Joseph H. Schwab

The Pediatrician's Role in Reducing Tobacco Exposure in Children

Objective. Pediatricians have a unique and important role to play in the prevention and treatment of childhood and adolescent tobacco use, the protection of patients from the harmful effects of environmental tobacco smoke, and the encouragement of smoking cessation among parents. However, because recent research indicates that physician training in tobacco dependence is woefully weak and lacks a model for training, this article constructs a useful approach to this problem. Methodology. A comprehensive review of the literature served as the basis for the development of a new model for pediatrician training in tobacco dependence. Results. A comprehensive model is presented for training pediatricians in the areas of reducing infant and child exposure to environmental tobacco smoke, preventing youth smoking initiation, and providing smoking cessation assistance for adolescents and parents. Conclusions. Pediatricians have been called on to play an active role in the antitobacco arena. Because of their unique opportunity to interact with children, adolescents, and parents, pediatricians can and should be antitobacco interventionists. For this to occur, however, additional guidance should be provided to pediatricians during their training to better prepare them to carry out effective assessment and intervention practices. smoking initiation, smoking prevention, smoking cessation, environmental tobacco smoke, pediatricians.

The surgical management of sacral chordomas.

Study Design. Retrospective case series. Objective. The purpose of this study was to evaluate factors that contribute to improved local control and survival. In addition, we sought to define the expected morbidity associated with treatment. Summary of Background Data. Sacral chordomas are rare tumors presumed to arise from notochordal cells. Local recurrence presents a major problem in the management of these tumors and it has been correlated with survival. Resection of sacral tumors is associated with significant morbidity. Methods. Forty-two patients underwent resection for sacral chordoma between 1990 and 2005. Twelve patients had their initial surgery elsewhere. There were 12 female and 30 male patients. The proximal extent of the sacrectomy was at least S2 in 32 patients. Results. Median survival was 84 months, and 5-year disease-free (DFS) and disease-specific survival (DSF) were 56% and 77%, respectively. Local recurrence (LR) and metastasis occurred in 17 (40%) and 13 (31%) patients, respectively. Local recurrence (P = 0.0001), metastasis (P = 0.0001), prior resection (P = 0.046), and higher grade (P = 0.05) were associated with a worse DSF. Prior resections (P = 0.0001) and intralesional resections (P = 0.01) were associated with a higher rate of LR. Intralesional resections were associated with a lower DSF (P = 0.0001). Wide contaminated margins treated with cryosurgery and/or radiation were not associated with a higher LR rate. Rectus abdominus flaps were associated with decreased wound complications (P = 0.01). Thirty-one (74%) patients reported that they self catheterize; and 16 (38%) patients required bowel training, while an additional twelve (29%) patients had a colostomy. Twenty-eight (67%) patients reported sexual dysfunction. Two (5%) patients died due to sepsis. Conclusions. Intralesional resection should be avoided as it is associated with a higher LR rate and worse survival. Rectus abdominus flaps ought to be considered as they lower the wound complication rate. Sacral resection is associated with significant morbidity.

CSPG4 in cancer: Multiple roles

Chondroitin sulfate proteoglycan 4 (CSPG4), also known as High Molecular Weight-Melanoma Associated Antigen, is a cell surface proteoglycan which has been recently shown to be expressed not only by melanoma cells, but also by various types of human carcinoma and sarcoma. Furthermore, at least in squamous cell carcinoma of head and neck and in basal breast carcinoma, CSPG4 is expressed by cancer stem cells. CSPG4 plays an important role in tumor cell growth and survival. These CSPG4-associated functional properties of tumor cells are inhibited by CSPG4-specific monoclonal antibodies (mAb) in vitro. Moreover, CSPG4-specific mAb can also inhibit tumor growth and metastasis in vivo. The anti-tumor effects of CSPG4-specific mAb are likely to reflect the blocking of important migratory, mitogenic and survival signaling pathways in tumor cells. These results indicate that CSPG4 is a promising new target to implement mAb-based immunotherapy of various types of cancer.

Long-term results of Phase II study of high dose photon/proton radiotherapy in the management of spine chordomas, chondrosarcomas, and other sarcomas.

Negative surgical margins are uncommon for spine sarcomas; hence, adjuvant radiotherapy (RT) may be recommended but tumor dose may be constrained by spinal cord, nerve, and viscera tolerance.

Giant Cell Tumor of Bone

&NA; Giant cell tumor (GCT) of bone is one type of giant cell‐rich lesion of bone. This benign mesenchymal tumor has characteristic multinuclear giant cells. Mononuclear stromal cells are the physiologically active and diagnostic cell type. Most GCTs are located in the epiphyseal regions of long bones. The axial skeleton—primarily the sacrum—is a secondary site of involvement. Most patients present with pain, swelling, joint effusion, and disability in the third and fourth decades of life. Imaging studies are important for tumor staging and radiographic grading. Typically, these clinically active but slow‐growing tumors are confined to bone, with relatively well‐defined radiographic borders. Monostotic disease is most common. Metastatic spread to the lungs is rare. Extended intralesional curettage with or without adjuvant therapy is the primary treatment choice. Local recurrence is seen in ≤20% of cases, and a second local intralesional procedure is typically sufficient in cases that are detected early. Medical therapies include diphosphonates and denosumab. Denosumab has been approved for use in osteoporosis as well as breast and prostate cancer metastatic to bone. Medical therapy and radiotherapy can alter the management of GCT of bone, especially in multifocal disease, local recurrences, and bulky central/axial disease.

Skeletal Metastases in Myxoid Liposarcoma: An Unusual Pattern of Distant Spread

BackgroundMyxoid liposarcoma (MLS), the second most common subtype of liposarcoma, occurs predominantly in the extremities of young adults and has a disproportionately high tendency to metastasize to unusual soft tissue locations, before disseminated spread or pulmonary metastases. Anecdotal evidence, mainly supported by isolated case reports, suggests that a subset of these patients also develop bone metastasis, especially within the spine, which was previously under-appreciated.Study DesignIn this study we investigate the incidence of osseous metastases in a wellannotated sarcoma database and correlate this endpoint with clinicopathologic and molecular findings.ResultsFrom a total of 230 patients with MLS diagnosis confirmed histologically, who were managed and followed prospectively at MSKCC, 40 (17%) developed skeletal metastases, comprising 56% of all metastatic events. A significant number of these bone metastases were identified early in the disease course, before the manifestation of disease in sites where sarcomas usually metastasize, such as lung. From the time of 1st metastasis, the 5 years median survival was 16%. The majority (78%) of MLS patients developing bone metastases had a histologic high grade primary tumor. The median overall survival for the high grade tumors was 55 months, as compared to 105 months for low grade cases. Eleven (84%) of 13 cases tested by RT-PCR demonstrated a type II TLS-CHOP fusion transcript.ConclusionThese findings suggest that MLS has a high incidence of osseous metastases, with predilection to spine, and often associated with the most common type of TLS-CHOP transcript. Screening should include images of the spine in high-risk MLS patients to exclude spinal metastases.

Chordoma and chondrosarcoma gene profile: implications for immunotherapy

Chordoma and chondrosarcoma are malignant bone tumors characterized by the abundant production of extracellular matrix. The resistance of these tumors to conventional therapeutic modalities has prompted us to delineate the gene expression profile of these two tumor types, with the expectation to identify potential molecular therapeutic targets. Furthermore the transcriptional profile of chordomas and chrondrosarcomas was compared to a wide variety of sarcomas as well as to that of normal tissues of similar lineage, to determine whether they express unique gene signatures among other tumors of mesenchymal origin, and to identify changes associated with malignant transformation. A HG-U133A Affymetrix Chip platform was used to determine the gene expression signature in 6 chordoma and 14 chondrosarcoma lesions. Validation of selected genes was performed by qPCR and immunohistochemistry (IHC) on an extended subset of tumors. By unsupervised clustering, chordoma and chondrosarcoma tumors grouped together in a genomic cluster distinct from that of other sarcoma types. They shared overexpression of many extracellular matrix genes including aggrecan, type II & X collagen, fibronectin, matrillin 3, high molecular weight-melanoma associated antigen (HMW-MAA), matrix metalloproteinaseMMP-9, and MMP-19. In contrast, T Brachyury and CD24 were selectively expressed in chordomas, as were Keratin 8,13,15,18 and 19. Chondrosarcomas are distinguished by high expression of type IX and XI collagen. Because of its potential usefulness as a target for immunotherapy, the expression of HMW-MAA was analyzed by IHC and was detected in 62% of chordomas and 48% of chondrosarcomas, respectively. Furthermore, western blotting analysis showed that HMW-MAA synthesized by chordoma cell lines has a structure similar to that of the antigen synthesized by melanoma cells. In conclusion, chordomas and chondrosarcomas share a similar gene expression profile of up-regulated extracellular matrix genes. HMW-MAA represents a potential useful target to apply immunotherapy to these tumors.

Definitive high-dose photon/proton radiotherapy for unresected mobile spine and sacral chordomas.

Study Design. A retrospective review. Objective. The purpose of this study is to report the results of high-dose proton based definitive radiotherapy for unresected spinal chordomas. Summary of Background Data. Spine chordoma is treated primarily by surgical resection. However, local recurrence rate is high. Adjuvant radiotherapy improves local control. In certain locations, such as high sacrum, resection may result in significant neurological dysfunction. Methods. We retrospectively reviewed 24 patients with newly diagnosed, previously untreated spinal chordomas (core biopsy only; no prior incision or resection) treated with high-dose definitive radiotherapy alone using protons and photons at our center from 1988 to 2009. Results. Reasons for radiotherapy alone included medical inoperability (3) and concern for neurological dysfunction based on spine level (21). Median age was 69.5 years. Tumor locations included cervical (2), thoracic (1), lumbar (2), S1–S2 (17), and S3 or below (2). Median maximal tumor diameter was 6.6 cm (1.4–25.5), and median tumor volume was 198.3 cm3 (4.65–2061). Median total dose was 77.4 GyRBE (proton dose unit, gray relative biological effectiveness). Analysis at median follow-up of 56 months showed overall survival of 91.7% and 78.1%, chordoma specific survival of 95.7% and 81.5%, local progression free survival of 90.4% and 79.8% and metastases free survival of 86.5% and 76.3%, at 3 and 5 years respectively. Tumor volume more than 500 cm3 was correlated with worse overall survival. Long-term side effects included 8 sacral insufficiency fractures (none required surgical stabilization), 1 secondary malignancy, 1 foot drop, 1 erectile dysfunction, 1 perineal numbness, 2 worsening urinary/fecal incontinence, and 4 grade-2 rectal bleeding. None required new colostomy. All surviving patients remained ambulatory. Conclusion. These results support the use of high-dose definitive radiotherapy for patients with medically inoperable or otherwise unresected, mobile spine or sacrococcygeal chordomas. Level of Evidence: 4

Insulin-like growth factor-I receptor tyrosine kinase inhibitor cyclolignan picropodophyllin inhibits proliferation and induces apoptosis in multidrug resistant osteosarcoma cell lines

Insulin-like growth factor-I receptor (IGF-IR) is an important mediator of tumor cell survival and shows prognostic significance in sarcoma. To explore potential therapeutic strategies for interrupting signaling through this pathway, we assessed the ability of cyclolignan picropodophyllin (PPP), a member of the cyclolignan family, to selectively inhibit the receptor tyrosine kinase activity of IGF-IR in several sarcoma cell line model systems. Of the diverse sarcoma subtypes studied, osteosarcoma cell lines were found to be particularly sensitive to IGF-IR inhibition, including several multidrug resistant osteosarcoma cell lines with documented resistance to various conventional anticancer drugs. PPP shows relatively little toxicity in human osteoblast cell lines when compared with osteosarcoma cell lines. These studies show that PPP significantly inhibits IGF-IR expression and activation in both chemotherapy-sensitive and chemotherapy-resistant osteosarcoma cell lines. This inhibition of the IGF-IR pathway correlates with suppression of proliferation of osteosarcoma cell lines and with apoptosis induction as measured by monitoring of poly(ADP-ribose) polymerase and its cleavage product and by quantitative measurement of apoptosis-associated CK18Asp396. Importantly, PPP increases the cytotoxic effects of doxorubicin in doxorubicin-resistant osteosarcoma cell lines U-2OSMR and KHOSMR. Furthermore, small interfering RNA down-regulation of IGF-IR expression in drug-resistant cell lines also caused resensitization to doxorubicin. Our data suggest that inhibition of IGF-IR with PPP offers a novel and selective therapeutic strategy for ostosarcoma, and at the same time, PPP is effective at reversing the drug-resistant phenotype in osteosarcoma cell lines. [Mol Cancer Ther 2009;8(8):2122–30]

Giant cell tumor of the mobile spine: a review of 49 cases.

Study Design. This is a retrospective review of 49 cases of giant cell tumor (GCT) of the mobile spine treated surgically. Objective. Our goal was to determine which factors influenced local recurrence. Summary of Background Data. GCT is a benign, locally aggressive tumor that rarely occurs in the spine. The management of local recurrence can be challenging. Methods. We performed a retrospective analysis of GCTs of the mobile spine managed between 1970 and 2005. Median follow-up was 145 months with a minimum of 2 years or until death. We used the Kaplan-Meier method to test whether Enneking stage, surgery type, and surgical margin had statistically significant impact on local recurrence. The log rank test was used for comparison, and a P value of less than 0.05 was deemed significant. Results. Of the 49 patients, 11 (22%) local recurrences occurred. The latest recurrence occurred at 60 months. Age less than 25 years was associated with a worse relapse-free survival (P = 0.03). En bloc resection was associated with better local control with Enneking stage III tumors (P = 0.01); however, intralesional resection provided adequate control of Enneking stage II tumors. There were 6 (12%) cases of metastasis, and 2 patients died from the progression of their disease. One patient died from the complications of the surgery. Conclusion. En bloc resection should be considered for Enneking stage III GCTs of the mobile spine. The choice of en bloc resection must be balanced with the inherent risks of the procedure. Intralesional resection of Enneking stage II tumors provides adequate local control. Patients should be followed for at least 5 years because local relapse can occur late.