Complete Tumor Resolution Research Articles

A Rare Case of Bilateral Non-Hodgkin’s Lymphoma of the Adrenal Gland

Bilateral Adrenal Lymphoma is a rare disease which, when it is discovered, may be associated with adrenal insufficiency. We report a case of an 81-year-old female, with no known co-morbidities, presenting with anorexia and flank pain. Initial CT imaging revealed bilateral adrenal masses measuring 6.4 x 7.4 cm on the right and 5.9 x 5.8 cm on the left with subsequent scans showing the masses to be rapidly enlarging. Aspiration biopsy revealed Non-Hodgkin’s Lymphoma, diffuse large B cell type. She underwent chemotherapy with almost complete resolution of the adrenal tumors.

Gamma Knife surgery of pediatric gliomas

While some low-grade pediatric gliomas may be cured with resection, many patients harbor tumors that cannot be completely resected safely, are difficult to access via an open surgical approach, or recur. Gamma Knife surgery may be beneficial in the treatment of these tumors. The authors reviewed a consecutive series of 24 pediatric patients treated at the authors' institution between 1989 and 2011. All patients harbored tumors that were either surgically inaccessible or had evidence of residual or recurrent growth after resection. Progression-free survival was evaluated and correlated with clinical variables. Additional outcomes evaluated were clinical outcome, imaging response, and overall survival. Between 1989 and 2011, 13 male and 11 female patients (median age 11 years, range 4-18 years) with gliomas were treated. Tumor pathology was pilocytic astrocytoma (WHO Grade I) in 15 patients (63%), WHO Grade II in 4 (17%), and WHO Grade III in 1 (4%). The tumor pathology was not confirmed in 4 patients (17%). The mean tumor volume at the time of treatment was 2.4 cm(3). Lesions were treated with a median maximum dose of 36 Gy, median of 3 isocenters, and median marginal dose of 15 Gy. The median duration of imaging follow-up was 74 months, and the median duration of clinical follow-up was 144 months. The tumors responded with a median decrease in volume of 71%. At last follow up, a decrease in tumor size of at least 50% was demonstrated in 18 patients (75%) and complete tumor resolution was achieved in 5 (21%). Progression-free survival at last follow-up was achieved in 20 patients (83%). Progression was documented in 4 patients (17%), with 3 patients requiring repeat resection and 1 patient dying. The initial tumor volume was significantly greater in patients with disease progression (mean volume 4.25 vs 2.0 cm(3), p < 0.001). Age, tumor pathology, tumor location, previous radiation, Karnofsky Performance Scale score, symptom duration, and target dosage did not differ significantly between the 2 groups. Gamma Knife surgery can provide good clinical control of residual or recurrent gliomas in pediatric patients. Worse outcomes in the present series were associated with larger tumor volumes at the time of treatment.

Effect of stimulation of natural killer cells with an anti-CD137 mAb on the efficacy of trastuzumab, cetuximab, and rituximab.

2514 Background: Antibody-dependent cell-mediated cytotoxicity (ADCC), mediated by natural killer (NK) cells, plays an important role in the efficacy of monoclonal antibodies (mAb)s. CD137 is a costimulatory molecule expressed on immune cells following activation, including NK cells. We hypothesize that as the antitumor efficacy of mAbs is due to ADCC, their activity can be enhanced by stimulation of NK cells with an anti-CD137 agonistic mAb. Methods: Upregulation of CD137 on NK cells was assessed using CD20+lymphoma, HER2+breast, and EGFR+head and neck cell lines and primary patient samples. NK cell degranulation, cytokine release and cytotoxicity were assessed by CD107a mobilization, IFN-γ secretion, and chromium release. Mechanism of synergy was explored by cell depletion in an immune competent mouse model. Xenotransplanted models were used to demonstrate anti-tumor activity and sufficiency of an innate immune response. Results: NK cells in human primary patient samples do not express CD137 at baseline, however CD137 is highly upregulated when encountering mAb-coated tumor cells. MAb-induced NK cell degranulation and cytotoxicity are enhanced by anti-CD137 agonistic mAb. In a murine lymphoma model, anti-CD137 mAb significantly enhances anti-tumor activity of anti-CD20 mAb leading to complete tumor resolution and prolonged survival. NK cell depletion completely abrogates the therapeutic effect. In seven xenotransplant models, sequential administration of rituximab, trastuzumab or cetuximab plus anti-CD137 mAb provided superior reduction in tumor burden and prolonged overall survival. In a phase 0 biomarker study, level of CD137 expression on circulating and intratumoral NK cells was influenced by disease burden, prior treatment, FcγRIII polymorphism, and time since mAb therapy. Conclusions: Our results demonstrate the synergy of anti-CD137 mAb and a tumor-targeting mAb by stimulation of mAb-activated NK cells with anti-CD137 mAb to enhance ADCC. These results support a novel, sequential antibody approach against CD20+B cell, HER2+breast, and EGFR+head and neck malignancies by targeting first the tumor and then the host immune system.

Abstract LB-138: Stimulation of natural killer cells with an anti-CD137 antibody enhances the efficacy trastuzumab, cetuximab, and rituximab in HER2-expressing breast cancer, EGFR+ head and neck cancer, and CD20+ lymphoma

Abstract Antibody-dependent cell-mediated cytotoxicity (ADCC), largely mediated by natural killer (NK) cells, is thought to play an important role in the efficacy of monoclonal antibodies (mAb)s including rituximab, an anti-CD20 mAb, trastuzumab, an anti-HER2 mAb, and cetuximab, an anti-EGFR mAb used to treat patients with B cell lymphomas, HER2-expressing breast cancer, and EGFR-expressing solid tumors. CD137 is a costimulatory molecule expressed on NK cells following activation. We hypothesize that as the antitumor efficacy of mAbs is due in part to ADCC, the anti-cancer activity of these mAbs can be enhanced with an anti-CD137 agonistic mAb. Induction of CD137 on NK cells was assessed using CD20+lymphoma, HER2+breast, and EGFR+head and neck cell lines and primary patient samples and respective mAbs. In-vitro NK cell degranulation, cytokine release and cytotoxicity were assessed by CD107a mobilization, IFN-γ secretion, and chromium release. A murine lymphoma tumor model was used to assess in-vivo synergy and mechanism was explored by T cell, NK cell, and macrophage depletion. Xenotransplanted models in nude or SCID mice with lymphoma, breast cancer, or head and neck cancer were used to demonstrate efficacy of anti-CD137 mAb and rituximab, trastuzumab or cetuximab, and sufficiency of an innate immune response. NK cells in human primary patient samples do not express CD137 at baseline, however these cells highly upregulate CD137 when encountering mAb-coated tumor cells. Monoclonal antibody-induced NK cell degranulation and cytotoxicity as measured by chromium release are enhanced by anti-CD137 agonistic mAb. In a murine lymphoma model, anti-CD137 mAb significantly enhances anti-tumor activity of anti-CD20 mAb leading to complete tumor resolution and prolonged survival. Sequential administration of anti-CD20 mAb followed by anti-CD137 mAb is required for the synergistic effect. NK cell depletion completely abrogates the therapeutic effect of anti-CD20 plus anti-CD137 mAb combination. In xenotransplant lymphoma, breast, and head and neck models, rituximab, trastuzumab or cetuximab plus anti-CD137 mAb provided superior reduction in tumor burden and prolonged overall survival. In a Phase 0 biomarker study, level of CD137 expression on circulating and intratumoral NK cells was influenced by circulating disease burden, extent of prior treatment, FcγRIII polymorphism, and time since mAb therapy. Our results demonstrate the synergy of anti-CD137 mAb and a tumor-targeting mAb (rituximab, trastuzumab, or cetuximab) by stimulation of mAb-activated NK cells with anti-CD137 mAb to enhance ADCC. These results support a novel, sequential antibody approach against CD20+B cell, HER2+breast, and EGFR+head and neck malignancies by targeting first the tumor and then the host immune system. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-138. doi:1538-7445.AM2012-LB-138

P3-14-26: The Effect of Biologic Subtype in Patients Treated with Neoadjuvant Chemotherapy: A UAB Experience.

Abstract Purpose: Previous studies have suggested that the pre treatment clinical stage drives loco-regional recurrence (LRR), distant metastasis (DM) and survival in patients treated with neoadjuvant chemotherapy. This retrospective analysis was performed to look at the effect of biologic subtype on patient outcomes. Methods: Between 1999 and 2005, 115 patients treated with neoadjuvant chemotherapy, surgery, and +/−radiation therapy at UAB were identified. Patient, tumor, and treatment characteristics were recorded. Pathologic complete response was defined as resolution of both invasive disease and DCIS in both the primary and nodal disease. Survival was measured using the Kaplan Meier statistics. Univariate and multivariate analyses of covariates associated with LRR, DM, progression-free (PFS) and overall survival (OS) were performed. Results: The mean age was 49 years, with a mean follow-up of 5.8 years. Subtype distribution was as follows: 52 luminal A, 17 luminal B, 36 triple negative, 9 Her2+ and one patient with an unknown biologic subtype. Distribution of clinical stage was as follows: 40 IIA, 34 IIB, 26 IIIA, 10 IIIB, and 5 IIIC. Tumors were down-staged following neoadjuvant therapy as follows: 18: pCR, 6: residual DCIS, 17: I, 38: IIA, 11: IIB, 13: IIIA, 5: IIIB, and 7: IIIC. Pre-treatment clinical stage did not significantly influence LRR, DM or progression free and overall survival; however, final pathologic T, N and group stage were associated with both progression free, p=0.003, 0.011, 0.005 and overall survival, p=0.02, 0.037, and 0.009. Complete resolution of tumor by mammographic or MR imaging to neoadjuvant chemotherapy, was associated with an increased overall survival, p=0.0025. Univariate analysis did not show a significant effect of biologic subtype, age, grade, use of radiation therapy or anti-hormonal therapy. Discussion: In this retrospective series, response to chemotherapy and the final pathologic stage, representing the volume of residual disease, were important predictors of survival. Further study to determine factors predictive of chemotherapy response is needed. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-26.

CyberKnife Radiosurgery for the Treatment of Intraocular and Periocular Lymphoma

To evaluate efficacy, patient tolerance, and adverse effects of CyberKnife radiosurgery for the treatment of intraocular and periocular lymphoma. Retrospective case series of 13 patients who underwent CyberKnife radiosurgery was conducted. Fourteen eyes of 13 patients were included. The tissue location of the lymphoma was orbit (7 eyes), conjunctiva (3 eyes), choroid (2 eyes), and retina (2 eyes). The lymphoma type was classified as extranodal marginal zone B-cell lymphoma in 7 eyes (50%), diffuse large B-cell lymphoma in 3 eyes (21%), follicular lymphoma in 2 eyes (14%), and benign reactive lymphoid hyperplasia in 2 eyes (14%). The mean treatment dose was 1718 centigrays (cGy) (range, 1350-2250 cGy) given over a mean of 5 days (range, 3-5 days) with a mean dose rate of 320 cGy per fraction. Complete tumor resolution without local recurrence over a mean follow-up of 23 months was documented in all cases. Radiation-associated adverse effects included mild dry eye in 2 patients and cataract in 1 patient with conjunctival lymphoma. There was no radiation retinopathy or papillopathy, and visual acuity was preserved or improved in 13 eyes and decreased in 1 eye due to the presence of cataract. CyberKnife radiosurgery is a well-tolerated technique for the treatment of intraocular and periocular lymphoma, allowing for local resolution of the lesions. An important benefit is that treatment was completed over 5 days.

Immunomodulation of NK Cells through 4-1BB (CD137) to Improve the Anti-Lymphoma Activity of Rituximab: Antibody-Based Anti-Lymphoma Synergy

AbstractAbstract 422 Background:Antibody-dependent cell-mediated cytotoxicity (ADCC), largely mediated by natural killer (NK) cells, is thought to play an important role in the efficacy of rituximab, an anti-CD20 monoclonal antibody (mAb) used to treat patients with B cell lymphomas. CD137 is a costimulatory molecule expressed on a variety of immune cells following activation, including NK cells. We hypothesized that the anti-lymphoma activity of rituximab could be enhanced by stimulation of NK cells with an anti-CD137 agonistic mAb. Methods:Rituximab induced upregulation of CD137 on NK cells was assessed using lymphoma cell lines and primary lymphoma patient samples. In-vitro NK cell degranulation and cytotoxicity were assessed by CD107a mobilization and chromium release. A murine lymphoma tumor model targeted by mouse anti-mouse CD20 mAb was used to assess in-vivo synergy of anti-CD20 and anti-CD137 mAbs. Mechanism of synergy was explored by T cell, NK cell, and macrophage depletion in the immune competent mouse model. A xenotransplant model in SCID mice with disseminated, luciferase-labeled lymphoma was used to demonstrate efficacy of anti-CD137 mAb and rituximab, and sufficiency of an innate immune response. Results:NK cells in human primary lymphoma samples do not express CD137 at baseline, however these cells highly upregulate CD137 when encountering rituximab-coated tumor B cells. Rituximab-induced NK cell degranulation and cytotoxicity as measured by CD107a mobilization (p=.006) and chromium release (p=.01) are enhanced by anti-CD137 agonistic mAb. In a murine lymphoma model, anti-CD137 mAb significantly enhances anti-tumor activity of anti-CD20 mAb leading to complete tumor resolution (p<.001) and prolonged survival (p=.048). Sequential administration of anti-CD20 mAb followed by anti-CD137 mAb (p=.027) is required for the synergistic effect. In-vivo administration of anti-CD20 mAb induces upregulation of CD137 on mouse NK cells (p=0.001), allowing subsequent targeting with anti-CD137 mAb. NK cell depletion completely abrogates the therapeutic effect of anti-CD20 plus anti-CD137 mAb combination (p<.001). In a xenotransplant disseminated lymphoma model (Figure 1A), rituximab plus anti-CD137 mAb provided superior reduction in tumor burden, as quantified by bioluminescence (p=.001; Figure 1B), and prolonged overall survival (p=.013; Figure 1C). Conclusions:Our results demonstrate the synergy of anti-CD137 mAb and rituximab by stimulation of rituximab-activated NK cells with anti-CD137 mAb to enhance ADCC. These results support a novel, sequential antibody approach against B cell malignancies by targeting first the tumor and then the host immune system. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

EUS-Guided Antitumor Therapy for Pancreatic Tumors

Endoscopic ultrasound (EUS) is a very useful modality for the diagnosis and staging of pancreatic masses. With the advent of EUS-guided fine-needle aspiration technology, this modality has made a tremendous leap from imaging modality to histologic diagnosis and therapeutic intervention. EUS offers high-resolution images of and unparalleled access to the pancreas. After locating the tip of the echoendoscope in the duodenum or stomach, several drugs or local treatment modalities can be delivered directly into the pancreas. EUS-guided ethanol lavage with/without paclitaxel injection has been tested for the treatment of cystic tumors of the pancreas, with complete resolution of cystic tumor being observed in up to 70-80% of patients. Ethanol injection is also performed for the management of solid neuroendocrine tumors of the pancreas. Various type of EUS-guided injection have also been investigated for the treatment of pancreatic cancer. An activated allogenic mixed lymphocyte culture (Cytoimplant) was injected in patients with advanced pancreatic cancer. A replication-deficient adenovirus vector carrying the tumor necrosis factor-alpha gene was also delivered intratumorally by EUS. ONYX-015 is an oncolytic attenuated adenovirus that exhibits replication preferentially in malignant cells, causing cell death, and this has also been injected into pancreatic cancers under EUS guidance. EUS-guided local ablation therapies such as radiofrequency ablation, photodynamic therapy, and brachytherapy are also under investigation. EUS-guided fine-needle injection for various solid or cystic lesions is a rapidly expanding field. This article reviews the various applications of EUS for the treatment of pancreatic tumors.

Role of neo-adjuvant chemoradiation in locally advanced rectal cancers.

To determine the radiologic downstaging and histological response after neo-adjuvant concurrent chemoradiation in locally advanced rectal cancers. Case series. Radiation Oncology department of Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, from December 2004 to November 2005. Thirty patients with histopathologically confirmed locally advanced carcinoma rectum who had not received any treatment (chemotherapy, radiotherapy or surgery) prior to presentation were enrolled. Radiation therapy was delivered with a three-field technique to a dose of 50.4 Gy over 5 weeks at the rate of 1.8 Gy/day. Two cycles of chemotherapy were given synchronously, which comprised of 5-fluorouracil 350 mg/m2 and folinic acid 20 mg/m2 continuous intravenous infusion over first five days and last five days of radiotherapy. Surgery was planned 4-6 weeks later to chemoradiation after radiologic post therapy staging. Viable specimens were identified and toxicity was observed. All patients completed treatment without modification. Radiologic downstaging was found in 56.7%, stable disease was seen in 30.0% and progressive disease was present in 13.3% of the patients. Radiologically complete resolution of tumour was not observed. Pathological complete resolution of tumour was achieved in 3.3% and near complete resolution was observed in 13.3% of the patients. In 86.6% cases, a total gross tumour resection with no macroscopic residual disease was possible. All the patients tolerated the treatment well. Neo-adjuvant chemoradiation for locally advanced rectal cancers is associated with high resectability rate and is relatively safe with acceptable morbidity which favours its use in future.

Radiofrequency Ablation Combined with KS-IL2 Immunocytokine (EMD 273066) Results in an Enhanced Antitumor Effect against Murine Colon Adenocarcinoma

Radiofrequency ablation (RFA) is a common treatment modality for surgically unresectable tumors. However, there is a high rate of both local and systemic recurrence. In this preclinical study, we sought to enhance the antitumor effect of RFA by combining it with huKS-IL2 immunocytokine [tumor-specific monoclonal antibody fused to interleukin-2 (IL2)] in mice bearing CT26-KS colon adenocarcinoma. Mice were treated with RFA, huKS-IL2 via intratumoral injection, or combination therapy. Treatment of mice bearing s.c. tumors with RFA and huKS-IL2 resulted in significantly greater tumor growth suppression and enhanced survival compared with mice treated with RFA or huKS-IL2 alone. When subtherapeutic regimens of RFA or huKS-IL2 were used, tumors progressed in all treated mice. In contrast, the combination of RFA and immunocytokine resulted in complete tumor resolution in 50% of mice. Treatment of a tumor with RFA and intratumoral huKS-IL2 also showed antitumor effects against a distant untreated tumor. Tumor-free mice after treatment with RFA and huKS-IL2 showed immunologic memory based on their ability to reject subsequent challenges of CT26-KS and the more aggressive parental CT26 tumors. Flow cytometry analysis of tumor-reactive T cells from mice with complete tumor resolution showed that treatment with RFA and huKS-IL2 resulted in a greater proportion of cytokine-producing CD4 T cells and CD8 T cells compared with mice treated with RFA or huKS-IL2 alone. These results show that the addition of huKS-IL2 to RFA significantly enhances the antitumor response in this murine model, resulting in complete tumor resolution and induction of immunologic memory.

Evaluation of dendritic cell based cancer vaccines with a huPBL-NOD/SCID/IL2r-gamma-null xenotransplant model (41.7)

Abstract Dendritic cells (DC) are antigen presenting cells that have shown great potential as cancer vaccines when tested in conventional animal models. However, relating the induction of antitumor responses in mice to the efficacy in humans has been difficult. Here-in we describe the development of a xenotransplant model to detect the capacity for a DC-based vaccine to generate human anti-tumor T cell responses in vivo. Immunodeficient NOD/SCID/IL2r-gamma-null mice allow efficient engraftment and expansion of human peripheral blood leukocytes (huPBL). Over 3 weeks, the lymphoid organs of recipient mice are reconstituted with more than 70% of the spleen cells expressing human CD45. To evaluate anti-tumor responses, mice were engrafted with huPBL, implanted with human tumor cells, and then vaccinated with autologous DC expressing tumor antigens. Spleen cells showed a normal CD4:CD8 ratio, while CD8+ cells predominated in the tumor infiltrating lymphcytes (TIL). There was a significant decrease in naïve CD45RA T cells and an increase regulatory T at the tumor site. Immunized mice showed a decrease in tumor size, an increase in tumor-specific T cells, but not complete tumor resolution. This model may allow the character of TIL and the induction of human immune responses against cancer to be more realistically evaluated in vivo. This study is funded by NIH/NIDA R01-DA03018 and by the NIH/NCI UCLA SPORE in Prostate Cancer.

Metastatic Bone Involvement of the Hallux Distal Phalanx and Cuboid in an Elderly Patient With Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma metastasis to bone is a rare occurrence in the lower extremity. There have been very few reported cases. Bone metastasis, when it occurs, usually affects the axial skeleton. This article presents a case of Waldenström macroglobulinemia, a variant of non-Hodgkin lymphoma, with metastasis to the right hallux distal phalanx and left cuboid, as well as cutaneous lesions of the right foot. The patient received radiation treatments to each involved area with complete resolution of symptoms and tumor.

Metastatic Bone Involvement of the Hallux Distal Phalanx and Cuboid in an Elderly Patient With Non-Hodgkin Lymphoma

Non-Hodgkin lymphoma metastasis to bone is a rare occurrence in the lower extremity. There have been very few reported cases. Bone metastasis, when it occurs, usually affects the axial skeleton. This article presents a case of Waldenström macroglobulinemia, a variant of non-Hodgkin lymphoma, with metastasis to the right hallux distal phalanx and left cuboid, as well as cutaneous lesions of the right foot. The patient received radiation treatments to each involved area with complete resolution of symptoms and tumor.

Treatment of recurrent vaginal melanoma with external beam radiation therapy and palladium-103 brachytherapy

Background Mucosal melanoma of the female genital tract that recurs locally after definitive surgery presents difficult challenges for salvage therapy. Methods and Materials A 71-year-old female was diagnosed with a 4.5-cm × 4.1-cm × 2.8-cm vaginal recurrence of genital tract mucosal melanoma after definitive vulvectomy, distal vaginectomy, and distal urethrectomy. She refused surgery and underwent combination external beam radiation therapy (46 Gy) and an ultrasound-guided palladium-103 brachytherapy implant (100 Gy). Results The patient experienced complete resolution of the gross tumor and was asymptomatic with a sustained response for over a year before developing metastatic disease. Conclusions Mucosal melanoma of the female genital tract is an aggressive and often fatal disease. Radical surgical excision is an option for some patients but may require pelvic exenteration and is rarely curative. In selected cases, high-dose conformal radiation therapy delivered by a combination of external beam radiation therapy and interstitial brachytherapy may be an excellent alternative, achieving local control without loss of organ function.

New treatment for cystic tumors of the pancreas: EUS-guided ethanol lavage with paclitaxel injection

Cystic tumors of the pancreas are frequently detected and encompass a wide pathologic spectrum, ranging from benign to malignant. A substantial proportion of cystic tumors cannot be histologically classified, even after extensive diagnostic evaluation, and, therefore, ultimately require surgical resection. Recently, complete resolution of cystic tumors by EUS-guided ethanol lavage was reported in a pilot study. The aim of this study was to evaluate the safety, feasibility, and response after EUS-guided ethanol lavage with paclitaxel injection (EUS-EP) for cystic tumors of the pancreas. A prospective study. A tertiary care, academic medical center, from July 2005 to November 2006. Fourteen patients who underwent EUS-EP were observed for more than 6 months. They were analyzed in terms of procedure safety, feasibility, and response. EUS-EP. To compare changes of cyst volume before and after an EUS-EP. An EUS-EP was successfully performed in all cases except one patient in whom the cyst fluid was so viscous that it could not be sufficiently aspirated. Acute pancreatitis occurred in one patient, and minor complications, including hyperamylasemia (n = 6) and vague abdominal pain (n = 1), were observed. Complete resolution of a cystic tumor was observed in 11 patients and partial resolution in two patients, and a cyst persisted in one patient. A small patient number, a short follow-up time, a single treatment arm. EUS-EP appears to be a safe, feasible, and effective method for treating cystic tumors of the pancreas. Further studies that involve larger populations and longer follow-ups are warranted.

Targeting the Effector Site with IFN-αβ-Inducing TLR Ligands Reactivates Tumor-Resident CD8 T Cell Responses to Eradicate Established Solid Tumors

Effective antitumor CD8 T cell responses may be activated by directly targeting the innate immune system within tumors. We investigated this response by injecting a range of TLR agonists into established tumors using a mouse model of malignant mesothelioma stably transduced with the hemagglutinin (HA) gene as a marker Ag (AB1-HA). Persistent delivery of the dsRNA mimetic poly(I:C) into established AB1-HA tumors resulted in complete tumor resolution in 40% of mice, with the remaining mice also showing a significant delay in tumor progression. Experiments in athymic nude mice along with CD8 depletion and IFN-alphabeta blocking studies revealed that tumor resolution required both CD8 T cells and type I IFN induction, and was associated with local changes in MHC class I expression. Surprisingly, however, tumor resolution was not associated with systemic dissemination or tumor infiltration of effector CD8 T cells. Instead, the antitumor response was critically dependent on the reactivation of tumor-resident CD8 T cell responses. These studies suggest that, once reactivated, pre-existing local CD8 T cell responses are sufficient to resolve established tumors and that in situ type I IFN is a determining factor.

The pathological response to neoadjuvant chemotherapy with FOLFOX-4 for colorectal liver metastases: a comparative study

FOLFOX-4 (folinic acid/5-fluorouracil/oxaliplatin) chemotherapy is used to treat patients with colorectal liver metastases. We aimed to assess hepatic histopathological responses to neoadjuvant FOLFOX-4 chemotherapy in patients with colorectal liver metastases. We selected all patients (n = 54) treated with FOLFOX-4 for colorectal liver metastases between June 2002 and June 2005. Only 25 underwent hepatectomy and formed the study group. Histological responses were assessed in the study group and a matched control group (n = 25) that did not receive neoadjuvant chemotherapy. The median (IQR) body mass index in the study and control groups was 24 (22-26) and 24 (23-25) kg/m(2), respectively, (P = NS). Complete histological resolution of tumour occurred in six (24%) patients in the study group. Median residual tumour cellularity was less (35 vs 70%) and fibrosis greater (50 vs 5%) in patients in the study group when compared with controls (P < 0.001). The liver surrounding the tumour was steatotic in 17 (68%) patients in the study group and five (20%) controls (P = 0.001). Hepatic sinusoidal dilatation was more pronounced in patients in the study group than in controls (P < 0.001). The response to FOLFOX-4 was associated with tumour necrosis, fibrosis and inflammation. More than two thirds of patients undergoing hepatectomy after FOLFOX-4 had steatosis despite being non-obese.

Retrospective analysis of the addition of cetuximab to induction chemotherapy (IC) with docetaxel, cisplatin, and 5-fluorouracil (TPF-C) for locally advanced squamous cell carcinoma of the head and neck (LA-HNSCC)

6072 Background: Achievement of a partial (PR) or complete (CR) tumor response at the primary site to IC has been used to predict for tumor sensitivity to definitive radiation (RT)-based treatment approaches in patients with LA-HNSCC. Three randomized trials of IC showed that TPF resulted in superior tumor response rates at the primary site in comparison to PF (TAX 323, TAX 324, and GORTEC). Based on the improved tumor response rate with the addition of cetuximab to cisplatin in metastatic HNSCC, TPF-C is a rational approach to improving tumor response rate to IC in LA-HNSCC. Methods: Between 2/06–12/06, 23 consecutive patients with LA-HNSCC were treated with IC that included TPF + cetuximab (400 mg/m2 loading dose followed by 250 mg/m2 weekly dose) for 1–3 cycles, followed by a standardized clinical assessment of tumor response at the primary site and at the regional nodes. TPF (docetaxel and cisplatin both 75 mg/m2 on day 1; 5-FU 750 mg/m2/d for 3 days) was given at every 3 week intervals. PR was defined as = 50% decrease and CR as complete resolution of tumor at the primary site. This is a retrospective analysis of the efficacy and the adverse effects (AE) of TPF-C in these patients. Results: Of 23 patients, 21 were evaluable for tumor response rate (RR). During IC, there were no deaths and grade 3–4 AE included: neutropenic fever (4), sepsis (1), and infusion reactions (4). Patients with favorable (PR or CR) tumor response to IC were treated with definitive RT-based therapy; whereas others were treated with surgery first. Conclusions: In this population of patients with LA-HNSCC with mostly (74%) T3 and T4 primary tumors, the tumor RR at the primary site to TPF-C was 71%. The addition of cetuximab to TPF was feasible. No significant financial relationships to disclose. [Table: see text]

Flt3-L gene therapy enhances immunocytokine-mediated antitumor effects and induces long-term memory.

Therapeutic treatment with hu14.18-IL-2 immunocytokine (IC) or Flt3-L (FL) protein is initially effective at resolving established intradermal NXS2 neuroblastoma tumors in mice. However, many treated animals develop recurrent disease. We previously found that tumors recurring following natural killer (NK) mediated IC treatment show augmented MHC class I expression, while the tumors that recurred following T cell dependent Flt3-L treatment exhibited decreased MHC class I expression. We hypothesized that this divergent MHC modulation on recurrent tumors was due to therapy-specific immunoediting. We further postulated that combining IC and Flt3-L treatments might decrease the likelihood of recurrent disease by preventing MHC modulation as a mechanism for immune escape. We now report that combinatorial treatment of FL plus hu14.18-IL-2 IC provides greater antitumor benefit than treatment with either alone, suppressing development of recurrent disease. We administered FL by gene therapy using a clinically relevant approach: hydrodynamic limb vein (HLV) delivery of DNA for transgene expression by myofibers. Delivery of FL DNA by HLV injection in mice resulted in systemic expression of >10 ng/ml of FL in blood at day 3, and promoted up to a fourfold and tenfold increase in splenic NK and dendritic cells (DCs), respectively. Furthermore, the combination of FL gene therapy plus suboptimal IC treatment induced a greater expansion in the absolute number of splenic NK and DCs than achieved by individual component treatments. Mice that received combined FL gene therapy plus IC exhibited complete and durable resolution of established NXS2 tumors, and demonstrated protection from subsequent rechallenge with NXS2 tumor.

Use of sirolimus for Epstein-Barr virus-positive smooth-muscle tumour

A 55-year-old Chinese woman was diagnosed in 1987 with end-stage renal failure secondary to chronic glomerulonephritis. She was given sirolimus and had complete remission of the disease. She received a cadaveric kidney transplantation in May, 1990. A routine abdominal ultrasound done in September, 2003, showed a liver nodule in each of segments six, seven, and eight. The largest nodule, in segment six, measured 1·9 cm (fi gure 1); those in segments seven and eight measured 1·1 cm each. At the time of this initial ultrasound, the patient was asymptomatic and her immunosuppresion regimen consisted of 75 mg ciclosporin twice a day, 8 mg prednisolone once a day, and 500 mg mycophenolate mofetil twice a day. She subsequently underwent an ultrasound-guided biopsy of the tumour in segment six in November, 2003. Pathological examination of the biopsy sample showed fascicles of elongated and rounded cells with scattered lymphocytes (fi gure 2). Histological analysis showed spindle-cell proliferation with nuclei staining positive for: Epstein-Barr virus (EBV)-encoded RNA (fi gure 2), which is characteristic of an EBV-associated smooth-muscle tumour; smoothmuscle actin, and Epstein-Barr virus nuclear antigen 2 (EBNA2). Total mammalian target of rapamycin (mTOR) and total protein kinase B (AKT) showed moderate staining for at least 60% of cells (fi gure 2). AKT phosphorylated at serine 473 was also positive, but phosphorylated mTOR (residue serine 2448) intensity was weak. EBV receptor CD21, proto-oncogene BCL2, and EBV protein latent membrane protein were negative, and Ki-67 expression (proliferating index) was also low. These fi ndings are consistent with other reports of EBV-positive smooth muscle tumour after organ transplantation. Because of a previous report of a poor response to chemotherapy in EBV-postive smooth-muscle tumour, we did not give her cytotoxic chemotherapy. To induce an immune-mediated host response against the tumour, we reduced her immunosuppression regimen to 60 mg ciclosporin twice a day and 7 mg prednisolone once a day, with complete withdrawal of mycophenolate mofetil. Despite a reduction in immunosuppression, a follow-up ultrasound in December, 2003, showed that the tumour in segment six had increased to 2·3 cm (fi gure 1). Because of the tumour progression and concomitant ciclosporin-induced arteriopathy detected on allograft biopsy, ciclosporin was gradually tapered off from March to April, 2004. She was simultaneously started on sirolimus in March, 2004. After a loading dose of 10 mg sirolimus, she received sirolimus once a day; sirolimus doses were titrated to a trough sirolimus concentration of 500–12 000 ng/L, attaining a fi nal maintenance dose of 2 mg once a day starting in May, 2004. An abdominal ultrasound in April, 2004, showed resolution of the lesions in segments seven and eight, with the lesion in segment six measuring 1·5 cm. Two subsequent ultrasound scans in August, 2004 (fi gure 1) and March, 2005, showed complete resolution of the nodule in segment six. An MRI scan of the liver in September, 2005, confi rmed sustained complete resolution of all lesions. Thus, complete tumour resolution was achieved within 5 months of sirolimus treatment and was sustained for more than 13 months, with no adverse eff ects from this drug. Lancet Oncol 2006; 7: 955–57