Histomolecular profiling of pleomorphic, spindle cell, and giant cell carcinoma of the lung for targeted therapies.

In pleomorphic, spindle cell, and giant cell carcinoma (PSCGC) of the lung, we wondered if an integrated diagnosis including morphological and immunohistochemical features could be related to molecular status. We performed immunohistochemistry on 35 PSCGCs against TTF1, napsin A, p40, ALK, ROS1, and c-MET. Mutational status regarding EGFR, KRAS, BRAF, HER2, and PIK3CA genes was established. Of 18 PSCGCs with adenocarcinomatous or "undifferentiated" carcinoma differentiation, 8 were mutated for EGFR (n = 1), KRAS (n = 2), BRAF (n = 1), HER2 (n = 3), and PIK3CA (n = 1). No PSCGC (0/4) with only squamous cell or adenosquamous (0/2) differentiation was mutated. c-MET overexpression was only seen in PSCGC with adenocarcinomatous or undifferentiated component (n = 5) without squamous cell component. ROS1 and ALK were negative. The presence of a "targetable mutation" was correlated to the presence of morphological or immunohistochemical adenocarcinomatous differentiation (P = .0137). Integrated diagnosis of an adenocarcinomatous component in PSCGC could be associated with the presence of targetable gene mutation. Because only PSCGC with adenocarcinomatous or undifferentiated carcinoma harbors mutations, whereas PSCGC with only squamous or adenosquamous differentiation does not in our study, this might represent a prescreening for patients with PSCGC to be tested for molecular targets. Our results emphasize that careful morphological examination and the use of immunohistochemistry might be useful for the selection of PSCGC tested for a mutational target.

Spondylectomy for Giant Cell Tumor After Denosumab Therapy.

STUDY DESIGN: A case report. OBJECTIVE: To report a case of the lumbar giant cell tumor (GCT) utilizing a new clinical treatment modality (denosumab therapy), which showed a massive tumor reduction combined with the L4 spondylectomy. SUMMARY OF BACKGROUND DATA: There are some controversies about spinal GCT treatments. Denosumab has provided good clinical results in terms of tumor shrinkage, and local control in a short-time follow-up clinical study phase 2, although for spinal lesions, it has not been described. Nonetheless, "en bloc" spondylectomy has been accepted as being the best treatments modalities in terms of oncological control. METHODS: A case study with follow-up examination and series radiological assessments 6 months after therapy started, followed by a complex spine surgery. RESULTS: The denosumab therapy showed on the lumbar computed tomography scans follow-up 6 months later, a marked tumor regression around 90% associated to vertebral body calcification, facilitating a successful L4 spondylectomy with an anterior and posterior reconstruction. The patient recovered without neurological deficits. CONCLUSION: A new therapeutic modality for spinal GCT is available and showing striking clinical results; however, it is necessary for well-designed studies to answer the real role of denosumab therapy avoiding or facilitating complex spine surgeries as spondylectomies for spinal GCT. LEVEL OF EVIDENCE: 5.

A Gelatinases-targeting scFv-based Fusion Protein Shows Enhanced Antitumour Activity with Endostar against Hepatoma.

Gelatinases play important roles in tumour invasion and metastasis and are thus considered promising targets for cancer therapy. In this study, a new single-chain variable fragment (scFv)-based fusion protein Fv-LDP, composed of the anti-gelatinases scFv and lidamycin apoprotein (LDP), was prepared, and its combination with angiogenesis inhibitor Endostar was then investigated. The fusion protein Fv-LDP specifically bound to various tumour cells, and its binding capability to human pulmonary giant cell carcinoma (PG) cells was higher than that of LDP. Fv-LDP inhibited the expression and secretion of gelatinases and could be internalized into tumour cells via endocytosis. Fv-LDP also suppressed the growth of human hepatoma cells and murine hepatoma 22 transplanted in Kunming mice in various degrees. In addition, Endostar could enhance the synergistic or additive inhibition of Fv-LDP on the growth, migration or invasion of human hepatoma cells shown by a colony formation assay and a transwell-based migration or invasion assay, respectively. In vivo, Fv-LDP/Endostar combination showed a significantly synergistic effect on the growth of a human hepatoma xenograft, with an inhibition rate of 80.8% compared with the Fv-LDP (44.1%) or Endostar (8.9%)-treated group. The above-mentioned results indicate that the fusion protein Fv-LDP is effective against transplantable hepatoma in mice and human hepatoma xenografts in athymic mice. Moreover, Endostar can potentiate the inhibition effect of Fv-LDP on the growth of human hepatoma cells and xenografts. These data will provide a new combined strategy for improving the therapeutic efficacy of treatments for hepatoma or other gelatinase-overexpressing tumours.

Successful treatment of locally advanced anaplastic thyroid carcinoma by chemotherapy and hyperfractionated radiotherapy.

The authors report a case of anaplastic thyroid carcinoma which was treated with chemotherapy and radiotherapy and proved to achieve pathological CR (complete response) after a radical operation. A 53-year-old female presented with a mass of about 4 cm in diameter arising from the left lobe of her thyroid and surrounding her cervical esophagus. Pre-operative aspiration cytology and open biopsy revealed the tumor was a giant cell anaplastic carcinoma. There was no sign of distant metastasis. Two cycles of chemotherapy were very effective in treating the tumor but regrowth appeared to occur during hyperfractionated radiotherapy. A radical operation, including a resection of the larynx, cervical trachea and esophagus, was successfully performed and no living cancer cells, only granulation and necrosis, were observed in the operation specimen. The patient has been alive for over 2 years since without any evidence of recurrence.

[An autopsied case of giant small cell carcinoma of the pancreas].

A 58-year-old man who complained of an abdominal tumor was admitted to our hospital. Abdominal CT scan showed that a 15-cm tumor occupied the entire right upper abdomen and that there were ascites and liver metastases. A liver biopsy was performed. The liver biopsy showed a small cell carcinoma pattern, but no definitive origin of the tumor was determined. Considering the extensive peritoneal invasion and multiple liver metastases, he received 2 / courses of cisplatin/etoposide chemotherapy, but his tumor became larger with concomitant abdominal pain and nausea. The patient suddenly died due to multiple organ failure caused by tumor necrosis. The autopsy revealed a pathological diagnosis of primary small cell carcinoma of the pancreas.

Berberine inhibits cyclin D1 expression via suppressed binding of AP-1 transcription factors to CCND1 AP-1 motif.

AIM: To verify the suppressive effect of berberine on the proliferation of the human pulmonary giant cell carcinoma cell line PG and to demonstrate the mechanisms behind the antitumoral effects of berberine. METHODS: The proliferative effects of PG cells were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide colorimetry. The cell cycle was examined by flow cytometry. The expression level of cyclin D1 was detected by RT-PCR. The activities of the activating protein-1 (AP-1) and NF-kappaB signaling pathways related to cyclin D1 were examined by luciferase assay. The cytoplasmic level of c-Jun was detected by Western blot analysis. An electrophoretic mobility shift assay was used to examine the binding of transcription factors to the cyclin D1 gene (CCND1) AP-1 motif. RESULTS: The results showed that the proliferation of PG cells treated with different concentrations (10, 20, and 40 microg/mL) of berberine for 24 and 48 h was suppressed significantly compared to the control group. After treatment with berberine, the proportion of PG cells at the G0/G1 phase increased, while cells at the S and G2/M phases decreased. Berberine could inhibit the expression of cyclin D1 in PG cells. Berberine inhibited the activity of the AP-1 signaling pathway, but had no significant effect on the NF-kappaB signaling pathway. Berberine suppressed the expression of c-Jun and decreased the binding of transcription factors to the CCND1 AP-1 motif. CONCLUSION: Berberine suppresses the activity of the AP-1 signaling pathway and decreases the binding of transcription factors to the CCND1 AP-1 motif. This is one of the important mechanisms behind the antitumoral effects of berberine as a regulator of cyclin D1.

Tumour cells resistance in cancer therapy

Resistance to chemotherapeutic drugs presents a big caveat for cancer treatment. In this review we will describe the molecular mechanisms involved in chemoresistance, discussing the mechanisms of resistance related to tumour microenvironment, as well as their intracellular mechanisms. Chemoresistance can also appear as a consequence to treatments with new anticancer drugs. In this sense, we will exemplify this type of resistance discussing mechanisms of action of epidermal growth factor receptor (EGFR) inhibitors. We conclude that the main problem of chemoresistance is due to its pleiotropic and multifactorial nature(AU)

Aggressive giant cell tumour of bone.

INTRODUCTION: The surgical treatment of Stage III or aggressive giant cell tumour of the bone, whether to perform intralesional or en-bloc resection, remains controversial. The aim of this study is to identify the effectiveness of en-bloc resection for local control and final oncological outcome of the disease. METHODS: The data of 20 consecutive patients with Stage III giant cell tumour were retrospectively reviewed to determine the local control and oncological outcome after treatment with wide resection. RESULTS: The majority of the patients presented late with mean duration of symptoms of 24 months, and four patients presented with recurrences. All patients were treated with wide resection except for two patients who underwent ablative surgery due to major neurovascular involvement. Ten patients required free vascularised tissue transfer to cover massive soft tissue defect. Local recurrence occurred in one patient who was again treated with wide resection and vascularised flap. Six patients had pulmonary metastases. Two patients with resectable disease were treated with thoracoscopic surgery and they remained disease-free 36 months after surgery. Two patients with multiple lung metastases were treated with chemotherapy and the disease remained non-progressive. The remaining two patients who refused chemotherapy showed radiological progression, and one succumbed to the disease with massive haemoptysis. CONCLUSION: Aggressive giant cell tumour of bone should be treated with wide resection for better local control, and treatment of pulmonary metastases is mandatory for overall prognosis.

Solitary muscle metastasis from lung carcinoma.

Recurrence after resection of non-small cell lung carcinoma is generally associated with a poor outcome. Limb muscle metastasis from lung cancer is extremely rare. We present a case of a 71-year-old man who presented with a solitary metastasis to his right lower limb two months after right upper lobectomy for lung cancer (stage: T2N0M0). Twenty-four months after surgical excision and chemotherapy he is alive without signs of neoplastic disease. We believe that a more aggressive approach might be considered for selected patients with solitary extracranial and extra-adrenal metastasis from lung cancer.

Giant cell carcinoma of the lung.

A 50-year-old non-smoking, hypertensive female, presenting with superior vena caval compression, was found to have giant cell carcinoma of the lung. She received intensive combination chemotherapy. However she died in the following 36 hours, as a consequence of refractory hypotension.