Surgical Excision Of Primary Tumor Research Articles

Neoantigen-Based Nanovaccine In Combination with Immune Checkpoint Inhibitors Abolish Postsurgical Tumor Recurrence and Metastasis.

The notorious limitation of conventional surgical excision of primary tumor is the omission of residual and occult tumor cells, which often progress to recurrence and metastasis, leading to clinical treatment failure. The therapeutic vaccine is emerging as a promising candidate for dealing with the issue of postsurgical tumor residuals or nascent metastasis. Here, a flexible and modularized nanovaccine scaffold based on the SpyCatcher003-decorated shell (S) domain of norovirus (Nov) is employed to support the presentation of varied tumor neoantigens fused with SpyTag003. The prepared tumor neoantigen-based nanovaccines (Neo-NVs) are able to efficiently target to lymph nodes and engage with DCs in LNs, triggering strong antigen-specific T-cell immunity and significantly inhibiting the growth of established orthotopic 4T1 breast tumor in mice. Further, the combination of Neo-NVs and anti-PD-1 monoclonal antibody (mAb) produces significant inhibition on postsurgical tumor recurrence and metastasis and induces a long-lasting immune memory. In conclusion, the study provides a simple and reliable strategy for rapid preparing personalized neoantigens-based cancer vaccines and engaging checkpoint treatment to restore the capability of tumor immune surveillance and clearance in surgical patients.

Elective neck dissection versus watchful waiting in the management of early tongue cancers with node negative neck: our experience of 68 cases

<p><strong>Background: </strong>Prognosis for tongue squamous cell carcinoma depends upon lymph node metastasis and the treatment plan depends upon the management of cervical lymph node metastasis.<strong></strong></p><p><strong>Methods: </strong>A prospective analysis of early squamous cell carcinoma oral tongue was done February 2017 to February 2020 in previously untreated and biopsy proven patients with T1-2N0 cancer of tongue and patients with clinically negative nodes on the basis of palpation, ultrasound and computerized tomography (CT) and previously untreated and biopsy proven patients with T1-2N0 cancer of oral cavity. After proper work up, patients were divided into two groups. Group 1 (n=35) patients that underwent a surgical excision of primary tumor with 15mm safe margin and selective neck dissection (level I, II, III), group 2 (n=33) patients that underwent surgical excision of primary tumor with 15 mm safe margin and neck observation. All patients with tumor thickness ≥4 mm were included in this group. </p><p><strong>Results: </strong>The study included 51 (75%) males and 17(25%) female patients. In this study, recurrence was significantly related to tumor thickness (p<0.05) i.e., >4 mm tumor thickness showed significantly higher local recurrence and nodal recurrences. Also, a significantly higher relationship was seen between nodal recurrence and postoperative close surgical margins (p<0.05).</p><p><strong>Conclusions: </strong>Elective neck dissection becomes necessary in patients with T2N0 tumors and tumor thickness of >4 mm as frequency of occult metastasis and recurrence is more in these patients.</p>

Primary cardiac angiosarcoma: a prolonged response to surgical resection followed by concurrent chemoradiotherapy with docetaxel.

IntroductionPrimary cardiac cancer is a very rare disease, among which primary cardiac angiosarcoma is one of the most frequent type and is characterized by extremely poor prognosis without established optimal treatment.Case descriptionHere we report a case of primary cardiac angiosarcoma with hemorrhagic pericardial effusion who achieved a durable response with tumor excision followed by concurrent chemoradiotherapy with docetaxel. A sixty year old man was presented with dyspnea and was diagnosed with primary cardiac angiosarcoma with hemorrhagic pericardial effusion. After surgical excision of primary tumor with microscopic residual disease followed by concurrent chemoradiotherapy with docetaxel, the patient showed durable response of progression free survival of 12 months.Discussion and evaluationThis case shows benefit of concurrent chemoradiotherapy with taxane. Further investigation of aggressive multimodal treatment strategy is warranted for primary cardiac angiosarcoma with pauci-metastasis even when achievement of complete resection seems unlikely.

Histopathological Parameters predicting Occult Nodal Metastases in Tongue Carcinoma Cases: An Indian Perspective.

It is a well-established fact that in squamous cell carcinoma cases, the presence of lymph node metastases decreased the 5-year survival rate by 50% and also caused the recurrence of the primary tumor with development of distant metastases. Till date, the predictive factors for occult cervical lymph nodes metastases in cases of tongue squamous cell carcinoma remain inconclusive. Therefore, it is imperative to identify patients who are at the greatest risk for occult cervical metastases. This study was thus performed with the aim to identify various histopathologic parameters of the primary tumor that predict occult nodal metastases. The clinicopathologic features of 56 cases of lateral tongue squamous cell carcinoma with cT1NoMo/cT2NoMo as the stage and without prior radiotherapy or chemotherapy were considered. The surgical excision of primary tumor was followed by elective neck dissection. The glossectomy specimen along with the neck nodes were fixed in formalin and 5 urn thick sections were obtained. The hematoxylin & eosin stained sections were then subjected to microscopic examination. The primary tumor characteristics that were analyzed include tumor grade, invading front, depth of tumor, lymphovascular invasion, perineural invasion and inflammatory response. The nodes were examined for possible metastases using hematoxylin & eosin followed by cytokeratin immunohistochemistry. A total of 12 cases were found with positive occult nodal metastases. On performing univariate analysis, the histopathologic parameters that were found to be statistically significant were lymphovascular invasion (p = 0.004) and perineural invasion (p = 0.003) along with a cut-off depth of infiltration more than 5 mm (p = 0.01). Histopathologic assessment of the primary tumor specimen therefore continues to provide information that is central to guide clinical management, particularly in cases of occult nodal metastases. Clinical significance The study highlights the importance of extensive histopathological screening, which holds the key for establishing occult metastases. Pathological upgrading of tumors is possible following histopathological studies similar to the present one. Presence of occult metastases justify neck dissection in these clinically N0 cases. In an Indian setting, histopathological evaluation assumes a bigger role than other expensive and advanced techniques.

Clinical management of Ewing sarcoma of the bones of the hands and feet: a retrospective single-institution review

Background/PurposeBones of the hands and feet are uncommon sites for Ewing sarcoma. In this study, we reviewed our experience in the management of these tumors. MethodsWe retrospectively reviewed clinical presentation, management, and outcome of patients with Ewing sarcoma of the bones of hands and feet treated at our institution (1981-2006). ResultsThe cohort included 6 males and 3 females (8 white, 1 African American; median age at diagnosis, 15 years). Primary tumor site was the hand in 6 and the foot in 3 patients. Three patients had distant metastatic disease at diagnosis (lung [n = 2]; ipsilateral axillary lymph node[(n = 1]). All patients had painful swelling at the primary site, and 2 (22%) had pathological fracture. All patients received chemotherapy and local control measures (surgery [n = 6], radiation [n = 2], surgery and radiation [(n = 1]). Three patients received radiotherapy for distant metastases. Three patients had systemic recurrence (lungs [n = 2], lung and brain [n = 1]); none had local tumor recurrence. Median follow-up was 5 years. Five patients (55.6%) are alive at last follow-up. ConclusionsChemotherapy and surgical excision of primary tumor are the mainstays of treatment. Radiotherapy is recommended for local control of lesions in the hand for patients declining excisional therapy.

A Comprehensive Review of the Treatment of Merkel Cell Carcinoma

Merkel cell carcinoma (MCC) is an uncommon but malignant cutaneous neuroendocrine carcinoma with a high incidence of local recurrence, regional lymph node metastases, and subsequent distant metastases. The etiology of MCC remains unknown. It usually occurs in sun-exposed areas in elderly people, many of whom have a history of other synchronous or metachronous sun-associated skin lesions. The outcome for most patients with MCC is generally poor. Surgery is the mainstay of treatment. The role of adjuvant therapy has been debated. However, data from recent development support a multimodality approach, including surgical excision of primary tumor with adequate margins and sentinel lymph node dissection followed by postoperative radiotherapy in most cases, as current choice of practice with better locoregional control and disease-free survival. Patients with regional nodal involvement or advanced disease should undergo nodal dissection followed by adjuvant radiotherapy and, perhaps, systemic platinum-based chemotherapy in most cases.

Surgical Resection of the Primary Tumor is Associated with Increased Long-Term Survival in Patients with Stage IV Breast Cancer after Controlling for Site of Metastasis

The benefit of surgical resection in patients presenting with metastatic breast cancer is not established. We hypothesized that surgical excision of primary tumors in patients with stage IV breast cancer would be associated with increased survival. Chart review identified 409 patients with stage IV breast cancer treated from 1996 to 2005; 187 received surgical excision of their primary tumor and 222 did not. One hundred and two patients had bone-only metastases, 281 had metastases to other organs +/- bone, and 26 had no metastases recorded. Patient characteristics were compared between groups using the chi-squared test. Cox regression models were used to calculate adjusted hazard ratios (aHR). The log-rank test compared the differences in survival between patients who did or did not undergo surgical resection. Mean age at diagnosis of all 409 patients was 57.8 +/- 15.0 years. After controlling for age, comorbidity, tumor grade, histology, and sites of metastasis, patients who underwent surgical resection had longer median survival when compared with patients who did not undergo surgical resection (31.9 vs. 15.4 months, p < 0.0001; aHR 0.53 [95% CI 0.42-0.67]). Surgical excision of the primary breast tumor was associated with significantly longer survival in this cohort of stage IV breast cancer patients, even after controlling for other factors associated with survival. Randomized clinical trials are needed to validate these findings.

Non-methotrexate based triple drug combination chemotherapy for untreated osteosarcoma

20512 Background: Considering the high cost of intensive high-dose methotrexate based chemotherapy, a non-methotrexate based chemotherapy regimen was evaluated in newly diagnosed osteosarcoma patients Methods: A total of 54 patients of newly diagnosed osteosarcoma (2000 to 2005) were included in the study. Chemotherapy protocol included 3 drugs viz. Doxorubicin (20 mg/m2 on Day1 to Day3), Cisplatin (100 mg/m2 on Day 1) and Ifosfamide (2000 mg/m2 on Day1 to Day 5) in combination as A1 cycle - Ifosfamide + Doxorubicin, B1 cycle - Doxorubicin + Cisplatin, C1 cycle - Cisplatin + Ifosfamide. The sequence was repeated as A2, B2 and C2 (total 6 cycles). Surgical excision of primary tumor was done after 3 cycles of chemotherapy Results: The median age at diagnosis was 15.5 years with a slight male preponderance (n=38, 70.4 %). Axial skeleton (maxillary) was affected only in one patient. Lower end of femur was the most common appendicular skeletal site for the primary tumor (n=27, 50 %). Forty two out of 54 (77.8 %) patients had nonmetastatic disease at diagnosis. Lung was the most common site of distant metastasis at diagnosis (11 out of 12 patients). Fifty patients received all 6 chemotherapy cycles as planned. Limb salvage with reconstruction surgery was performed in 35 (64.8 %) patients. Complete (100%) tumor necrosis was seen in 18 (33.3 %) patients. The median duration of follow-up was 16 months. The actuarial disease free and overall survival at 3 years would be 41.4 % and 43.6 % respectively. The incidence of febrile neutropenia was 11.85 % and of grade III/IV thrombocytopenia was 10 % of all chemotherapy cycles. Easily controllable emesis was the commnoest non-hematological toxicity, experienced by 31.5 % of patients. Two patients died due to post chemotherapy neutropenic sepsis. With univariate analysis, complete histological response (100 % tumor necrosis) alone could be identified as independent favorable prognostic factor (3 year OS of 73.6 %, P=0.003). The overall survival outcome was not statistically different in subgroups of sex, age group and pathological tumor size. Conclusions: Non-methotrexate based triple drug combination chemotherapy is an effective treatment option for patients with newly diagnosed osteosarcoma in developing countries like India. No significant financial relationships to disclose.

Resection of metastatic pulmonary lesion of ossifying fibromyxoid tumor extending into the left atrium and ventricle via pulmonary vein

The ossifying fibromyxoid tumor (OFMT) of soft parts is a rare soft tissue neoplasm of uncertain lineage. The most common metastases are found in the lung. Herein, we present the first case report of pulmonary metastasis of ossifying fibromyxoid tumor with intracardiac extension, which was resected carefully using cardiopulmonary bypass and cardiac arrest. Subsequently pulmonary left lower lobectomy was performed. The patient recovered uneventfully and was discharged in after a few days. Recently, OFMT has been considered as a tumor of intermediate malignancy. We recommend wide surgical excision of primary tumor and radiotherapy. Early follow-up is mandatory.

Merkel cell cancer of the skin

Merkel cell carcinoma (MCC) is a rare malignant cutaneous tumor of the elderly with rapidly growing skin nodules found predominantly on sun-exposed areas of the body. The vast majority of patients present with localized disease, while up to 30% have regional lymph node metastases. Despite local excision and the incidence of local recurrence, regional lymph node metastases and distant metastases is high and usually occurs within 2 years of primary diagnosis. The optimal treatment for patients with MCC remains unclear. The best outcome is achieved with multidisciplinary management including surgical excision of primary tumor with adequate margins and post-operative radiotherapy (RT) to control local and regional disease. Patients with regional nodal metastases should be treated with lymph node dissection plus RT. Adjuvant chemotherapy (CT) should be considered as part of the initial management. In case of metastatic disease CT based on regimens used for small-cell lung cancer is the standard treatment of care.

High dose melphalan in the treatment of advanced neuroblastoma: Results of a randomised trial (ENSG‐1) by the European Neuroblastoma Study Group

High dose myeloablative chemotherapy ("megatherapy"), with haematopoietic stem cell support, is now widely used to consolidate response to induction chemotherapy in patients with advanced neuroblastoma. In this study (European Neuroblastoma Study Group, ENSG1), the value of melphalan myeloablative "megatherapy" was evaluated in a randomised, multi-centre trial. Between 1982 and 1985, 167 children with stages IV and III neuroblastoma (123 stage IV > 1 year old at diagnosis and 44 stage III and stage IV from 6 to 12 months old at diagnosis) were treated with oncovin, cisplatin, epipodophyllotoxin, and cyclophosphamide (OPEC) induction chemotherapy every 3 weeks. After surgical excision of primary tumour, the 90 patients (69% of the total) who achieved complete response (CR) or good partial response (GPR) were eligible for randomisation either to high dose melphalan (180 mg per square meter) with autologous bone marrow support or to no further treatment. Sixty-five (72%) of eligible children were actually randomised and 21 of these patients were surviving at time of this analysis, with median follow-up from randomisation of 14.3 years. Five year event-free survival (EFS) was 38% (95% confidence interval (CI) 21-54%) in the melphalan-treated group and 27% (95% CI 12-42%) in the "no-melphalan" group. This difference was not statistically significant (P = 0.08, log rank test) but for the 48 randomised stage IV patients aged >1 year at diagnosis outcome was significantly better in the melphalan-treated group-5 year EFS 33% versus 17% (P = 0.01, log rank test). In this trial, high dose melphalan improved the length of EFS and overall survival of children with stage IV neuroblastoma >1 year of age who achieved CR or GPR after OPEC induction therapy and surgery. Multi-agent myeloablative regimens are now widely used as consolidation therapy for children with stage IV disease and in those with other disease stages when the MYCN gene copy number in tumour cells is amplified. Because they are more toxic, complex, and costly these combination megatherapy regimens should be compared with single agent melphalan in randomised clinical trials.

Development of Anti-tumor Immunity against a Non-immunogenic Mammary Carcinoma through Somatic GM-CSF, IL-2, and HSVtk Combination Gene Therapy

Gene therapy for cancer using suicide genes such as the herpes simplex virus thymidine kinase gene (HSVtk) has been explored extensively in preclinical and clinical studies. We have improved the use of HSVtk by combining it with two cytokine genes encoding granulocyte/macrophagecolony-stimulating factor (GM-CSF) and interleukin-2 (IL-2), and determined their additive/synergistic effects on tumor regression and inhibition of metastases in the non-immunogenic, spontaneously metastatic mammary tumor model, 4T1. Two adenoviral vectors (AV) were constructed, one carrying HSVtk (AV-TK) and the second (AV-GM/IL2) carrying Gm-CSf and Il2. Only the combination of AV-TK/GCV and AV-GM/IL2 showed a significant decrease in tumor growth and reduction of distant metastases with 25% of the tumors undergoing complete regression. When surgical excision of primary tumors was included in the regimen, local treatment with AV-TK/GCV plus AV-GM/IL2 further enhanced long-term survival. A fraction of the treated mice developed anti-tumor immunity and survived a second challenge with 4T1. Functional analyses demonstrated infiltration of lymphocytes within the tumor and a strong tumor-specific cytotoxic T lymphocyte response in TK- plus cytokine-treated animals. These data indicate that the coexpression of GM-CSF and IL-2 can augment the effect of HSVtk suicide gene therapy.

Development of Anti-tumor Immunity against a Non-immunogenic Mammary Carcinoma through in Vivo Somatic GM-CSF, IL-2, and HSVtk Combination Gene Therapy

Gene therapy for cancer using suicide genes such as the herpes simplex virus thymidine kinase gene (HSVtk) has been explored extensively in preclinical and clinical studies. We have improved the use of HSVtk by combining it with two cytokine genes encoding granulocyte/macrophage-colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2), and determined their additive/synergistic effects on tumor regression and inhibition of metastases in the non-immunogenic, spontaneously metastatic mammary tumor model, 4T1. Two adenoviral vectors (AV) were constructed, one carrying HSVtk (AV-TK) and the second (AV-GM/IL2) carrying Gm-CSf and Il2. Only the combination of AV-TK/GCV and AV-GM/IL2 showed a significant decrease in tumor growth and reduction of distant metastases with 25% of the tumors undergoing complete regression. When surgical excision of primary tumors was included in the regimen, local treatment with AV-TK/GCV plus AV-GM/IL2 further enhanced long-term survival. A fraction of the treated mice developed anti-tumor immunity and survived a second challenge with 4T1. Functional analyses demonstrated infiltration of lymphocytes within the tumor and a strong tumor-specific cytotoxic T lymphocyte response in TK- plus cytokine-treated animals. These data indicate that the coexpression of GM-CSF and IL-2 can augment the effect of HSVtk suicide gene therapy.

Efficacy of herpes simplex virus thymidine kinase in combination with cytokine gene therapy in an experimental metastatic breast cancer model.

Immunotherapy in combination with suicide gene therapy for breast cancer was tested using a metastatic animal model. Subcutaneous injection of the nonimmunogenic breast cancer cell line 4T1 in BALB/C mice gave rise to tumors in 100% of mice with both micrometastases and macrometastases in the lung. We used the herpes simplex virus thymidine kinase (HSV-TK) gene along with the cytokine genes granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2) to determine their effect on tumor regression and inhibition of lung metastasis. Adenoviral (AV) vectors carrying these transgenes, in separate constructs, were used in this study. Intratumoral administration of AV-TK followed by 10 days of ganciclovir treatment resulted in a delay in tumor growth and, in some cases, in a low to moderate reduction in tumor volume. Inclusion of either GM-CSF or IL-2 gene with HSV-TK resulted in a slightly greater reduction in tumor volume, although these data were not significantly different from those obtained for TK treatment alone. However, when both cytokine genes were combined with TK, a substantial reduction in tumor growth was observed compared with HSV-TK alone (P < .02). Tumor weight data also exhibited superior efficacy of TK/GM-CSF/IL-2 treatment when compared with animals treated with TK gene only (P < .01). More importantly, TK/GM-CSF/IL-2 combination gene therapy induced a significant reduction in lung metastasis compared with any other treatment groups in the 4T1 model (P < .001 between TK GM-CSF/IL-2 versus TK only). Surgical excision of primary tumors after TK/GM-CSF/IL-2 plus ganciclovir treatment resulted in anti-metastatic activity that was similar to that observed for animals in which no surgery was performed. Survival analysis showed a significant difference between animals treated with AV-TK/GM-CSF/IL-2 and animals treated with TK only at 35 days after virus injection (P < .01). Immunophenotypic data suggest infiltration of lymphocytes within the tumor microenvironment in TK- and cytokine gene-treated animals. Thus, the overall data presented here demonstrate that TK gene therapy in combination with GM-CSF and IL-2 gene-mediated immunotherapy strategies have important implications in the treatment of breast cancer.

Antiangiogenic gene therapy targeting the endothelium-specific receptor tyrosine kinase Tie2.

Angiogenesis is required for tumor growth and metastasis, and inhibition of angiogenesis is a promising approach for anticancer therapy. Tie2 (a.k.a Tek) is an endothelium-specific receptor tyrosine kinase known to play a role in tumor angiogenesis. To explore the therapeutic potential of blocking the Tie2 pathway, an adenoviral vector was constructed to deliver a recombinant, soluble Tie2 receptor (AdExTek) capable of blocking Tie2 activation. Two days after i.v. injection of AdExTek, the plasma concentration of ExTek exceeded 1 mg/ml and was maintained for about 8 days. Administration of AdExTek to mice with two different well established primary tumors, a murine mammary carcinoma (4T1) or a murine melanoma (B16F10.9), significantly inhibited the growth rate of both tumors (64% and 47%, respectively). To study the effect of ExTek on tumor metastasis, both tumor cell lines were coinjected i.v. with either AdExTek or a control virus. Mice coinjected with control virus developed numerous large, well vascularized lung metastases. In contrast, mice coinjected with AdExTek virus developed few, if any, grossly apparent metastases, and histologic examination revealed only small avascular clusters of tumor cells. Administration of AdExTek also inhibited tumor metastasis when delivered at the time of surgical excision of primary tumors in a clinically relevant model of tumor metastasis. This study demonstrates the potential utility of gene therapy for systemic delivery of an antiangiogenic agent targeting an endothelium-specific receptor, Tie2.

Cell-mediated immunity in breast cancer patients

In clinical practice, reports have been made on immunosuppression after surgical excision of primary tumor or at relapse. However, the relationship between undefined or overt metastases and the host immune system has not been sufficiently examined over a prolonged period. These aspects were investigated in 160 breast cancer patients followed up post-operatively with serial controls over a long period. One hundred and thirty-four cases (91 node negative, (N-), 43 node positive (N+)) were disease-free and 26 relapsed. In all patients, serum T cell populations, serum B lymphocytes and skin reaction of delayed hypersensitivity (SRDH) were serially determined for 39 +/- 12 months (m +/- SD). The reference values for these parameters were assessed as follows: T populations were evaluated in 24 healthy donors and SRDH in 95 healthy females. In non-relapsed patients, constant CD8+ T cell decrease and T4/T8 ratio increase were observed; the T4/T8 ratio was significantly higher (ranging from P < 0.05 - P < 0.001) than in the control group. The mean values of NK cells and B lymphocytes, the former parameter being highly significant (P < 0.001), were higher than in controls. In the 26 metastatic patients, the T4/T8 ratio from 20 months before to 30 months after the first sign of relapse decreased from 3.2 to about 1 (r = -0.256, P < 0.05) and from 30 to 92 months after relapse progressively increased to 2. Similarly, in the former subinterval a progressive decrease in the number of positive antigens and score was found (from 2.4 to 0 and from 10 to zero respectively). A significant inverse correlation between these two parameters and observation time occurred (P < 0.01 and P < 0.001 respectively). From 30 to 86 months after relapse, a progressive increase in the number of positive antigens and scores up to 2 and 12 were observed. A significant direct correlation (P < 0.05) was noted. In conclusion, these data indicate significant changes in T populations during the disease-free interval in breast cancer patients. The decrease in circulating CD8+ T cells is compatible with the hypothesis of CD8+ T cell localization at the site of the micrometastases. The increase in circulating B lymphocytes and NK cells suggests activation of aspecific humoral immunity and NK function. In addition, they show that progressive deficiency in cell-mediated immunity appears many months before and that recovery continues for a long time after overt metastatic disease.

DT-5461, a new synthetic lipid A analogue, inhibits lung and liver metastasis of tumor in mice.

We have investigated the antimetastatic effect of a new synthetic lipid A analogue, of low endo‐toxicity, DT‐5461, against two highly metastatic tumor cell lines, L5178Y‐ML25 T‐lymphoma and B16‐BL6 melanoma cells in mice. Four intermittent i.v. administrations of DT‐5461 at intervals of 4 days resulted in a significant inhibition of liver metastasis caused by i.v. injection of L5178Y‐ML25 cells and lung metastasis of B16‐BL6 cells in the experimental metastasis models. Intraperitoneal and intranasal administrations as well as i.v. administration of DT‐5461 were also effective in preventing lung metastasis of the melanoma cells. Multiple administrations of DT‐5461 before the surgical excision of primary tumors significantly reduced the number of lung colonies of melanoma cells and primary tumor size. Similarly, this treatment modality after the surgical excision of primary tumors showed a greater reduction of lung tumor colonies as compared with lipopolysaccharide, a synthetic lipid A (No. 506) and its analogue as well as untreated control in the spontaneous lung metastasis model. Furthermore, the group that received DT‐5461 after the inoculation of lymphoma or melanoma cells showed significantly enhanced survival rate compared with the untreated control. These results suggested that DT‐5461 may he therapeutically useful for the inhibition of tumor metastasis.

Inhibition of lung metastasis by synthetic and recombinant fragments of human fibronectin with functional domains.

We have investigated the antimetastatic effect of synthetic or recombinant peptides containing the functional domains of fibronectin on experimental and spontaneous lung metastases of murine tumor cells. CS1 peptide which is present within type III homology connecting segment (IIICS) as well as C‐274 (cell‐binding domain) were able to inhibit experimental lung metastasis when co‐injected intravenously (iv) with B16‐BL6 melanoma cells, while H‐271 (heparin‐binding domain) could not. In the spontaneous metastasis model, multiple iv administrations of CS1 or C‐274 after surgical excision of primary tumors caused a significant reduction of metastatic colonies in the lung. Both CS1 and C‐274 significantly inhibited cell adhesion and migration to fibronectin‐coated substrates when added freely in solution. CS1 peptide also inhibited the cell adhesion and migration to laminin‐coated substrates, but C‐274 did not. H‐271 did not have any inhibitory effect on cell adhesion or migration to either of the substrates. Similarly, CS1 inhibited tumor invasion to both Matrigel/fibronectin‐ and Matrigel/laminin‐coated filters, whereas C‐274 inhibited the invasion to only Matrigel/fibronectin‐coated filter. These results indicate that CS1 peptide of fibronectin, lacking the Arg‐Gly‐Asp‐containing domain, actively inhibits tumor metastases in spontaneous and experimental metastasis models. The use of such a peptide might offer a promising therapeutic approach for combatting or preventing cancer metastasis.

Antimetastatic effect of endogenous tumor necrosis factor induced by the treatment of recombinant interferon gamma followed by an analogue (GLA-60) to synthetic lipid A subunit.

We have investigated the effect of endogenous production of tumor necrosis factor (TNF) induced by the combination of recombinant interferon gamma (rIFN gamma) as a primer followed by GLA-60 as a trigger (rIFN gamma/GLA-60) on murine lung metastases caused by B16-BL6 melanoma. In order to examine the therapeutic effect of endogenous TNF on tumor metastasis, the ability of multiple administrations of rIFN gamma/GLA-60 to induce TNF production was also tested. The multiple administrations of rIFN gamma/GLA-60 at intervals of 2 days were effective for the induction of endogenous TNF in mice but continuous multiple administrations of them for 2-4 days were not. In tumor-bearing mice, the production of endogenous TNF by rIFN gamma/GLA-60 was less than that of normal mice, but treatment 3 days after the surgical excision of primary tumors showed the endogenous TNF production to be similar to that in normal mice. In the experimental lung metastasis model, intravenous administration of rIFN gamma followed by intravenous or intranasal administration of GLA-60 showed potent inhibition of lung metastases of B16-BL6 melanoma, whereas the reverse sequence of administration (GLA-60/rIFN gamma) or administration of a mixture of rIFN gamma and GLA-60, which cannot induce the production of TNF, caused no inhibition of lung metastases. These results indicated that the regression of tumor metastases by rIFN gamma/GLA-60 was mediated by the production of endogenous TNF in addition to the direct effects of both immunostimulants. Furthermore, the administration of rIFN gamma and GLA-60 significantly inhibited the tumor metastases in spontaneous lung metastasis model. These results may provide a promising approach for the treatment of cancer metastasis as a result of its ability to induce endogenous TNF.

ADRIAMYCIN CONTINUOUS I.V. INFUSION-HYPERFRACTIONATED RADIATION THERAPY FOR THE TREATMENT OF RECURRENT PEDIATRIC SOLID TUMORS

The prognosis of most pediatric solid tumors is poor upon development of recurrent disease. The study was designed to test the efficacy of Adriamycin (ADR) I.V. continuous infusion (CI) given simultaneously with hyperfractionated (HFT) radiation therapy (XRT) to such patients. The rationale for the study was: 1. ADR enhances XRT lethality of human cancer cells In vitro by inhibiting XRT repair process. 2. Small doses of XRT when given more than once daily may prevent tumor repopulation to a greater extent than higher doses given once daily. The study consists of ADR I.V. CI 12mg/m2/day x5 days and XRT tumor dose 100 rads twice a day at 6 hours intervals x5 days. Courses were repeated at 3-4 weeks intervals. Three children have been treated; 1 Ewing's sarcoma (ES), 1 fibrosarcoma and 1 hemangiopericytoma, all have previously received ADR 480, 60 and 460mg/m2 respectively. The patient with ES has also received 5400 rads to the primary tumor. All 3 patients achieved partial remission after 2 courses of ADR I.V. CI-HFT-XRT and complete surgical excision of primary tumor was performed in the patient with ES after the 3rd course. Two patients developed progressive disease outside the XRT field 3 and 6 months post-therapy. The 3rd patient's tumor is still under control while receiving the 3rd dose of therapy. This preliminary data suggests that the simultaneous administration of ADR I.V. CI-HFT-XRT can be an effective therapy for recurrent pediatric malignancies and should be tested in a larger number of patients.