Molecular determinants of clinical outcomes with pembrolizumab versus paclitaxel in a randomized, open-label, phase III trial in patients with gastroesophageal adenocarcinoma.

BACKGROUND: In the phase III KEYNOTE-061 trial (NCT02370498), pembrolizumab did not significantly improve overall survival versus paclitaxel as second-line therapy for gastric/gastroesophageal junction (GEJ) adenocarcinoma with programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 tumors. The association of tissue tumor mutational burden (tTMB) status and clinical outcomes was determined, including the relationship with CPS and microsatellite instability-high (MSI-H) status. PATIENTS AND METHODS: In patients with whole exome sequencing (WES) data [420/592 (71%); pembrolizumab, 218; paclitaxel, 202], the association of tTMB with objective response rate (ORR; logistic regression), progression-free survival (PFS; Cox proportional hazards regression), and overall survival (OS; Cox proportional hazards regression) were measured using one-sided (pembrolizumab) and two-sided [paclitaxel] P values. tTMB was also evaluated using FoundationOne®CDx [205/592 (35%)]. Prespecified equivalent cut-offs of 175 mut/exome for WES and 10 mut/Mb for FoundationOne®CDx were used. RESULTS: WES-tTMB was significantly associated with ORR, PFS, and OS in pembrolizumab-treated (all P < 0.001) but not paclitaxel-treated patients (all P > 0.6) in univariate analysis. The area under the receiver operating characteristics curve for WES-tTMB and response was 0.68 [95% confidence interval (CI) 0.56-0.81] for pembrolizumab and 0.51 (95% CI 0.39-0.63) for paclitaxel in univariate analysis. There was low correlation between WES-tTMB and CPS in both treatment groups (r ≤ 0.16). WES-tTMB remained significantly associated with all clinical endpoints with pembrolizumab after adjusting for CPS and with PFS and OS after excluding known MSI-H tumors (n = 26). FoundationOne®CDx-tTMB demonstrated a positive association with ORR, PFS, and OS in pembrolizumab-treated patients (all P ≤ 0.003) but not PFS or OS in paclitaxel-treated patients (P > 0.1). CONCLUSION: This exploratory analysis from KEYNOTE-061 is the first to demonstrate a strong association between tTMB and efficacy with pembrolizumab but not paclitaxel in patients with gastric/GEJ adenocarcinoma in a randomized setting. Data further suggest tTMB is a significant and independent predictor beyond PD-L1 status.

Thoracoscopic enucleation of a gastrointestinal stromal tumor of the esophagus.

Since the introduction of thoracoscopy in surgery, many thoracic interventions have been considered feasible and safe via the thoracoscopic route. We report the case of a 42-year-old man with a 7.5-cm esophageal gastrointestinal stromal tumor. Thoracoscopic enucleation of the tumor was performed and the patient was discharged on the third postoperative day after tolerating a full oral diet. Given the well-known advantages of minimally invasive surgery, we believe that removal of esophageal submucosal tumors can be attempted using a thoracoscopic approach, even if the tumor is large.

Overexpression of dihydrodiol dehydrogenase as a prognostic marker of non-small cell lung cancer.

By using mRNA differential display to examine specimens of non-small cell lung cancer (NSCLC), we have identified overexpression of dihydrodiol dehydrogenase (DDH) that was not detected in the corresponding normal lung tissue. Normally DDH is associated with catalysis of polycyclic aromatic hydrocarbons (PAHs) in the liver; in NSCLC cells, DDH expression would implicate an association with disease progression. In this study we investigated the prognostic significance of DDH expression in patients with NSCLC. By using immunohistochemistry, we measured DDH expression in 381 patients with NSCLC. The relationship between DDH expression and clinicopathological parameters (age, gender, smoking history, mitotic index, histological type, stage, cell differentiation, and lymphovascular invasion) was analyzed by chi2 analysis. Survival curves were plotted with the method of Kaplan-Meier, and statistical difference of survivals between different groups was compared by a log-rank test. Our results showed that DDH overexpression could be detected in 317 (83.2%) of 381 pathological sections and in 77.9% (60 of 77) of metastatic lymph nodes. Expression of DDH was confirmed by immunoblotting. Compared with patients with DDH overexpression in tumors, patients with low DDH expression had significantly lower incidence of early tumor recurrence and distant organ metastasis (46.7 versus 29.7%; P = 0.045). Interestingly, survival was also significantly better in patients with low DDH expression than in those with DDH overexpression (P = 0.0017). Using univariate analysis, we correlated three important factors, DDH overexpression, tumor stages, and gender, with poor prognosis for NSCLC patients. Nevertheless, biological function and involvement of DDH in the disease progression of NSCLC require additional studies.

Radiation Necrosis in Pediatric Patients with Brain Tumors Treated with Proton Radiotherapy.

BACKGROUND AND PURPOSE: Proton radiotherapy has been increasingly utilized to treat pediatric brain tumors, however, limited information exists regarding radiation necrosis among these patients. Our aim was to evaluate the incidence, timing, clinical significance, risk factors, and imaging patterns of radiation necrosis in pediatric patients with brain tumors treated with proton radiation therapy. MATERIALS AND METHODS: A retrospective study was performed on 60 consecutive pediatric patients with primary brain tumors treated with proton radiation therapy. Radiation necrosis was assessed by examining serial MRIs and clinical records to determine the incidence, timing, risk factors, imaging patterns, and clinical significance associated with the development of radiation necrosis in these patients. Radiation necrosis was defined as areas of new enhancement within an anatomic region with previous exposure to proton beam therapy with subsequent decrease on follow-up imaging without changes in chemotherapy. RESULTS: Thirty-one percent of patients developed radiation necrosis with a median time to development of 5.0 months (range, 3-11 months). Risk factors included multiple chemotherapy agents (>3 cytotoxic agents) and atypical teratoid rhabdoid tumor pathology (P = .03 and P = .03, respectively). The most common imaging patterns were small (median, 0.9 cm) and multifocal (63% of patients) areas of parenchymal enhancement remote from the surgical site. The median time to complete resolution on imaging was 5.3 months (range, 3-12 months). Among patients with imaging findings of radiation necrosis, 25% demonstrated severe symptoms with medical intervention indicated. CONCLUSIONS: Pediatric patients with brain tumors treated with proton radiation therapy demonstrate a high incidence of radiation necrosis and a short time to development of necrosis. Multiple small areas of necrosis are frequently identified on imaging. Exposure to multiple chemotherapy agents was a significant risk factor associated with radiation necrosis in these patients.

Gastric mucosal damage induced by arecoline seizure in rats.

In an attempt to know the relation of seizure and gastric mucosal damage, we challenged arecoline (ACL) centrally to induce seizure and investigated gastric hemorrhagic injury in acid-irrigated stomachs of rats. The protective effects of several drugs also were evaluated. After deprivation of food for 24 h, rats were received laparotomy under diethylether-anesthesia. Both pylorus sphincters and carotid esophagus were ligated. The forestomach was equipped with a cannula for gastric irrigation. After recovery from anesthesia (approximately 1 h), the stomach was irrigated for 2 h with an acid solution containing 100 mM HCl and 54 mM NaCl or the same volume of normal saline. Intracerebroventricular (i.c.v.) ACL (0, 1, 3 or 10 mg/kg dissolved in 10 microl of CSF) was challenged to rats immediately after gastric irrigation. The seizure in rats was produced by ACL in a dose-related manner. The ulcerogenic parameters such as decrease of gastric mucosal glutathione levels and increase of histamine concentrations and lipid peroxide generations as well as the raise of luminal hemoglobin contents and exacerbated mucosal lesions were obtained depending on the doses of ACL challenged. These ulcerogenic parameters produced in ACL (10 mg/kg, i.c.v.) seizure rats were markedly ameliorated by gastric vagotomy or central anticholinergics. Intraperitoneal ketotifen, zinc sulfate, diphenhydramine or cimetidine also produced significant (p<0.05) inhibitions of these ulcerogenic parameters in ACL seizure rats. In conclusion, central ACL seizure may produce gastric oxidative stress and hemorrhagic lesions via vagal nervous activation and histamine release in acid-irrigated stomachs of rats.

Detection of esophageal carcinoma using single-photon emission computed tomography of thallium-201: a preliminary report.

The aim of this preliminary study was to evaluate the potential usefulness of thallium-201 (Tl-201) in detecting esophageal carcinoma. A total of 15 patients with esophageal carcinoma were arranged for Tl-201 single-photon emission computed tomography (SPECT) of the chest. Thirteen of the patients had epidermoid carcinoma and two had adenocarcinoma. Meanwhile, 7 normal controls without any history of esophageal disease also accepted Tl-201 SPECT of the chest for comparison. From the 15 patients, Tl-201 chest SPECT detected esophageal carcinoma in 13 (86.7%) but not in 2 (13.3%) patients with epidermoid carcinoma. In contrast, all 7 normal controls (100.0%) had negative results of Tl-201 chest SPECT. Our study showed that the Tl-201 chest SPECT scan could be considered as a non-invasive useful imaging method in detection of esophageal carcinoma.

Well-differentiated fetal adenocarcinoma of the lung.

We describe the case of a 43-year-old woman with a tumor shadow in the upper lobe of the left lung. The tumor was initially suspected to be a carcinoid tumor, following percutaneous needle biopsy. Subsequently, a left upper lobectomy was performed, and a well-differentiated fetal adenocarcinoma was diagnosed histologically. Unlike the biphasic epithelial and stromal features of pulmonary blastoma, it was composed solely of malignant glands of embryonal appearance.

Coelomocytes express SpBf, a homologue of factor B, the second component in the sea urchin complement system.

A homologue of factor B, SpBf, has been cloned and sequenced from an LPS-activated coelomocyte cDNA library from the purple sea urchin, Strongylocentrotus purpuratus. The deduced amino acid sequence and domain structure show significant similarity to the vertebrate Bf/C2 family proteins. SpBf is a mosaic protein, composed of five short consensus repeats, a von Willebrand Factor domain, and a serine protease domain. It has a deduced molecular mass of 91 kDa, with a conserved cleavage site for a putative factor D protease. It has ten consensus recognition sites for N-linked glycosylation. Amino acids involved in both Mg2+ binding and in serine protease activity in the vertebrate C2/Bf proteins are conserved in SpBf. Phylogenetic analysis of SpBf indicates that it is the most ancient member of the vertebrate Bf/C2 family. Additional phylogenetic analysis of the SCRs indicates that five SCRs in SpBf may be ancestral to three SCRs, which is the typical pattern in the vertebrate Bf/C2 proteins. RNA gel blots show that SpBf transcripts are 5.5 kb and are specifically expressed in coelomocytes. Genome blots suggest that the SpBf gene (Sp152) is single copy gene per haploid genome. This is the second complement component to be identified from the sea urchin, and, with the sea urchin C3 homologue, these two components may be part of a simple complement system that is homologous to the alternative pathway in higher vertebrates.

Hematogenous osteomyelitis with inflammatory cyst formation mimicking a soft-tissue tumor.

Reported is a case of hematogenous osteomyelitis of the femur with inflammatory cyst formation mimicking a soft-tissue tumor. A 15-year-old boy with a three-year history of a gradually enlarging soft-tissue mass of his left thigh was found to have an aborted acute hematogenous osteomyelitis complicated by an inflammatory cyst that was probably caused by inadequate antibiotic therapy. The osteomyelitis and its inflammatory cyst were treated with excisional debridement and six weeks of antibiotic therapy. The patient remains well five years later, with no clinical or radiologic evidence of recurrence. This is a new variant of chronic osteomyelitis that has not previously been reported.

Expression of SpC3, the sea urchin complement component, in response to lipopolysaccharide.

The homologue of the vertebrate complement component C3 that is expressed in the coelomocytes of the purple sea urchin, Strongylocentrotus purpuratus, designated SpC3, was investigated for changes in response to immune challenge or injury. Immunoquiescent animals were used in this study because they have reduced or no detectable SpC3 in their coelomocytes or coelomic fluid (CF). Animals were injected with lipopolysaccharide (LPS) or sterile sea water (SSW, injury control). Changes in the amounts of SpC3 in coelomic fluid and in coelomocytes were then followed over time by Western blots and ELISA. Changes in mRNA from the SpC3 gene (Sp064) were also followed by RT-PCR. Although all animals responded to injury with increased levels of SpC3 in the coelomic fluid, those challenged with LPS had greater amounts of SpC3 in both CF and coelomocytes than those receiving SSW. In most of the animals receiving LPS, initial increases in SpC3 were observed within 1 h post-injection, while the earliest response in the animals receiving SSW was 6 h. The appearance of SpC3 in the coelomocytes was delayed compared to its appearance in CF, and was first detected several days after challenge. Changes in mRNA from the Sp064 gene paralleled the appearance of SpC3 in the coelomic fluid. Increases in the number of coelomocytes per milliliter of CF and in the percentage of coelomocytes that were SpC3+ also occurred after challenge with LPS or in response to injury, with a slightly greater increase in response to LPS. Although the changes in SpC3 were not as great as those identified previously for human C3 expressed in macrophages, the kinetics of the response are similar to that of acute-phase reactants in mammals.

Traumatic diaphragmatic hernia with delayed presentation.

BACKGROUND: Traumatic diaphragmatic rupture may occur in patients with thoracoabdominal injuries, and still poses a diagnostic challenge to surgeons. Those patients who survive the events without being diagnosed in the acute phase develop chronic traumatic diaphragmatic hernia. In this study, we reviewed cases of chronic traumatic diaphragmatic hernia managed over the past 35 years. METHODS: We retrospectively evaluated the clinical courses and radiologic images of 24 cases with chronic traumatic diaphragmatic hernia. RESULTS: Motor vehicle accident with blunt abdominal trauma was the most important mode of injury. Herniation was more common to the left plural cavity than to the right. The interval between injury and the onset of symptoms ranged from two weeks to 40 years (average, 7.3 years). Vague chest pain, shortness of breath, and bowel obstruction are the most common presentations. Chest radiographic findings suggested the diagnosis of diaphragmatic hernia in 20 patients. Barium study of the gastrointestinal tract was required to confirm the diagnosis. The most common herniated abdominal viscera were the stomach and colon. All patients received thoracotomy with reduction of hernia organs and closure of the diaphragmatic defect. The hospital course was uneventful with no operative mortality. CONCLUSIONS: Careful interpretation of radiographic images and early surgical intervention are essential in the management of patients with chronic traumatic diaphragmatic hernia. Thoracotomy with reduction of herniated organs can be performed safely with satisfactory results.

Galloway-Mowat syndrome: a glomerular basement membrane disorder?

We report a female infant with Galloway-Mowat syndrome. In addition to the characteristic dysmorphic appearance, neurological anomalies and early-onset nephrotic syndrome, she had arachnodactyly, an observation thus far reported uniquely in Taiwan. Also, her elder sister had the same condition. Renal pathology on light microscopy showed cystic dilatation of the renal tubules. Electron microscopy showed an irregular glomerular basement membrane and effacement of foot processes. This observation suggests that malformation of the glomerular basement membrane may cause the glomerulopathy in Galloway-Mowat syndrome.

DNA flow cytometric analysis of chest-wall chondroma and chondrosarcoma.

DNA flow cytometric analysis was performed for prediction of malignancy potential, and hence of outcome, in 17 patients aged 29-76 (mean 52) years with cartilaginous tumour of the chest wall. Histologically there were nine chondromas and eight chondrosarcomas. The chondrosarcomas (3 grade I, 4 grade II, 1 grade III) were significantly larger than the chondromas (13.6 +/- 7.8 vs 4.2 +/- 2.0 cm, p < 0.001). DNA flow cytometry was performed on paraffin-embedded blocks of resected tumour. In eight of the 17 tumours (6 chondromas, 1 grade I and 1 grade II chondrosarcoma) measurement of DNA content failed because of low cellularity and severe calcification. Aneuploid DNA content was detected only in three chondrosarcomas (2 grade II, 1 grade III). The synthetic phase fraction was less than 15% in all the studied chondromas, but exceeded 25% in four of six chondrosarcomas. This case series though small, may indicate a trend towards association between higher histologic grading and greater incidence of aneuploidy with higher synthetic phase fraction. Tumour size, histologic grade, DNA ploidy and adequacy of surgical resection are the main influences on prognosis.

Leiomyosarcoma of the gastric cardia and fundus.

BACKGROUND: Gastric leiomyosarcoma is rare among gastric malignancies, and only 20% of the cases are located in the gastric cardia or fundus. It has clinical manifestations different from tumors in other sites of the stomach. We reviewed cases of leiomyosarcoma of the gastric cardia or fundus to evaluate their clinicopathologic characters and patient survival. METHODS: From May, 1981, to June, 1998, a total of 15 patients who underwent curative resection of leiomyosarcoma of the gastric cardia or fundus were retrospectively identified and studied. All the clinical and pathologic data were reviewed and recorded. RESULTS: There were 11 men and four women. Their mean age was 59.1 years (range, 37-73 years). Tarry stools and epigastric fullness and pain were the most common symptoms, followed by body weight loss. All 15 patients had submucosal tumors in the gastric cardia or fundus, as shown by endoscopy, barium contrast radiography and computerized tomography. The incidence of esophageal involvement by the tumors was quite low. The mean tumor size was 10 cm, ranging from 4 cm to 20 cm. Locoregional organs were involved in nine patients. The median and mean survivals were 17.8 months and 31.7 months, respectively (range, 10.1-80.1 months) after curative resection. The three-year and five-year survival rates were 53% and 22%, respectively. CONCLUSIONS: The definitive preoperative diagnosis of the tumor is difficult before surgery, even though imaging studies show positive findings. Surgical resection with an adequate safe margin of normal tissue is the treatment of choice. Tumor size, serosal invasion with locoregional organ involvement and high tumor grade were the prognostic factors in the study.