a los pacientes en el entorno clínico futuro de la inmunoterapia para los pacientes con cáncer de esófago.

Minimally invasive esophagectomy may contribute to long-term respiratory function after esophagectomy for esophageal cancer.

Evidence suggests that minimally invasive esophagectomy has several advantages with regard to short-term outcomes, compared to open esophagectomy in esophageal cancer patients. However, the impact of minimally invasive esophagectomy on long-term respiratory function remains unknown. The objective of this study is to assess the association between use of the minimally invasive esophagectomy and long-term respiratory dysfunction in esophageal cancer patients after esophagectomy. This retrospective single institution study using prospectively collected data included 87 consecutive esophageal cancer patients who had undergone esophagectomy. All patients underwent a respiratory function test before, and one year after esophagectomy. Logistic regression analysis was used to compute the hazard ratio for long-term respiratory dysfunction. Minimally invasive esophagectomies were performed in 53 patients, and open esophagectomies in 34 patients. The two groups showed no significant differences in terms of postoperative complications and postoperative course. Nor were any differences observed between the two groups in terms of volume capacity (L) and forced expiratory volume 1.0 (L) before esophagectomy (P > 0.34). However, one year after esophagectomy, the decreases in volume capacity and forced expiratory volume 1.0 were significantly less in the minimally invasive esophagectomy group than in the open esophagectomy group (P = 0.04 and P = 0.007, respectively). Multivariate analyses revealed that minimally invasive esophagectomy was an independent favorable factor for maintenance of forced expiratory volume 1.0 (hazard ratio = 0.17, 95% confidence interval 0.04-0.71; P = 0.01). Minimally invasive esophagectomy may be an independent favorable factor for maintenance of long-term respiratory function in esophageal cancer patients after esophagectomy.

Inflammatory pseudotumor of the liver in association with spilled gallstones 3 years after laparoscopic cholecystectomy: report of a case.

We report on a case of a female patient diagnosed with inflammatory pseudotumor of the liver in association with spilled gallstones 3 years after laparoscopic cholecystectomy for calculous acute cholecystitis. She was asymptomatic, but CT revealed an intrahepatic mass and two other extrahepatic masses between the liver and the diaphragm. Furthermore, diffusion-weighted MRI and PET suggested all three lesions could be malignant tumors. As the preoperative diagnosis was intrahepatic cholangiocellular carcinoma with peritoneal disseminations, we performed a posterior segmentectomy of the liver combined with partial resection of the diaphragm. Histological examination showed the intrahepatic tumor was an inflammatory granuloma with abscess formations. There were bilirubin stones between the liver and the diaphragm. Therefore, the tumor was diagnosed as inflammatory pseudotumor of the liver in association with spilled gallstones. In conclusion, the liver tumor emerged after laparoscopic cholecystectomy and may involve inflammatory pseudotumor of the liver in association with spilled gallstones.

A case of acute phlegmonous gastritis successfully treated with antibiotics.

Acute phlegmonous gastritis is a rare disorder in which bacterial infection occurs in the gastric wall. Gastrectomy involving the affected area has been thought to be an effective form of treatment. The authors report a case of a 32-year-old woman who had severe upper abdominal pain without signs of peritoneal irritation. Endoscopy showed edematous and reddened gastric mucosa with a mass lesion in the gastric antrum. Endoscopic ultrasonography showed thickening of the antral wall and a low-echoic mass in the gastric antrum, thought to represent a fluid collection. White pus was aspirated from the mass. Localized type of acute phlegmonous gastritis with a gastric abscess was diagnosed. Culture of the pus showed Streptococcus pneumoniae. Through early diagnosis without laparotomy, the patient's gastritis was successfully treated with antibiotics alone.

Effects of lumbar sympathectomy on the properties of both endothelium and smooth muscle cells of the canine femoral artery and autogenous vein grafts under poor runoff conditions.

The purpose of this study was to determine whether or not a lumbar sympathectomy would modulate the functions of the endothelium, in terms of endothelium-derived relaxing factor (EDRF), under poor distal runoff conditions. First, a poor distal runoff model was developed in the canine right and left femoral arteries. After 5 weeks, a unilateral left sympathectomy was performed from L-3 to L-6. In experiment I, changes in blood flow and endothelium-dependent responses were examined in the canine femoral artery 5 weeks after the lumbar sympathectomy. In experiment II, 5 weeks after the development of a poor runoff model, a unilateral left sympathectomy was performed and both femoral veins were also grafted to the femoral arteries on both sides. Then after 4 weeks, endothelium-dependent responses and intimal thickening of both autogenous vein grafts were examined. The endothelium-dependent responses were examined by mechanical tension recording. In both experiments, the mean blood flow of the left femoral arteries (denervated, 92.2 +/- 47.1 ml/min) and vein grafts (denervated, 100.0 +/- 35.4 ml/min) was significantly higher than that of the right femoral arteries (innervated, 46.9 +/-25.7 ml/min) and vein grafts (innervated, 50.0 +/- 20.1 ml/min) (P < 0.01). In experiment I, the endothelium-dependent relaxations to acetylcholine, ADP, and A23187 were comparable between the right and left femoral arteries. In experiment II, the endothelium-independent contractions to acetylcholine and endothelium-dependent relaxations to ADP and A23187 were all comparable between the right and left vein grafts. In addition, the intimal thickening of the vein graft was comparable between the two groups (denervated, 95.6 +/- 10.8 microm; innervated, 105.0 +/- 15.0 microm). In both experiments, the NE-induced contractions and SNP-induced relaxations were closely similar between the two groups, irrespective of the flow change. These results suggest that lumbar sympathectomy does not alter endothelial function in terms of EDRF, although mean blood flow of the denervated femoral arteries and vein grafts was significantly higher than that of the innervated femoral arteries and vein grafts. These results suggest that continuous vasodilation following sympathectomy may be a more potent factor with respect to regulation of vascular tonus than physiologic regulation of EDRF.

[Surgical treatment of aorto-iliac occlusive disease].

Recently, various endovascular techniques were applied to the short segmental stenosis of aorto-iliac artery. However, bypass operation is the most reliable treatment for multiple stenotic or occlusive lesion. Preoperative systemic evaluation is important for the adequate selection of the patients and the operations. Dipyridamole-thallium scintigraphy is more useful than exercise stress testing to assess cardiac risks of patients with peripheral arterial diseases. Anatomical bypass is the standard operation resulting in favorable patency. Despite of relatively inferior long term patency, extra-anatomical bypass operations are useful alternatives for the patients having high systemic risks or severe sclerosis of aorto-iliac arteries. The improved medical care of the elderly patients with severe systemic diseases results in the increase of extra-anatomical bypass and extended operation combined with infrainguinal revascularization.

Eicosapentanoic acid reduces the intimal thickening of autogenous vein grafts and enhances endothelium-derived relaxing factor.

The present study examined the effect of purified eicosapentanoic acid (EPA) on intimal thickening of an autogenous vein graft. In addition, experiments were performed to determine whether EPA supplementation would alter the endothelium-dependent responses of the reversed vein graft. Segments of femoral veins were grafted into the femoral arteries of dogs. Six dogs received regular chow (control group) and six other dogs regular chow with 1500 mg/day 90.0% pure EPA (EPA group). At 6 weeks after surgery, the vein grafts were removed from the dogs, cut into rings, and suspended in organ chambers for isometric tension recording. In some rings, the endothelial cells were removed. When the rings taken from the control group were contracted with norepinephrine, adenosine diphosphate (ADP) and A23187 caused endothelium-dependent relaxations. In the EPA group, the endothelium-dependent responses to ADP were significantly augmented, while A23187 caused comparable endothelium-dependent relaxations. Direct relaxation in response to sodium nitroprusside was comparable between the two groups. Intimal thickening of the grafts in the control group (29.0 +/- 1.8 microns) was significantly (P < 0.05) greater than in the EPA group (12.5 +/- 1.8 microns). These results suggest that EPA enhances the release of endothelium-derived relaxing factor in autogenous vein grafts. This may be one of the effects of EPA in reducing the intimal thickening of autogenous vein grafts.

Endothelium-dependent relaxation in response to adenosine diphosphate is impaired under poor runoff conditions in the canine femoral artery.

To examine whether poor distal runoff conditions of the canine femoral artery modulates endothelium-dependent relaxations, we developed a poor distal runoff limb in the canine right femoral artery (poor runoff group). The left femoral artery was used as a control. Endothelium-dependent responses were examined in vitro. The rings of femoral artery were obtained from dogs pretreated with 6 weeks of poor distal runoff. In the control, flow rate and tau-variation were 79.1 ml/min and 214.2 dynes/cm2, respectively. In the poor runoff group, the flow rate and tau-variation were 27.4 ml/min and 52.7 dynes/cm2. There were significant differences between the two groups. In the rings taken from the control group contracted with norepinephrine, adenosine diphosphate (ADP) and A23187 caused endothelium-dependent relaxations. In the poor runoff group, the endothelium-dependent relaxations in response to ADP were impaired, while A23187 caused comparable endothelium-dependent relaxations. Direct relaxations in response to sodium nitroprusside were comparable between the two groups. These experiments indicate that under poor runoff conditions, the endothelium-dependent relaxations to ADP are impaired without changing the properties of the smooth muscle cells. This dysfunction of the endothelium under conditions of abnormal flow may accelerate a loss of late patency of the reconstructed arteries.

Comparison of endothelial function between in situ and reversed vein graft: differences in endothelium-dependent responses.

BACKGROUND: The endothelium releases endothelium-derived relaxing factors that are potent vasodilators and inhibitors of platelet aggregation. Experiments were performed to determine whether the endothelium-dependent responses differed between in situ and reversed vein grafts. The influence of valve disruption or of dissection of the adventitia was also examined. METHODS: Segments of canine jugular veins were grafted into the carotid arteries during procedures such as reversed grafting, in situ grafting with valve disruption, in situ grafting without valve disruption, and in situ grafting with dissection of adventitia. After 4 weeks the endothelium-dependent responses of the grafts were examined by isometric tension recording. RESULTS: In the reversed and in situ vein graft with valve disruption, acetylcholine caused endothelium-independent contractions, whereas in the in situ vein graft without valve disruption acetylcholine-induced endothelium-dependent relaxations were preserved. Adenosine diphosphate (ADP) caused comparable endothelium-dependent relaxations in the in situ vein graft irrespective of valve disruption. In the reversed vein graft ADP-induced relaxations were significantly impaired. In the in situ vein graft with dissection of the adventitia, relaxations in response to acetylcholine and ADP were significantly reduced. CONCLUSIONS: These results suggest that endothelial function, in terms of endothelium-derived relaxing factors in the in situ vein graft, can be preserved and that adventitial dissection in the in situ vein graft should be minimized to preserve endothelial function.

Successful simultaneous resection and reconstruction of abdominal aortic aneurysm and esophageal cancer.

A simultaneous resection and reconstruction of abdominal aortic aneurysm (AAA) and esophageal cancer was performed on an eighty-year-old Japanese man. In spite of his advanced age, preoperative assessments revealed that the general functions of the patient were quite satisfactory. An esophagram, endoscopy and CT scan all demonstrated the esophageal cancer to be in a relatively early stage without any lymph node metastasis, while the CT scan demonstrated an infrarenal type of fusiform abdominal aortic aneurysm with a maximum transverse diameter of 7.0 cm. A simultaneous resection and reconstruction of both the AAA and esophageal cancer was performed on August 8, 1991. First, the operation for AAA was done through a retroperitoneal approach, and next, a resection and reconstruction of the esophageal cancer was performed with a right thoracotomy and laparotomy using the gastric tube as an esophageal substitute. The postoperative course was uneventful except for a temporary purulent discharge through the mediastinal drain. The patient was discharged on the 56th postoperative day. Therefore, when the general conditions are considered to be tolerable for operation, such a simultaneous operation may be indicated even inpatients of advanced age by utilizing isolated approaches and taking great care.

Late graft failure of autologous vein grafts for arterial occlusive disease: clinical and experimental studies.

Late graft failure following arterial reconstructive surgery, especially after infrainguinal reconstruction, remains a major concern for vascular surgeons. To more effectively predict the outcome of reconstructed arteries, we herein propose an intraoperative flow waveform analysis which correlates well with the long-term patency rate of grafts. According to this flow waveform analysis, late graft failure was occasionally seen in grafts with type II waveforms when poor distal runoff vessels had been shown by the preoperative arteriogram. Next, to investigate which events occurring in autologous vein grafts under abnormal hemodynamics may contribute to late graft failure, a distal poor-runoff model was made in the canine femoral artery. In this review, we present the results of our investigation on autologous vein grafts using this poor-runoff model. We also relate our recent findings on the function of regenerated endothelium in autologous vein grafts.

Intimal hyperplasia of experimental autologous vein graft in hyperlipidemic rabbits with poor distal runoff.

Poor distal runoff and hyperlipidemia are factors affecting the fate of an implanted graft. In the present study, combined effects of poor distal runoff and hyperlipidemia on intimal hyperplasia (IH) of the vein graft were examined in a newly developed poor distal runoff model in rabbits. A poor distal runoff model was prepared in the right hindlimb of 30 rabbits. These animals were divided into two groups, depending on the diet provided; normolipidemic diet group (Group NL, n = 14) and hyperlipidemic 1% cholesterol diet group (Group HL, n = 16). Four weeks after preparing the poor runoff model, the femoral vein was implanted into the ipsilateral femoral artery. At 2, 4 and 6 weeks, the grafts were harvested. IH of the graft was measured and macrophages in the IH were examined immunohistochemically. Intimal cell proliferation was also determined by bromodeoxyuridine (BrdU) incorporation. IH of the vein graft was significantly accelerated in cases of poor distal runoff and hyperlipidemia. There were no macrophages in the IH in the NL group. In the HL group, macrophages infiltrated the outer layer of IH, sometimes just above the internal elastic lamina, and increased with time. In the poor distal runoff limbs at 6 weeks, macrophages also appeared in the subendothelial layer but were absent in that layer in the controls. Intimal cell proliferation expressed as the BrdU labeling index (LI) was maximum at 2 weeks. In the HL group, BrdU LI of IH in the poor distal runoff limb was higher than in the control at 2 and 4 weeks. Throughout the experiments, BrdU LIs in the HL group were significantly higher than in the NL. Hyperlipidemia accelerates intimal cell proliferation to a greater extent, then does IH. In cases of a poor distal runoff, the enhancement of cell proliferation by hyperlipidemia is augmented. These responses, in the presence of a hyperlipidemia, may be closely related to the migration of macrophages.

Detection of active cytomegalovirus infection in inflammatory aortic aneurysms with RNA polymerase chain reaction.

PURPOSE: We previously reported the possible role of human cytomegalovirus in the pathogenesis of inflammatory aortic diseases. To further analyze the viral cause of human aortic diseases, in this study we examined the presence and the replication of human Herpesviridae in 60 aortic tissues, including 7 inflammatory aneurysms, 37 atherosclerotic aneurysms, and 16 normal aortas. METHODS: To detect the genome of herpes simplex virus (type 1, type 2), cytomegalovirus, and Epstein-Barr virus, DNA polymerase chain reaction for each virus was performed. To analyze these herpesviral replications, the viral transcript was detected with RNA polymerase chain reaction. RESULTS: The DNA polymerase chain reaction showed that either herpes simplex virus or cytomegalovirus was present more frequently in inflammatory (29% or 86%, respectively) and atherosclerotic aneurysms (27% or 65%, respectively) than in normal aortic tissues (6% or 31%, respectively), whereas the Epstein-Barr viral genome was not detected in any aortic tissue specimens. By the use of RNA polymerase chain reaction, only the cytomegaloviral transcript was recognized in 71% of the inflammatory aneurysms but was not recognized in any other tissue specimens. No other herpesviral transcripts were detected in any tissue specimens examined in this study. CONCLUSIONS: Our results thus suggest that the human herpesviruses may play various roles in the pathogenicity of aortic diseases, in particular the replicating infections of the cytomegalovirus might potentially cause the formation of inflammatory aneurysms.

Do patients with intermittent claudication need surgical treatment?

To determine whether surgical intervention is of therapeutic significance for patients with intermittent claudication (IC), 315 patients with IC followed in our outpatient clinics for the past 8 years 3 months (mean of 3 years 10 months), including 142 non-operated and 173 operated patients, were investigated as to changes in symptoms and the prognosis. Changes in symptoms in both groups were analyzed according to the variable distances of claudication and location of the diseased artery. To examine the degree of association between surgery and improvement of symptoms, Goodman and Kruskal's gamma was used. For all subgroups with a variable claudication distance (group A; distance < 100 m, B: 100-500 m, C: > 500 m), surgery inversely correlated with improvement in symptoms (group A; gamma = -0.378, group B; gamma = -0.651, group C; gamma = -0.828). According to location of the diseased artery, surgery correlated with improvement in symptoms in aorto-iliac (gamma = -0.811), aorto-ilio-superficial femoral (gamma = -0.641), and superficial femoral-distal (gamma = -0.533) groups but not in superficial femoral (gamma = -0.427) or infrapopliteal (gamma = -0.194) alone groups. Concerning the prognosis, no significant difference was noted between operated and non-operated groups (p = 0.35). These computed data show that surgical intervention has therapeutic significance for patients with IC, except for cases of claudication with segmental occlusion of the superficial femoral or infrapopliteal artery alone.

Persistent sciatic artery: two case reports and a review of the literature.

Persistent sciatic artery (PSA) sometimes shows variant vascular symptoms such as chronic or acute limb ischaemia and a pulsatile mass in the buttocks caused by aneurysmal dilatation. This report presents two cases of surgically treated PSA that caused lower-limb ischaemia. The first patient, a 58-year-old man, showed acute limb ischaemia in the chronic clinical course, and thrombectomy and patch angioplasty were performed. The second patient, a 70-year-old woman, had an incomplete type of PSA without development of the femoral artery while complaining of a 10-year history of coldness and numbness in the left lower limb. A left common iliac to profunda femoris arterial bypass was performed. This is the second case of symptomatic incomplete PSA reported in the literature. This report also reviews 45 cases of PSA published since 1977. The diagnosis of PSA requires arteriography that includes the bilateral iliac systems. Femoropopliteal bypass and, in the case of sciatic artery aneurysm, a ligature of the sciatic artery are recommended for the surgical treatment of PSA.

Surgical strategy of concomitant abdominal aortic aneurysm and gastric cancer.

PURPOSE: Selecting the most appropriate surgical approach for patients with abdominal aortic aneurysm (AAA) and concurrent gastric cancer remains controversial. In an attempt to develop guidelines for the management of two concurrent lesions, a retrospective review of patients with concomitant AAA and gastric cancer was undertaken. METHODS: During the period from January 1985 to December 1992, a total of 222 patients with AAA were admitted to our hospital. Among these, seven patients (3.2%) had gastric cancer and concurrent AAA. Six of the seven patients were treated surgically for both lesions with either a one- or two-stage operation. One patient underwent only an exploratory laparotomy because of the peritoneal dissemination of the gastric cancer. Four of the six patients underwent a two-stage operation. In three cases, the resection of the malignancy was performed first because the gastric cancer was diagnosed as advanced before operation. In one case, the aneurysmectomy was performed first because the aneurysm was more than 6 cm in diameter and the gastric cancer was in an early stage of development. Two of the six patients underwent a one-stage operation and a simultaneous resection was carried out by way of segregated approaches, such as the retroperitoneal approach for AAA and the transperitoneal approach for the malignant lesion. RESULTS: Five of the seven patients (71.4%) are still alive. The length of follow-up for these patients ranged from 4 months to 4 years. CONCLUSIONS: The principles of our surgical approaches for concomitant AAA and gastric cancer are as follows. (1) The lesion that absolutely indicates urgent operation should be operated on first. (2) If the malignant lesion is advanced, it is resected first. (3) If the malignancy is not advanced, the AAA should be resected first by the retroperitoneal approach. (4) Simultaneous resection by way of segregated approaches is useful in some patients with early gastric cancer. (5) Both lesions must be resected eventually for improvement of the long-term survival chances.

Blood flow and kinetics of smooth muscle cell proliferation in canine autogenous vein grafts: in vivo BrdU incorporation.

The effects of blood flow on the kinetics of smooth muscle cell (SMC) proliferation were examined in canine autogenous vein grafts with a distal poor run-off model. The in vivo bromodeoxyuridine (BrdU, a thymidine analogue) incorporation method was used to label proliferating SMCs in each layer of the vein graft. The BrdU labeling index (LI) was defined as a percentage of labeled cells compared to the total number of SMCs, and BrdU LIs were measured in the media and the intima of the graft. The development of intimal thickening of grafts was accelerated at 2 to 4 weeks after implantation. In poor run-off limbs with an abnormal blood flow condition, as characterized by a low flow and a low shear stress variation, the intima of the graft thickened more progressively than that in control limbs with a normal blood flow. In both groups, the medial BrdU LIs reached a maximum 3 to 5 days after implantation and decreased thereafter. The peak of the intimal BrdU LIs occurred at 1 week in both groups. The intimal LIs of the grafts in poor run-off limbs (6.34% at 1 week and 2.97% at 2 weeks) were significantly higher than those in control limbs (5.34 and 1.98%) for 2 weeks after implantation (P < 0.05). The medial SMC proliferation and the following intimal SMC proliferation of vein grafts were accelerated prior to development of the intimal thickening. SMC proliferation in the intima was prominent in a poor run-off limb with a low flow and a low shear stress variation.