TKI-resistant ALK-rearranged lung adenocarcinoma with secondary CTNNB1 p.S45V and tertiary ALK p.I1171N mutations.

Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) is an important molecular subgroup of tumors that are typically sensitive to tyrosine kinase inhibitors (TKIs). Although a substantial portion of patients benefit from TKIs, this approach is complicated by intrinsic and acquired resistance. We report a patient with ALK-rearranged NSCLC who showed an initial response to targeted therapy, but developed resistance to multiple TKIs. Serial comprehensive genomic profiling (CGP) was performed at four independent points during the clinical course. We review the pathology and clonal progression of the tumor, with CGP identifying a secondary CTNNB1 p.S45V mutation after the initiation of targeted therapy, followed by tertiary ALK p.I1171N. The presence of an alteration in a second oncogenic driver gene suggests a possible mechanism for resistance, and a secondary therapeutic target. Due to the involvement of Wnt signaling in the pathogenesis of many tumors and its association with immune evasion, a variety of therapeutic strategies are being developed to target this pathway. This case exemplifies the challenges of targeted therapeutics in the face of tumor progression, as well as the increasing role of genomics in understanding tumor biology.

Lessons Learned From an Untreated "Benign" Thoracic Tumor.

We describe a patient with Doege-Potter syndrome (solitary fibrous tumor of the pleura presenting with hypoglycemia) and illustrate several important lessons learned from the case. Seven years after the initial diagnosis, the tumor showed significant growth and developed a high-grade undifferentiated component. Solitary fibrous tumors do grow and cannot be deemed benign. Resection should be considered in all patients who are candidates for operation upon diagnosis. Our case also serves as a reminder of this rare syndrome, inasmuch as early recognition of the association of hypoglycemia with these tumors may have allowed for earlier diagnosis and avoidance of extensive tests in our patient.

Interobserver Agreement of Usual Interstitial Pneumonia Diagnosis Correlated With Patient Outcome.

CONTEXT: - The histopathologic criteria for idiopathic pulmonary fibrosis were revised in the American Thoracic Society/European Respiratory Society/Japan Respiratory Society/Latin American Thoracic Association guidelines in 2011. However, the evidence of diagnosis based on the guidelines needs further investigation. OBJECTIVE: - To examine whether the revised histopathologic criteria for idiopathic pulmonary fibrosis improved interobserver agreement among pathologists and the predicted prognosis in patients with interstitial pneumonia. DESIGN: - Twenty, consecutive, surgical lung-biopsy specimens from cases of interstitial pneumonia were examined for histologic patterns by 11 pathologists without knowledge of clinical and radiologic data. Diagnosis was based on American Thoracic Society/European Respiratory Society guidelines of 2002 and 2011. Pathologists were grouped by cluster analysis, and interobserver agreement and association to the patient prognosis were compared with the diagnoses for each cluster. RESULTS: - The generalized κ coefficient of diagnosis for all pathologists was 0.23. If the diagnoses were divided into 2 groups: usual interstitial pneumonia (UIP)/probable UIP (the UIP group) or possible/not UIP (the non-UIP group), according to the 2011 guidelines, the κ improved to 0.37. The pathologists were subdivided into 2 clusters in which 1 showed an association between UIP group diagnosis and patient prognosis (P < .05). CONCLUSIONS: - Agreement about pathologic diagnosis of interstitial pneumonia is low; however, results after division into UIP and non-UIP groups provided favorable agreement. The cluster analysis revealed 1 of the 2 clusters providing high interobserver agreement and prediction of patient prognosis.

A case of recurrent desmoplastic malignant melanoma presenting as empyema with underlying lung mass.

Desmoplastic malignant melanoma (DMM) is an extremely rare subtype of cutaneous melanoma that has diverse clinical presentations. We describe the unique case of a 57-year-old man presenting with empyema secondary to vascular occlusion from metastatic DMM. Only two other cases of DMM presenting as a lung mass have been previously reported in the literature. This report highlights potential insidious pathology of DMM, which requires a high clinical suspicion to properly diagnose and manage.

Lobectomy by Video-Assisted Thoracic Surgery vs Muscle-Sparing Thoracotomy for Stage I Lung Cancer: A Critical Evaluation of Short- and Long-Term Outcomes.

BACKGROUND: Propensity-matched studies have shown lobectomy by VATS to be superior to thoracotomy. However, these studies do not control for institution or surgeon expertise and do not compare VATS strictly with muscle-sparing thoracotomy (MST). STUDY DESIGN: From a single surgeon experienced in both VATS and MST, patients undergoing lobectomy for clinical stage I non-small cell cancer were evaluated. Video-assisted thoracic surgery was chosen if the patient requested this approach, otherwise MST was used. Short-term and long-term outcomes were compared. RESULTS: From 2007 to 2012, two hundred and ninety-eight patients were evaluated, 74 (25%) VATS and 224 (75%) MST. There were no statistically significant differences in demographics, chest tube days, and postoperative complications between the 2 surgical groups. Operative time was longer for VATS (median 130 minutes for VATS vs 90 minutes for MST; p<0.001). Hospital length of stay was longer for MST (median 4.5 days for VATS vs 5 days for MST; p=0.007). There was no difference in disease-free survival (5-year: 76% for VATS vs 78% for MST; p=0.446) and overall survival (5-year: 80% for VATS vs 79% for MST; p=0.840) for clinical stage I disease. Results were unchanged using propensity score matching of 60 VATS and 60 MST patients for postoperative complications, disease-free survival, and overall survival between the 2 matched groups. CONCLUSIONS: Our current comparison of VATS vs MST, from a single surgeon experienced with both approaches, found operative time (favoring MST) and hospital days (favoring VATS) to be the only difference between the 2 groups; and major outcomes, such as postoperative complications, disease-free survival, and overall survival, were not different. A multi-institution randomized trial should be considered before deeming any one approach to be superior.

Long-term survival after pneumonectomy for primary pulmonary malignant melanoma.

As few as 30 cases of primary malignant melanoma of the lung have been reported in the literature. Many patients die within months of diagnosis; few published cases describe patients who survive long-term after treatment. We report a case of primary pulmonary malignant melanoma in a patient who remains disease-free 60 months after pneumonectomy.

Solitary pulmonary nodule: pleuropulmonary synovial sarcoma.

Pleuropulmonary synovial sarcoma (PPSS) is an extremely rare primary malignancy of the lung. We present a case of a middle-aged female with PPSS that was initially discovered as an incidental indeterminate nodule on chest radiograph. Following evaluation with computed tomography (CT), the patient went on to positron-emission tomography (PET)/CT for work-up of the solitary pulmonary nodule, which demonstrated mild FDG-avidity and no other evidence of FDG-avid disease. The patient then underwent thoracotomy and right upper lobectomy for definitive treatment. Only after evaluation of the gross pathology, histology, immunohistochemistry and cytogenetics was the diagnosis of synovial sarcoma made. Importantly, the preceding PET/CT, in addition to physical exam of the upper and lower extremities, helped exclude the more common extra-thoracic soft-tissue variety of synovial sarcoma, which frequently metastasizes to lung, carrying a worse prognosis. Discussion of synovial sarcoma and PPSS follows.

Soft tissue perineurioma of the lacrimal gland: a case report.

A 17-year-old Caucasian man presented with an enlarging, painless mass causing a bulge in the lateral aspect of the left upper eyelid. An MRI demonstrated a well-circumscribed lacrimal gland mass without bony erosion. A 1-cm lacrimal gland mass was excised. The morphology and immunohistochemical findings were supportive of a soft tissue perineurioma. To the authors' knowledge, they present the first case report of a soft tissue perineurioma involving the lacrimal gland.

Pathologic response after neoadjuvant carboplatin and weekly paclitaxel for early-stage lung cancer: a Brown University oncology group phase II study.

INTRODUCTION: Pathologic complete response (pCR) to neoadjuvant chemotherapy is associated with improved survival in solid tumors. Southwest Oncology Group 9,900 demonstrated a 9% pCR after three cycles of paclitaxel/carboplatin every 21 days. We evaluated pCR rate with intensive weekly paclitaxel in a phase II study. METHODS: Patients with non-small cell lung cancer, stage IB to IIIA, were eligible and received carboplatin, area under the curve = 6, every 21 days ×3 and paclitaxel 80 mg/m weekly ×9. Primary outcome was the pCR rate. RESULTS: Twenty patients with clinical stage IB (n = 16), IIA (n = 1), IIB (n = 1), and IIIA (n = 2) were enrolled. Mean age was 65 years. Toxicity included grade 4 neutropenia in 1 (5%), grade 3 neutropenia in 3 (15%), grade 3 neuropathy in 1 (5%), and grade 3 nausea in 1 (5%). After neoadjuvant therapy, one patient refused surgery and one died of a nontreatment-related event. Eighteen patients underwent complete resection, 15 by lobectomy, and 3 by pneumonectomy. Pathology revealed 3 (17%) patients with pCR. The median follow-up is 67 months. For clinical stage IB (n = 16), the median overall survival has not been reached, and the 5-year overall survival is 69%. All patients with pCR (n = 3) remain alive and disease-free. Improved overall survival was seen in patients who were pathologically down-staged versus patients who were not, p = 0.05. CONCLUSIONS: Neoadjuvant chemotherapy with intensive weekly paclitaxel and carboplatin is well tolerated and does not increase surgical morbidity. This intense regimen achieves rates of pCR and survival that compares favorably with other reported induction regimens and merits further investigation.

Marrow cell genetic phenotype change induced by human lung cancer cells.

Microvesicles have been shown to mediate varieties of intercellular communication. Work in murine species has shown that lung-derived microvesicles can deliver mRNA, transcription factors, and microRNA to marrow cells and alter their phenotype. The present studies evaluated the capacity of excised human lung cancer cells to change the genetic phenotype of human marrow cells. We present the first studies on microvesicle production by excised cancers from human lung and the capacity of these microvesicles to alter the genetic phenotype of normal human marrow cells. We studied 12 cancers involving the lung and assessed nine lung-specific mRNA species (aquaporin, surfactant families, and clara cell-specific protein) in marrow cells exposed to tissue in co-culture, cultured in conditioned media, or exposed to isolated lung cancer-derived microvesicles. We assessed two or seven days of co-culture and marrow which was unseparated, separated by ficoll density gradient centrifugation or ammonium chloride lysis. Under these varying conditions, each cancer derived from lung mediated marrow expression of between one and seven lung-specific genes. Microvesicles were identified in the pellet of ultracentrifuged conditioned media and shown to enter marrow cells and induce lung-specific mRNA expression in marrow. A lung melanoma and a sarcoma also induced lung-specific mRNA in marrow cells. These data indicate that lung cancer cells may alter the genetic phenotype of normal cells and suggest that such perturbations might play a role in tumor progression, tumor recurrence, or metastases. They also suggest that the tissue environment may alter cancer cell gene expression.

Intraoperative triple antenna hepatic microwave ablation.

OBJECTIVE: Microwave ablation is emerging as a new treatment option for patients with unresectable hepatic malignancies. This two-center study shows the results of a phase 1 clinical trial of patients with known hepatic masses who underwent synchronous triple antenna microwave ablation before elective hepatic resection. SUBJECTS AND METHODS: Intraoperative microwave ablation was performed before hepatic resection. Hepatic lesions were targeted using real-time intraoperative sonography with three microwave antennas positioned in a triangular configuration. Microwave ablation was performed at 45 W for 10 minutes. Hepatic resection was then completed in the standard fashion. Gross specimens were sectioned and measured to determine tumor and ablation sizes. Representative areas were stained with H and E stain and vital histochemical nicotinamide adenine dinucleotide (NADH) stain. RESULTS: Ten patients with a mean age of 64 years (range, 48-79 years) were treated. Tumor histology included colorectal carcinoma metastases and hepatocellular carcinoma. The mean maximal tumor diameter was 4.4 cm (range, 2.0-5.7 cm). The mean maximal ablation diameter was 5.5 cm (range, 5.0-6.5 cm), while the average ablation zone volume was 50.8 cm3 (range, 30.3-65.5 cm3). Gross and microscopic examinations of areas after microwave ablation showed clear coagulation necrosis, even surrounding large hepatic vessels (> 3 mm in diameter). A marked thermallike effect was observed with maximal intensity closest to the antenna sites. NADH staining confirmed the uniform absence of viable tumor in the ablation zone. CONCLUSION: This study shows the feasibility of using multiple microwave antennas simultaneously in the treatment of liver tumors intraoperatively. Additional percutaneous studies are currently under way to investigate the safety and efficacy in treating nonsurgical candidates.

Hepatocellular carcinoma: microwave ablation with multiple straight and loop antenna clusters--pilot comparison with pathologic findings.

The purpose of this study was to evaluate the clinical implementation of triangular and spherical designs for simultaneous multiple-antenna ablation of human hepatocellular carcinoma (HCC) with a recently engineered microwave coagulation system. Institutional review board approval and informed consent were obtained, and the study was compliant with HIPAA requirements. Nine patients (five men, four women; age range, 53-79 years; mean age, 66.2 years) with resectable HCC (diameter, 2.9-6.0 cm; mean, 4.2 cm) underwent intraoperative ultrasonography-guided tumor ablation followed by resection and pathologic examination. Standard single-straight (n = 2), triangular triple-straight (n = 4), and spherical triple-loop (n = 3) antenna configurations produced mean estimated coagulation volumes of 16.7, 51.7, and 54.3 cm(3), respectively, during a single concurrent 5-10-minute ablation cycle. The triple-loop configuration yielded the most uniformly round ablation shape. Simultaneous activation of multiple straight or loop antennae is a potentially promising technique for rapid and effective treatment of large HCCs.

p27kip1 deficiency confers susceptibility to gastric carcinogenesis in Helicobacter pylori-infected mice.

BACKGROUND & AIMS: Determining how Helicobacter pylori promotes gastric cancer and whether H pylori eradication decreases cancer risk would be helped by suitable murine models. Mice lacking the cyclin-dependent kinase inhibitor p27kip1 are susceptible to carcinogen-induced tumors. Furthermore, p27 stimulates gastric epithelial apoptosis and inhibits proliferation, expression is decreased by H pylori, and low levels are associated with a poor prognosis in gastric cancer. We therefore evaluated p27-deficient mice as a model for H pylori-associated gastric cancer. METHODS: Wild-type and p27-/- C57BL/6 mice were infected with H pylori mouse-adapted Sydney strain at 6-8 weeks of age and 6-10 mice of each type were euthanized 15, 30, 45, 60, and 75 weeks later. RESULTS: Uninfected p27-/- mice developed gastric hyperplasia. H pylori-infected p27-/- mice frequently developed intestinal metaplasia (40% at 30 weeks, 67% at 45 weeks), and after 60 weeks 7 of 12 mice developed significant dysplasia and gastric cancer, recapitulating human intestinal-type gastric carcinogenesis. Wild-type mice developed intestinal metaplasia only after 75 weeks of infection; significant gastric dysplasia was observed in 1 animal (P < .05 for each comparison with p27-/- mice). No disease developed in uninfected mice. H pylori infection in p27-/- mice was associated with significantly decreased apoptosis and increased epithelial proliferation, inflammation, and H pylori density compared with infection in wild-type mice. CONCLUSIONS: p27 loss and H pylori colonization cooperate to produce gastric cancer. The p27-deficient mouse affords opportunities to examine the pathogenesis of H pylori in gastric carcinogenesis and to test eradication and chemopreventive strategies.

Angiogenic cytokines in cartilage tumors.

Pathologic neovascularization has been described in numerous types of cancers. The angiogenic cytokines vascular endothelial growth factor and basic fibroblast growth factor are thought to be the primary inducers of angiogenesis in these tumors. Hypoxia-inducible transcription factor is a nuclear transcription factor that promotes vascular endothelial growth factor expression. Prior studies have shown pathologic neovascularization in chondrosarcoma, which correlates with pathologic grade of the tumor. Angiogenic and nonangiogenic cartilage tumors were studied for expression of vascular endothelial growth factor, basic fibroblast growth factor and hypoxia-inducible transcription factors by immunohistochemistry and Northern blot analysis. Expression of vascular endothelial growth factor and hypoxia-inducible transcription factor were increased significantly in angiogenic tumors. Fibroblast growth factor expression was similar in angiogenic and nonangiogenic specimens. This may have implications for tumor grading and surgical decision-making, and potential treatment with antiangiogenesis chemotherapeutic agents.

Pathologic neovascularization in cartilage tumors.

Tumor-induced angiogenesis is necessary to sustain radial growth of tumors. Increased microvascularity has been correlated with increased metastatic potential in breast, gastrointestinal, and gynecologic tumors, but has not been well studied in cartilaginous tumors. Grade II and Grade III chondrosarcomas have increased metastatic potential compared with Grade I tumors. One reason for this may be pathologic neovascularization. The purpose of the current study was to quantify the microvessel density of cartilage tumors. Seven Grade III, 17 Grade II, and eight Grade I chondrosarcomas, and 22 benign cartilage tumors were examined. Specimens were stained with antiCD34 antibody. Microvessel densities then were determined by direct counting and estimated using the Chalkley technique. Microvessel densities for Grade III and Grade II chondrosarcomas were 45.9 and 46.2 per high-power field and for Grade I and benign tumors the microvessel densities were 9.3 and 10.3. Microvessel densities of the aggressive tumors (Grades III and II) were greater than the microvessel densities of the nonaggressive tumors (Grade I and benign). Chalkley estimates confirmed the results. Microvascularity in cartilage tumors correlates with their biologic aggressiveness and seems promising as a variable to help with histopathologic grading and as a target for new treatment modalities.