Chemotherapy after nivolumab for advanced gastric cancer (REVIVE): a prospective observational study.

BACKGROUND: Nivolumab therapy is a standard-of-care treatment for heavily pretreated patients with advanced gastric cancer (AGC). Previous studies have reported improvement in the objective response rate to chemotherapy after nivolumab therapy for other types of cancer. This study evaluated the efficacy and safety of chemotherapy after nivolumab therapy in AGC. PATIENTS AND METHODS: We conducted a prospective, multicenter, observational study in pretreated patients with nivolumab-refractory or -intolerant AGC. Patients received irinotecan, oxaliplatin-containing regimens, or trifluridine/tipiracil. The primary endpoint was overall survival. RESULTS: A total of 199 patients were included (median age: 69 years; male: 70%; female: 30%). Median overall survival and progression-free survival were 7.5 months [95% confidence interval (CI): 6.7-9.7 months] and 2.9 months (95% CI: 2.2-3.5 months), respectively. Objective response and disease control rates were 16.8% (95% CI: 11.6% to 23.6%) and 18.9% (95% CI: 38.9% to 54.6%), respectively. A prognostic index using alkaline phosphatase and the Glasgow Prognostic Score was generated to classify patients into three risk groups (good, moderate, and poor). The hazard ratios of the moderate and poor groups to the good group were 1.88 (95% CI: 1.22-2.92) and 3.29 (95% CI: 1.92-5.63), respectively. At the initiation of chemotherapy, 42 patients had experienced immune-related adverse events due to prior nivolumab therapy. The most common grade 3-4 adverse events were neutropenia (7.5%), anemia (8.0%), and anorexia (7.5%). CONCLUSIONS: The administration of cytotoxic chemotherapy after nivolumab therapy may give rise to a synergistic antitumor effect in AGC. Further investigation is warranted to confirm these findings.

A phase II study to explore biomarkers for the use of mFOLFOX6/XELOX plus bevacizumab as a first-line chemotherapy in patients with metastatic colorectal cancer (WJOG7612GTR).

BACKGROUND: The purpose of this prospective study was to assess the ability of plasma vascular endothelial growth factor-A short isoforms (pVEGF-Asi) to predict bevacizumab (BV) efficacy and to explore other circulating biomarkers in metastatic colorectal cancer (mCRC) patients treated with modified FOLFOX6/XELOX plus BV (mFOLFOX6/XELOX + BV). PATIENTS AND METHODS: Pre-treatment plasma samples were collected from 100 mCRC patients receiving first-line chemotherapy with mFOLFOX6/XELOX + BV. The plasma levels of 11 angiogenesis-associated molecules, including pVEGF-Asi and 22 cancer-associated gene mutations in circulating tumor DNA, were analyzed. For the primary endpoint, we assumed that the hazard ratio (HR) for progression-free survival (PFS) calculated using a Cox proportional hazards model was <1.15, comparing patients with a high versus those with a low pVEGF-Asi level divided according to the median pVEGF-Asi value. RESULTS: The median value of pVEGF-Asi was 37 (range 6.5-262) pg/ml. The HR for PFS between the high and low pVEGF-Asi patient groups was 1.3 [95% confidence interval (CI) 0.8-2.1; log rank, P = 0.25], which was larger than the predefined threshold of 1.15. The multivariate analysis demonstrated that PFS was significantly associated with plasma intercellular adhesion molecule-1 (pICAM-1) (≥190.0 versus <190.0 ng/ml; HR 2.1; 95% CI 1.3-3.5), RAS (mutant versus wild; HR 2.5; 95% CI 1.5-4.3), and FBXW7 (mutant versus wild; HR 2.8; 95% CI 1.2-6.8), whereas overall survival was significantly associated with pICAM-1 (HR 2.0; 95% CI 1.1-3.7) and RAS (HR 2.6; 95% CI 1.5-4.6). CONCLUSIONS: The addition of BV was unable to compensate for the poor PFS associated with a high pVEGF-Asi level, suggesting that pVEGF-Asi is unlikely to be a good predictive biomarker of the efficacy of mFOLFOX6/XELOX + BV therapy. The clinical significance of circulating ICAM-1, mutant RAS, and mutant FBXW7 levels should be studied further.

Hypocapnic alkalosis enhances oxidant-induced apoptosis of human alveolar epithelial type II cells.

Apoptosis of alveolar epithelial type II (AEC-II) cells induced by reactive oxygen species (ROS) contributes to extensive alveolar damage during acute lung injury. Hypercapnic acidosis and hypocapnic alkalosis are known to modulate ROS-mediated lung damage. This study assessed the effects of acid-base balance disturbances on hydrogen peroxide (H2O2)-induced apoptosis of the AEC-II-like human cell line A549, which was cultured under different conditions of pH and CO2 tension (normal pH and CO2, hypercapnic acidosis, metabolic acidosis, hypocapnic alkalosis and metabolic alkalosis). H2O2-induced apoptosis was assessed by a dye-uptake bioassay and induction of caspase activity, which were quantified using analytical digital photomicroscopy. Acidosis or alkalosis of the culture medium alone did not induce A549 cell apoptosis. Hypocapnic alkalosis significantly increased H2O2-induced apoptosis and caspase activation of A549 cells. Metabolic alkalosis non-significantly increased H2O2-induced A549 cell apoptosis and caspase activation. These data suggest that hypocapnic alkalosis intensifies oxidative-induced apoptosis of alveolar epithelial cells.

Surgical treatment of arch-type dissecting aortic aneurysms.

We have proposed calling dissecting aortic aneurysm with entry of the dissection in the aortic arch "arch-type". We described the procedures and results of surgery for 12 cases of this disorder. The dissection was localized (type a) in six cases, and extended (type b) in the other six. Seven cases were treated by patch or direct closure of the entry, with one operative death and two later deaths. Five cases were treated by reconstruction of the ascending aorta and the aortic arch with a prosthetic graft, with two operative deaths and one later death. Efforts must be directed towards improving the outcome of the latter operation.

Two cases of postoperative erythroderma.

Postoperative erythroderma is a rare disease of which the clinical course is almost always fatal. It is characterized by fever, skin rash, hepatic dysfunction and leukopenia, and many of the cases occur after cardiovascular surgery. We have experienced two cases of this disease which are suspected to be related to a large amount of blood transfusion. In the second case, we observed genetical mismatch of the HLA typing between the patient and his family members. This observation strongly suggests the possibility that postoperative erythroderma is a form of graft-versus-host (GVH) reaction induced by transfused lymphocytes. The reason why the patient's immunity is so suppressed as to cause GVH reaction is still unknown. Cardiopulmonary bypass and a large amount of fresh blood transfusion are suspected for immune suppression. The fact that postoperative erythroderma occurs almost exclusively in the Japanese cannot be fairly explained, either. Racial homogeneity in Japan might cause immune tolerance in blood transfusion.

A clinical study of cerebral circulation during extracorporeal circulation.

The objective of this study is to clarify the relationship of cerebral blood flow to extracorporeal circulation flow and mean arterial pressure during nonpulsatile extracorporeal circulation under moderate hypothermia. Cerebral blood flow was determined by an argon saturation and desaturation method after that of Pevsner and colleagues with a mass spectrometer in 21 adult patients undergoing cardiac operations. Cerebral blood flow was 25, 33, 35, and 42 ml/100 gm/min, ranging from 19 to 50 ml/100 gm/min, at extracorporeal circulation flow rates of 40, 50, 60, and 70 ml/kg/min, respectively. Cerebral blood flow increased proportionally to extracorporeal circulation flow. Cerebral blood flow scattered almost transversely to mean arterial pressure and was 31 ml/100 gm/min in a hypotensive group (mean arterial pressure 34 to 50 mm Hg) and 34 ml/100 gm/min in another group (mean arterial pressure 51 to 94 mm Hg). Mean arterial pressure did not significantly influence cerebral blood flow. Cerebral oxygen consumption did not remarkably decrease and remained in the reasonable range when cerebral blood flow was 23 to 40 ml/100 gm/min. Subsequently, we assumed that the average cerebral blood flow value of 25 ml/100 gm/min at an extracorporeal circulation flow rate of 40 ml/kg/min also would be in the safe range. All of the patients are living without cerebral complications. We conclude that (1) cerebral blood flow was extracorporeal circulation flow dependent and (2) cerebral blood flow in the safe range was maintained even in the hypotensive range, provided the extracorporeal circulation flow rate was 40 ml/kg/min or higher.

Giant pseudoaneurysm of the right sinus of Valsalva.

A pseudoaneurysm of the sinus of Valsalva is a very rare cardiac abnormality. We report a surgical case of the pseudoaneurysm of the right sinus of Valsalva in a 77-year- old woman. The histopathological examination of the resected aneurysmal wall revealed that it was a pseudoaneurysm without any specific inflammatory changes. Although we cannot identify the clear cause of the formation of the pseudoaneurysm, we believe it may have been a type of spontaneous rupture of the sinus of Valsalva.

Rupture of an aneurysm of a coronary arteriovenous fistula.

Coronary arteriovenous fistula is a relatively rare congenital malformation. The course of this malformation is generally benign, and rupture of the fistula is thought to be very rare. We report a case of rupture of an aneurysm of a coronary arteriovenous fistula that originated from the distal left circumflex coronary artery and drained into the right atrium; this rupture was successfully treated with an operation.

Left atrial ball thrombus in a patient without mitral valve disease.

We experienced a large left atrial ball thrombus in a patient without mitral valve disease. By transthoracic echocardiography the mass was appeared to be free-floating and swinging randomly in the left atrium. An urgent operation was performed successfully. Operative findings revealed the mass to be a large ball thrombus loosely attached to atrial wall. We suggest that surgical removal is indicated as soon as possible, because of a very high risk of embolism or circulatory collapse.

Cardiac extension of intravenous leiomyomatosis with successful resection.

A case of intravenous leiomyomatosis spreading to the right ventricle is described. A 28-year-old woman had been previously diagnosed as having a smooth muscle tumor of borderline malignancy after hysterectomy for a large uterine tumor, because of its unusual invasive character. Based on the above diagnosis, the patient had been managed clinically as having a uterine sarcoma. One year after her hysterectomy, a local recurrence in the pelvic cavity was detected. Two years later, the tumor appeared as a cardiac tumor causing syncope. The tumor was totally resected in two surgical stages, and the correct diagnosis of an intravenous leiomyomatosis was made. The diagnostic and operative considerations are reviewed and the preferred surgical procedure is discussed.

[A case report of combined composite valve graft replacement of the aortic root and graft replacement of the abdominal aorta].

A 55-year-old man who had both aortic root aneurysm with severe aortic regurgitation and enlarging abdominal aortic aneurysm was admitted to our hospital. We employed the combined composite valve graft replacement of the aortic root and Y-graft replacement of the infrarenal abdominal aorta at one stage operation. At the operation, median sternotomy was made and the composite graft replacement of the aortic root was performed under cardiopulmonary bypass prior to the abdominal procedure. After cardiopulmonary bypass was removed, abdominal incision was made. Although ventricular arrhythmias and mild hypotension transiently occurred when the abdominal aorta was clamped, the Y-graft replacement was also completed uneventfully, and no complication occurred postoperatively. We conclude that the combined operation of the aortic root and the abdominal aorta is clinically feasible in certain situation.

[A case report of Tetralogy of Fallot in the adult with severe congestive heart failure].

We operated on a 47-year-old male for Tetralogy of Fallot with severe right heart dysfunction (RVEF 25%, RVEDP 15 mmHg, massive TR) and right heart failure (ascites and edema). The operation was completed successfully. However, persistent severe arrhythmia occurred in the CCU and assisted circulation was used for 6 days until the patient's condition stabilized. Arrhythmia diminished and hemodynamic status improved gradually. The patient improved sufficiently to be able to eat and read books. Unfortunately, he died of sudden ventricular arrhythmia on 69 POD. It was suspected that the right ventricle in this case had deteriorated beyond the threshold for surviving the radical operation for Tetralogy of Fallot.

[A case of inflammatory breast cancer well treated with intraarterial infusion chemotherapy-- evaluation of therapy by contact thermography].

A case of inflammatory breast cancer, for which an intra-arterial infusion chemotherapy was reported that it was effective. A 63 year-old woman was admitted with the complaint of left breast mass and reddish skin. Clinically it was diagnosed to be inflammatory breast cancer and was treated with an intra-arterial infusion. Contact thermography was employed for the efficacy of the treatment. Three weeks after the chemotherapy the temperature of the tumor site was decreased with a reduction of the tumor size. But, the opposite symptoms appeared before the tum or size increased. Contact thermography seemed to be useful for an evaluation of the preoperative chemotherapy for inflammatory breast cancer.

[Effect of intraperitoneal chemotherapy with implantable reservoir against unresectable gastric cancer].

Intraperitoneal chemotherapy was applied for eight unresectable gastric cancer patients, including two exploratory laparotomy and six gastrojejunostomy. Chemotherapeutic agents were given ip at a dose of 75 mg/body of cisplatin and 150 mg/body etoposide and iv at a dose of 10 mg/body of mitomycin C as well as orally 5-FU. This treatment was repeated three to ten times. An overall response rate against primary lesion was 40%. Six month and 1 year survival rate of this therapy were 87.5% and 75% respectively, while those of control group were 42% and 0%. Median duration of survival was 518 days in this chemotherapy group and 172 days in the control. In this study, intraperitoneal chemotherapy group showed a significant improvement of survival compared to the control. All patients were able to stay home between therapies. This method seemed to be beneficial to the unresectable gastric cancer patients.

[So-called "carcinoid tumor of the breast"--a case report].

A 70-year-old woman underwent modified radical mastectomy following excisional biopsy of a right breast mass. The excised tumor was 1.4 cm in diameter. The mastectomy specimen and lymph nodes were negative for malignancy. Histologically, the tumor cells were mainly oval and had formed solid nests in the thick fibrous stroma. The cytoplasm was fine granular and contained many argyrophilic granules. The argentaffin reaction was negative. Electron microscopy revealed oval-shaped light cells and stellate-shaped dark cells. Both types of tumor cells contained abundant filaments, well-developed rough surfaced endoplasmic reticulum and many neurosecretory-type granules measuring 190 approximately 360 nm in diameter. Intracytoplasmic lumina were not discerned. The relationship between carcinoid and conventional breast carcinoma was discussed.

[A case of complete circumferential aortic rupture due to blunt chest trauma].

A case of complete circumferential rupture of the thoracic aorta due to blunt chest trauma is presented. A 46-year-old woman was admitted after a traffic accident. The admission chest X-ray film demonstrated rib fractures and mediastinal widening. CT scanning and aortography were performed, but acute rupture of the aorta was not detected. Twelve days later, aortography was performed again and an aneurysm was noted at the aortic isthmus. Surgery was performed immediately and aorta was found to be completely disrupted for a length of 1 cm. A short segmental prosthesis was interposed between the two ends of the aorta under temporary bypass. Patients with aortic rupture due to blunt chest trauma are increasing, but only a few cases treated in the acute stage have been reported. To our knowledge, this is the 6th case of complete aortic disruption which has been treated successfully in the acute stage in Japan.

[A median sternotomy approach for symptomatic right subclavian artery in the adult].

A case of 33-year-old woman with aberrant right subclavian artery was reported. She was admitted to the hospital complaining of progressive dysphagia of six months' duration. The esophagogram revealed an oblique tubular defect in the superior thoracic esophagus. Aortograms confirmed the presence of an anomalous right subclavian artery arising as a fourth branch of the aortic arch, passing behind the esophagus in its course to the right arm. Operation was performed on Sept. 4, 1990. Through a median sternotomy, the ascending aorta and the two carotids were dissected free. With gentle forward retraction of the ascending aorta to the left, the origin of the aberrant right subclavian artery could easily be exposed. The right subclavian artery was then divided and its origin from the distal aortic arch oversewn. The vessel was removed from the retroesophageal position and blood flow reestablished to the right arm by an end-to-side anastomosis to the right carotid artery, using a temporary shunt tube. These procedures were accomplished without difficulty. Postoperatively, the patient made an uneventful recovery and was discharged 16 days after the procedure. A postoperative esophagogram confirmed the removal of the esophageal compression. The blood pressure was equal in the two upper extremities. In follow-up study, her symptoms had completely disappeared.

Accumulation of phosphate-containing granules in the nucleoid area of Pseudomonas aeruginosa.

Many electron-dense granules were found in the nucleoid area of Pseudomonas aeruginosa strain K by electron microscopy with the technique of the freeze-substitution method. These granules contained phosphorus and calcium as determined by X-ray microanalysis. The size and the numbers of the granules decreased when the bacteria was cultured in the medium from which phosphate-containing compounds were depleted. From these observations we concluded that the granule was a phosphate-containing granule and possibly a polyphosphate granule. The excellent preservation of the fine structures by the freeze-substitution technique enables us to show very small polyphosphate granules in the nucleoid area of the bacterial cells which cannot be revealed by the conventional chemical fixation method. As we could not see the granules in other bacteria cultured in nutrient medium such as Serratia, Escherichia, Bacillus and Vibrios, the accumulation of the phosphate granules in Ps. aeruginosa might be a unique character of this bacteria and might be related to the growing capability of this bacteria in extremely low nutrient supply.

[A case of successful surgical retrieval of the intracoronary interlocked Palmaz-Schatz stent].

We presented a case of a 48-year-old male with failed delivery of the Palmaz-Schatz stent, who subsequently required CABG with successful retrieval of the stent. The patient had presented recurrent angina, approximately one and a half year since the last PTCA to the LAD. Re-PTCA was performed, but resulted in a severe local dissection. The stent implantation was tried, but was inadvertently dropped in the vessel. Since the patient was hemodynamically stable, we tried to remove the stent with Retriever endovascular snare, which ended up with interlocking the stent in the more proximal segment of the LAD and the snare itself was not removed. We, therefore, resort to the emergent operation, with successful retrieval of the snare device and the stent and carried on to the the bypass operation to the distal LAD without any complications. To our best knowledge, this is the first report in Japan for surgical retrieval of the Palmaz-Schatz stent, which was failed in delivery and interlocked in the vessel with retriever device.

[Effect of autologous platelet rich plasma on adult open heart surgery].

To reduce the rate and the volume of homologous blood transfusion, we have used autologous platelet rich plasma (PRP) in adult open heart surgery. From Jan. 1988 to Jun 1992, 191 patients have underwent open heart surgery of coronary artery disease or valvular heart disease in our institution. We divided these patients into two groups: (1) PRP group; autologous PRP was used in 99 cases, (2) C (Control) group; autologous PRP was not used in 92 cases. Patient characteristics of age, sex, body weight, preoperative hematocrit values, preoperative platelet counts, and CPB time were same in these groups. Intraoperative and postoperative blood loss in PRP group were significantly less than those in C group (376 ml and 458 ml vs 511 ml and 568 ml; p < 0.01). Homologous blood transfusion rate (number of patients receiving homologous blood transfusion/all patients) was lower in PRP group (11.1% vs 32.6%; p < 0.01). The volume of homologous blood transfusion in the patients receiving transfusion were smaller in PRP group (7.5 U vs 13.3 U; p < 0.05). We conclude autologous PRP is useful in adult open heart surgery to reduce the perioperative blood loss, the rate, and the volume of homologous blood transfusion.