Large Tumor Burden Research Articles

Cryosurgical ablation of hepatic colorectal metastases

Hepatic resection is the treatment of choice for primary and secondary hepatic tumors but only 15-25% of patients with hepatic colorectal metastases are eligible for a curative hepatic resection. Cryosurgical ablation (CSA) is employed when curative resection of metastases cannot be obtained. Sixty-four patients (35 males, 29 females, mean age 58.8 years, range 30-79 years) with hepatic colorectal metastases underwent CSA, under laparoscopic control (15 cases) or with open surgery (49 cases), with subsequent close follow-up. Intraoperative bleeding occurred in 32 out of 49 patients in the open group and only in 2 patients in the laparoscopic group. Minor morbidity that resolved with conservative treatment was 54.8% in the open group and 53.3% in the laparoscopic group. Major morbidity occurred in 11 cases (26.2%) in the open group and in 1 case (6.7%) in the laparoscopic group. Mortality occurred in two patients, both in the open group, from renal insufficiency in one case and from liver failure in the other case. Mean hospital stay was 16.7 days in the open group (range 8-72 days) and 10.6 days in the laparoscopic group (range 3-18 days). No patient was lost to follow-up. At a mean follow-up of 87.1 months (range 52.2-125.2 months), selected patients undergoing laparoscopic CSA had an overall survival rate of 66.7% (10 patients), with 30% of patients (3) who are disease-free. Median survival was 94.2 months. Recurrence was observed in seven patients. None of the intrahepatic recurrences was at the cryoablation site. In the open group, median survival was 22.9 months with a survival rate of 30.9% (13 patients) at a mean follow-up of 39.3 months (range 1.9-124.5 months); 9 patients (19.1%) are disease-free. In selected patients, laparoscopic CSA is associated with survival rates which are similar to those after hepatic resection. In patients with a larger tumor burden, CSA offers a curative treatment to patients with otherwise a dismal prognosis and it improves survival as compared to patients receiving chemotherapy alone. However, the procedure is associated with substantial morbidity, particularly bleeding, and therefore careful patient selection is recommended.

DKK1-Specific Cytotoxic T Lymphocytes Are Potent Effector Cells for the Treatment of Multiple Myeloma in SCID-hu Model.

Dickkopf-1 (DKK1), a secreted protein and Wnt signaling pathway inhibitor, is highly expressed by the tumor cells of most multiple myeloma (MM) patients and contributes to osteolytic bone disease by inhibiting the differentiation of osteoblasts. DKK1 has been targeted as a myeloma-associated antigen by immunotherapeutical approaches based on DKK1-directed monoclonal antibodies and DKK1-specific cytolytic T lymphocytes (CTLs). The present study was conducted to develop a treatment strategy through adoptive transfer of DKK1-specific CTLs in a SCID-hu system. Using DKK1 peptide-pulsed dendritic cells (DCs), we successfully generated DKK1-specific CTL lines and clones from HLA-A2+ MM patients in vitro. These CTLs not only had cytolytic activity against DKK1 peptide-pulsed T2 cells, but also significantly lysed autologous myeloma tumor cells, HLA-A2+ and DKK1+ MM cell lines U266 and IM-9, and primary tumor cells in vitro. No killing was observed against HLA-A2+ normal lymphocytes, including B cells and HLA-A2+ DKK1- XG1 or HLA-A2- myeloma cell lines or primary myeloma cells from patients. To determine the in vivo antitumor activity, SCID-hu mice were engrafted with primary MM cells expressing high levels of DKK1 from patients and treated with DKK1-specific CTLs after one month of tumor injection. Control mice were treated with naïve CD8+ T cells or PBS alone. All mice were examined by X-ray, tumor burden was measured according to levels of circulating human IgG, and survival rates were determined. All mice established human myeloma within one month after tumor inoculation, at which time the level of circulating human IgG was greater than 600 ng/ml in mouse serum. After another 3 weeks, the level of circulating human IgG was greater than 2,500 ng/ml in the serum of all control mice, while only 40% mice treated with DKK1-specific CTLs had high levels of circulating human IgG. X-ray examination showed that osteolytic bone disease and a large tumor burden were found in all control mice, while the established tumor was eradicated in 60% mice treated with DKK1-specific CTLs. Results of immunofluorescence studies showed that only tumor-reactive DKK1-specific CD8+ T cells were able to infiltrate into the tumor and mediate apoptosis in tumor cells. All control mice succumbed to myeloma within one month of establishment of the myeloma, while 9 out of 15 mice treated with DKK1-specific CTLs were macroscopically disease-free at the end of the experiment. These results suggest that DKK1-specific CTLs are able to eradicate established patient-derived primary myeloma in the host and that adoptive transfer of DKK1-specific CTLs may be used for myeloma therapy.

Roles of Idiotype-Specific T Cells in Myeloma Cell Growth and Survival: Th1 and CTL Cells Are Tumoricidal While Th2 Cells Promote Tumor Growth.

Despite advances in therapy for multiple myeloma (MM), it remains an incurable malignancy. Therefore, immunotherapy may be an option for new treatments to stabilize or even eradicate minimal residual tumors achieved after high-dose chemotherapy supported by autologous stem cell transplantations. Idiotype protein (Id), secreted by myeloma cells, is a tumor-specific antigen, and Id-based immunotherapy has been explored in patients with MM and other B-cell tumors for inducing and/or enhancing Id-specific immune responses that could control the tumor cells. Although previous studies have demonstrated that Id-specific CD8+ cytotoxic T lymphocytes (CTLs) are able to lyse myeloma cells, it is unclear whether other types of Id-specific T cells, such as CD4+ type-1 (Th1) and type-2 helper (Th2) cells, are also able to suppress or kill myeloma tumor cells. As Id-based immunotherapy may induce the responses by all of these T-cell subsets, it is important to understand the functions of these T cells in the context of tumor cells. In this study, we used the 5TGM1 myeloma murine model to generate Id-specific T-cell subsets. Mice were immunized with mature dendritic cells pulsed with Id conjugated with KLH. Using limiting dilution assay, we obtained and identified T-cell clones of different subsets based on surface expression of CD4+ or CD8+ molecules and secretion of IFN-γ or IL-4 in response to Id protein. CTL, Th1, and Th2 T-cell clones were selected, expanded, and subjected to functional tests. The standard 51Cr release and Annexin-V-binding assays were used to examine the cytotoxic activity of these T cells. CTL and Th1 but not Th2 cells specifically lysed 5TGM1 myeloma cells and Id-pulsed but not unpulsed DCs. We examined the suppressive activity of the T-cell clones against myeloma cells by measuring 3H-thymidine incorporation and Id protein secretion. 5TGM1 myeloma cells cultured with irradiated CTL or Th1 cells displayed significantly lower growth rate and secretion of Id protein, while 5TGM1 myeloma cells cultured with irradiated Th2 showed increased proliferation and production of Id protein compared with the tumor cells cultured with irradiated, irrelevant T cells. The in vivo function of these T cells on the tumor cells was also examined in the mouse model. After adoptive transfer of the T cells into 5TGM1 tumor-bearing C57BL/KaLwRij mice, 80% and 60% of mice that received CTL or Th1 cells respectively survived without further increase in serum Id proteins. In contrast, all mice that received PBS or normal splenocytes as controls, or Id-specific Th2 cells developed myeloma with a drastic increase in serum Id proteins. Compared with controls, mice that received Th2 cells had larger tumor burdens and shorter survival time. Thus, these results demonstrate that Id-specific CTL and Th1 but not Th2 responses are beneficial to patients receiving Id-based immunotherapy. Further studies are needed to develop novel strategies to induce only Th1 and CTL responses following Id vaccination.

Percutaneous Nephrostomy in Patients with Tumors of Advanced Stage: Treatment Dilemmas and Impact on Clinical Course and Quality of Life

The purpose of this study was to evaluate the outcome, in respect to safety, survival, and quality of life (QoL), after performance of percutaneous nephrostomy in patients with obstructive nephropathy caused by various types of advanced malignancy. A cohort of 270 patients with established nephropathy because of advanced pelvic or nonpelvic tumors was evaluated. A decision to obtain percutaneous access was made; primary stenting had either failed or was not feasible because of complicated anatomy. Patients were divided in equal groups by type of malignancy (54 patients each). In addition, each malignancy group was further divided in two equal subgroups by tumor burden (27 patients each). Correlations were made with respect to renal function outcome, overall survival after the procedure, and QoL differences both before and after the procedure. No serious complications, such as severe bleeding or sepsis, were experienced because of the procedure. Statistical analysis showed no significant differences in survival among patients with different types of cancer. Only patients with prostate (P < 0.0365) and colorectal (P < 0.0307) cancer with lower tumor burden had significantly longer survival when compared with patients with large tumor burden. Regarding QoL scores, only patients with prostate cancer in the subgroup with low tumor burden demonstrated a positive statistically significant difference (P < 0.001). Despite the fact that percutaneous nephrostomy has shown good safety characteristics and beneficial impact on renal function, only patients with specific cancers most likely to respond to ongoing palliative therapy or with cancers that progress slowly by nature may statistically benefit from the procedure. This questions the universal application of this procedure for all types and stages of advanced malignancy.

A novel proteoliposomal vaccine induces antitumor immunity against follicular lymphoma

AbstractClinical studies suggest that treatment with vaccines comprised of idiotype protein may be associated with improved clinical outcome in follicular lymphoma patients. The time-consuming process required to generate patient-specific vaccines is a major limitation, however. Here we report results of a pilot clinical trial with a novel autologous, tumor-derived proteoliposome vaccine formulation that could be rapidly produced within a single day. Vaccination was safe, induced autologous tumor-specific type 1 cytokine responses in 5 out of 10 follicular lymphoma patients, and was associated with induction of a sustained complete response in one patient. Other patients had large tumor burdens and progressed after a median duration of 8 months. These results suggest that further testing of this vaccine formulation, particularly in the setting of minimal disease, is warranted. Furthermore, the proteoliposome formulation may provide a model for vaccine development for other human cancers, for which tumor-associated antigens need not be defined.

105: The role of CD40 in the development of tumor-specific T regulatory cells and its potential use in immune therapy for cancer

Introduction: CD40/CD40L engagement regulates the function of both antigen presenting cells and T cells. It has been shown that agonistic anti-CD40 can reverse immune tolerance. However, the underlying mechanism is not well characterized. In previous studies, we found that immune suppression/tolerance was associated with the accumulation of myeloid suppressor cells (MSCs) and an increase in the number of T regulatory cells (Tregs) in mice with large tumor burdens. We also found that MSC induced the development of Foxp3+ T Tregs that are anergic and suppressive in tumor-bearing mice.

Differences in characteristics of patients with and without known risk factors for hepatocellular carcinoma in the United States

To examine the clinical characteristics of a subgroup of patients with hepatocellular carcinoma (HCC) and compare them to those with known risk factors. We used the HCC database of 306 patients seen at our institution from January 1, 1995 to December 31, 2001. Of the 306 patients, 63 (20%, group 1) had no known risk factors (hepatitis C virus, hepatitis B virus, alcohol, hemochromatosis or cirrhosis from any cause) and 243 (group 2) had one or more risk factors. The median age was similar in both groups, but there were disproportionate numbers of younger (< 30 years old), older (> 80 years) patients, women (33% vs 18%), and Caucasians (81% vs 52%) in group 1 as compared to group 2. There were fewer Asians (2% vs 11%) and African Americans (13% vs 27%) in group 1. Abdominal pain (70% vs 37%) was more common while gastrointestinal bleeding (0% vs 11%) and ascites (4% vs 17%) were less common in group 1 compared to group 2. Group 1 had larger tumor burden (median size 9.4 cm vs 5.7 cm) at the time of presentation, but there were no differences in the site (right, left or bilateral lesions), or number of tumors between the two groups. HCC patients without identifiable risk factors have different characteristics and clinical presentation compared to those with known risk factors. Absence of cirrhosis and larger tumor burden may explain the differences in the presenting symptoms.

Orthotopic liver or multivisceral transplantation as treatment of metastatic neuroendocrine tumors

Liver transplantation can be a therapeutic option for individual patients with neuroendocrine tumors metastatic only to the liver. In this consecutive series of 15 patients (5 multivisceral and 10 orthotopic liver transplantations) with well-differentiated carcinoids, or endocrine pancreatic tumors, we allowed higher proliferation rate (Ki67 <10%), large tumor burden, and higher age than previous studies. Liver transplantation offered good relief of symptoms, long disease-free intervals, and potential cure in individual patients. The survival of grafts and patients compared well with transplantation for benign disease. The overall 5-year survival was 90%. The recurrence-free survival of both multivisceral and liver transplantation related to the time after transplantation (about 20% at 5 years) despite inclusion of patients with higher risk. In conclusion, the critical prognosticators for long-term outcome still remain to be defined. The experience with multivisceral transplantation for patients with endocrine tumors of the pancreatic head is still limited.

Accelerated hyperfractionated radiotherapy and concomitant chemotherapy in small cell lung cancer limited-disease. Dose response, feasibility and outcome for patients treated in western Sweden, 1998–2004.

Addition of thoracic radiation therapy (TRT) to chemotherapy (CHT) can increase overall survival in patients with small cell lung cancer limited-disease (SCLC-LD). Accelerated fractionation and early concurrent platinum-based CHT, in combination with prophylactic cranial irradiation, represent up-front treatment for this group of patients. Optimised and tailored local and systemic treatment is important. These concepts were applied when a new regional treatment programme was designed at Sahlgrenska University Hospital in 1997. The planned treatment consisted of six courses of CHT (carboplatin/etoposide)+TRT±prophylactic cranial irradiation (PCI). Standard TRT was prescribed as 1.5 Gy BID to a total of 60 Gy during 4 weeks, starting concomitantly with the second or third course of CHT. However, patients with large tumour burdens, poor general condition and/or poor lung function received 45 Gy, 1.5 Gy BID, during 3 weeks. PCI in 15 fractions to a total dose of 30 Gy was administered to all patients with complete remission (CR) and “good” partial remission (PR) at response evaluation.Eighty consecutive patients were treated between January 1998 and December 2004. Forty-six patients were given 60 Gy and 34 patients 45 Gy. Acute toxicity occurred as esophagitis grade III (RTOG/EORTC) in 16% and as pneumonitis grade I–II in10%. There were no differences in toxicity between the two groups. Three- and five-year overall survival was 25% and 16%, respectively. Median survival was 20.8 months with no significant difference between the two groups. In conclusion, TRT with a total dose of 60 or 45 Gy is feasible with comparable toxicity and no difference in local control or survival. Distant metastasis is the main cause of death in this disease; the future challenge is thus further improvement of the systemic therapy combined with optimised local TRT.

Dramatic Reduction in Tumour Size in Hepatocellular Carcinoma Patients on Thalidomide Therapy

A 73-year-old man presented with abdominal bloating. His past medical history was significant for peptic ulcer disease with partial gastrectomy, hypertension and a remote smoking history. Investigations included contrast-enhanced computed tomography of the abdomen, which revealed innumerable hypervascular lesions, with early enhancement in the arterial phase. These were larger and more frequent in the right lobe of the liver, although they were also present in the left lobe. Most lesions measured 1.0 cm to 2.0 cm in diameter but there was a dominant lesion measuring 7.0 cm × 4.1 cm (Figure 1) in segments 5 and 8 of the right hepatic lobe. No extrahepatic or nodal metastases were identified. Serum alpha-fetoprotein level was 74.8 μg/L (normal level is less than 9 μg/L). Core biopsy of the liver confirmed multifocal grade II hepatocellular carcinoma. Figure 1) Computed tomography scan of the abdomen revealing multifocal, enhancing lesions including a dominant lesion in the right lobe of the liver After having discussed the therapeutic alternatives with the patient, it was concluded that a trial of thalidomide 100 mg once daily, be used. This was obtained through a Health Canada special access program at a cost of $26.35 per 50 mg capsule and was continued for one month. Figure 2 shows the post-treatment computed tomography demonstrating that the dominant lesion was no longer hypervascular and was hypoattenuating, consistent with internal necrosis. All the other lesions also appeared necrotic. The patient developed recurrence at the site of the dominant lesion and despite another course of thalidomide, he succumbed to his disease 17 months after diagnosis. Figure 2) Repeat computed tomography scan of the abdomen after one month of therapy with thalidomide. The dominant tumour and the smaller nodules are now hypoattenuating, consistent with necrosis For patients with advanced, multifocal hepatocellular carcinoma, there are no attractive treatment options (1). Tamoxifen has been best studied, but a meta-analysis (2) of seven randomized, controlled trials failed to show either tumour shrinkage or a survival benefit. Octreotide has shown conflicting results in smaller studies and thus, further study is required (3). Similar comments apply to the use of androgens. Chemoembolization has been used as a palliative therapy; however, our patient’s large tumour burden precluded this procedure. There are accumulating data to suggest that antiangiogenic agents may lead to tumour regression in advanced, unresectable hepatocellular carcinoma. The underlying mechanism of action remains to be clearly defined, although data suggests that thalidomide-induced inhibition of basic fibroblast growth factor and vascular endothelial growth factor inhibits endothelial cellular proliferation and microvascular formation (4,5). A small case series (6) in patients with advanced hepatocellular carcinoma treated with low-dose thalidomide (200 mg/day to 600 mg/day) had significant reduction in alpha-fetoprotein levels, tumour shrinkage and improved median survival (62.4 weeks, 95% CI 31.2 to 93.6 weeks in responders versus 18.7 weeks, 95% CI 11.8 to 25.6 weeks in the entire group that received thalidomide). The results of a phase II clinical trial (7) involving 32 patients found that at doses of 1000 mg/day, there was a 3% minor response rate, 3% partial response rate and a 31% stable disease rate, while 63% had disease progression. The overall median survival was 6.8 months. Thalidomide is a relatively simple therapy that the patient can self-administer. The most common adverse effects include drowsiness, constipation, skin rash and peripheral neuropathy. Although preliminary studies are encouraging, further prospective trials are warranted to evaluate thalidomide in the treatment of advanced hepatocellular carcinoma.

Efficacy of a novel histone deacetylase inhibitor in murine models of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, yet effective therapeutic options for advanced HCC are limited. This study was aimed at assessing the antitumor effect of a novel phenylbutyrate-derived histone deacetylase (HDAC) inhibitor, OSU-HDAC42, vis-à-vis suberoylanilide hydroxamic acid (SAHA), in in vitro and in vivo models of human HCC. OSU-HDAC42 was several times more potent than SAHA in suppressing the viability of PLC5, Huh7, and Hep3B cells with submicromolar median inhibitory concentration (IC(50)) values. With respect to SAHA, OSU-HDAC42 exhibited greater apoptogenic potency, which was associated with reduced levels of the apoptotic regulators phosphorylated Akt B-cell lymphoma-xL, survivin, cellular inhibitor of apoptosis protein 1, and cellular inhibitor of apoptosis protein 2. The in vivo efficacy of OSU-HDAC42 versus SAHA was assessed in orthotopic and subcutaneous xenograft tumor models in athymic nude mice. Daily oral treatments with OSU-HDAC42 and SAHA, both at 25 mg/kg, suppressed the growth of orthotopic PLC5 tumor xenografts by 91% and 66%, respectively, and of established subcutaneous PLC5 tumor xenografts by 85% and 56%, respectively. This differential tumor suppression correlated with the modulation of intratumoral biomarkers associated with HDAC inhibition and apoptosis regulation. Moreover, the oral administration of OSU-HDAC42 at 50 mg/kg every other day markedly suppressed ectopic tumor growth in mice bearing large tumor burdens (500 mm(3)) at the start of treatment. OSU-HDAC42 is a potent, orally bioavailable inhibitor of HDAC with a broad spectrum of antitumor activity that includes targets regulating multiple aspects of cancer cell survival. These results suggest that OSU-HDAC42 has clinical value in therapeutic strategies for HCC.

Tumour immunity and T cell memory are induced by low dose inoculation with a non-replicating adenovirus encoding TAP1

Despite continued progress in understanding the pathophysiology of tumours, curative therapeutic options are still lacking for the metastatic form of the disease. One approach that has gathered considerable interest is the creation of therapeutic vaccines using genetically engineered non-replicating viruses as vehicles to revive immunosurveillance mechanisms that may eradicate residual tumour cells. A perceived problem with this approach is that the number of non-replicating viruses used as a vaccine inoculum does not remotely approximate the total number of cells in the body, nor even the number of tumour cells in the case of large tumour burden or metastasis. Here, we addressed the hypothesis that a limited amount of inoculum (1 × 10 8 PFU) of recombinant non-replicating adenovirus encoding human TAP1 (AdhTAP1) can induce protective immunity against 1.5 × 10 5 TAP-deficient, metastatic melanoma cells transplanted into a normal mouse (total of ∼1 × 10 11 body cells). We show that efficacious anti-tumour cytolytic T cell responses are indeed induced by injecting melanoma-bearing animals with small numbers of recombinant viruses, resulting in increases in tumour-infiltrating dendritic cells, enhanced memory T cell subpopulations and, most importantly, in increased animal survival. This novel approach uses a limited input inoculum relative to the tumour cell mass, and thus achieves an efficacious outcome that has so far eluded other vaccine, immunotherapeutic or gene therapeutic strategies where there is a requisite for the majority of tumour cells to be transduced for beneficial outcome to be achieved.

90Y-Zevalin® (90Y-Ibritumomab Tiuxetan) Radioimmunotherapy (RIT) Consolidation of FCM Induction Chemotherapy in Mantle Cell Lymphoma (MCL) Patients: Results from the PLRG upon Completed Enrollment.

Background: The 5-yr survival rate is <20% for MCL. Standard chemotherapy for MCL includes fludarabine, cyclophosphamide, and mitoxantrone (FCM). Adding rituximab (R) to FCM increases the overall response rate (ORR) from 46% to 58%. MCL patients (pts) with large tumor burdens and no initial cytoreduction have a limited response to conventional non-myeloablative RIT.Aims: The Polish Lymphoma Research Group Trial (PLRG MCL1) assessed whether 90Y-Zevalin (Z) could consolidate the response achieved from FCM ± R and improve ORRs and time to progression (TTP).Methods: Thirty MCL pts (stage III–IV) not suitable for SCTs were enrolled in 8 PLRG centers: 13 pts were newly diagnosed, 7 pts had a PR after first-line therapy, and 10 pts were in first relapse. Tumor burden was reduced by induction therapy with 3–6 cycles of FCM ± R (375 mg/m2) in all pts and staged after the third and subsequent cycles to assess tumor regression. Pts were in CR (no palpable lymph nodes or measurable masses on CT) or PR (<25% bone marrow [BM] infiltration, <30 mm lymph node diameter, <12 cm spleen diameter, no massive extranodular involvement). All CR and PR pts with PMNs >1500/mL, PLTs >100,000/mL, and no BM hypoplasia received Z consolidation, starting with 2 doses of 250 mg/m2 R on days 1 and 8, followed by Z (0.3 or 0.4 mCi/kg, based on initial PLT count; maximum dose 32 mCi). ORR (CR + PR) and hematologic toxicity were determined. Response was monitored at 6 wk, 3 mo, and 3-mo intervals for up to 2 yr to assess TTP.Results: To date, 29 pts were evaluated. Of the 13 newly diagnosed pts 2 were in CR after completing FCM and 10 achieved CR after Z consolidation. Five of the 7 pts treated at first PR achieved a CR after Z and 2 pts achieved a PR. For the 10 pts treated at first relapse, 5 shifted from a PR after FCM to a CR after Z, 1 shifted from a CRu to a CR, and 3 pts achieved a further PR after Z. However, 5 of these 10 pts relapsed and 1 died due to hemorrhagic stroke. Of the 17 pts who shifted from PR to CR after Z, 13 continue in CR 8–20 mo after Z and 3 continue in CR 1–4 mo after Z. Overall, 19 of 20 pts treated at diagnosis or first PR are alive. Responses were accompanied by neutro- and thrombocytopenias 4–5 wk after Z, lasting 3–21 wk. To date, 7 pts required G-CSF (mean 21.3 doses; range 5–60), and 14 pts received red blood cell (mean 5.1 units; range 1–18) and/or PLT (mean 4.2 units; range 1–24) transfusions. No pts developed life-threatening infections. Hematologic toxicity was less severe in pts who had received only 3 FCM cycles, compared with patients requiring 5–6 FCM cycles.Conclusions: Following Z consolidation, 22 of 29 pts achieved a CR and 17 of these 22 shifted from a PR after FCM ± R to a CR. Therefore, Z consolidation is a feasible approach for MCL patients; it might have curative potential for pts treated at diagnosis or at first PR and may afford palliation for relapsed cases. Hematologic toxicity from FCM-Z is significant, but manageable, and correlates with the number of FCM cycles. Survival with FCM-Z seems superior to that reported for R-CHOP×4-Z. FCM-Z may be the preferred therapeutic approach.

Utility of Computed Tomography and Magnetic Resonance Imaging Staging Before Completion Lymphadenectomy in Sentinel Lymph Node–Positive Melanoma

TO THE EDITOR: In their excellent study, Aloia et al have confirmed our results that modern computed tomography and magnetic resonance imaging do not detect distant metastases in patients with melanoma metastatic to sentinel lymph nodes. With the addition of their 314 patients to the 185 already reported, the detectable distant metastasis rate in stage III melanoma patients at the time of selective sentinel lymph node dissection (SLND) can be more accurately estimated at approximately 1.2% (range, 0.5% to 1.9%). Furthermore, because Aloia et al had several patients with distant metastases, the risk factors for detectable distant metastasis within 3 months of SLND have been further refined to include patients with very thick ( 3.5 mm) ulcerated melanomas with large tumor burdens metastatic to regional lymph node basins. Conversely, these data should not be interpreted in a way that results in tumors that are thick or ulcerated or have high regional tumor burden being classified as needing further imaging via computed tomography or magnetic resonance imaging. False-positive rates of 12% to 14% make this a potentially dangerous treatment protocol (for example, although ulceration was shown to be an independent risk factor for distant metastasis; P .018; 107 of 112; 96%; ulcerated melanomas were negative for distant metastasis). What would be particularly interesting is to know whether or not any of the five patients with distant metastases were symptomatic. In our original study, only asymptomatic patients received SLND. However, when the history of the one patient with true distant metastasis was reviewed, he had developed constitutional symptoms after initial diagnosis but before SLND. If in retrospect these patients were actually symptomatic, a valuable clue would be added to the ones already brought forth by Aloia et al, aiding the discrimination of those patients with stage III disease who do need imaging for staging from the majority who do not.

Allogeneic stem cell transplantation for patients with metastatic renal cell carcinoma

Allogeneic stem cell transplantation and donor lymphocyte infusions are currently under clinical investigation as an innovative therapeutic option for patients with metastatic renal cell carcinoma. A variety of trials have proven the clinical efficacy of allogeneic stem cell transplantation using reduced-intensity conditioning protocols and donor lymphocyte infusions, as demonstrated by the induction of objective remissions in metastatic renal cell carcinoma patients. However, despite clinical remissions, reduced-intensity conditioning protocols and donor lymphocyte infusions were associated with a high treatment-related mortality rate of approximately 17%. The disproportion between clinical efficacy and treatment-related mortality may mainly be caused by the selection of patients that had often been heavily pretreated, with a large tumor burden and rapidly progressing tumors. The improvement of efficacy with the preservation of a powerful graft-versus-tumor effect while reducing the toxicity, is the major experimental and clinical challenge of allogeneic stem cell transplantation in the treatment of metastatic renal cancer and other solid tumors. Recently, there has been a revolutionary development of molecular-targeted agents in metastatic renal cancer. These inhibitors of angiogenesis and signal-transduction pathways have demonstrated clinical efficacy and significant survival prolongation in the first- and second-line settings, while causing moderate toxicity. Some of these agents have already been approved by the US FDA and will probably replace standard cytokines, such as interferon-α2 and interleukin-2, in metastatic renal cancer. In the context of these innovative clinical developments, allogeneic stem cell transplantation clearly has to be regarded an investigational clinical treatment approach. Therefore, patients should only be treated at centers that are experienced in clinical trials, and patient selection remains a critical factor for a successful transplant procedure.

Tumor Lysis Syndrome Associated With Reduced Immunosuppression in a Lung Transplant Recipient

Tumor lysis syndrome usually occurs after Initiation of chemotherapy or radiation therapy in cancer patients with a moderate to high tumor burden. To our knowledge, the occurrence of this syndrome after discontinuation or reduction of an immunosuppressive regimen has not been reported in the literature. We describe a patient who had undergone lung transplantation and who was receiving immunosuppression and experienced an episode of acute pancreatitis. During the course of the work-up, the patient was found to have a B-cell lymphoma (posttransplantation lymphoproliferative disease). His tacrolimus dosage was decreased, and azathioprine was discontinued. The patient subsequently developed tumor lysis syndrome. Other than the decrease in immunosuppression, we found no other factor that could have accounted for this syndrome.

Tumor Lysis Syndrome Induced by Dexamethasone

Tumor Lysis Syndrome Induced by Dexamethasone

Ethnic distribution of estrogen receptor-α polymorphism is associated with a higher prevalence of uterine leiomyomas in black Americans

To investigate whether polymorphisms in the estrogen receptor alpha (ERalpha) gene are associated with an increased risk of uterine leiomyomas (ULMs). Genomic DNA was isolated from normal myometrium samples collected at the time of the hysterectomy. Volunteers in an academic research environment. One hundred ninety-eight women with surgically confirmed ULMs and 229 matched controls with nonfibroid uteri. Hysterectomy samples were collected from volunteers. The two PvuII and XbaI intronic polymorphisms in the ERalpha gene using polymerase chain reaction and restriction fragment length polymorphism. The ERalpha PP genotype was associated with a significantly increased risk of ULM in black and white women, but not in Hispanic women. Women with the ERalpha PP genotype were 6.42 times (confidence limits 2.04-20.16) more likely to have ULMs than other genotypes. The ERalpha PP genotype was also significantly associated with larger tumor burden (>400 g). The overall prevalence of the PP genotype was significantly higher in black women (35%) than white (13%) or Hispanic (16%) women. Myometrial cell lines expressing the PP genotype exhibited enhanced proliferative response to estrogen in vitro compared with their pp counterparts. The ERalpha PP genotype is a genetic risk factor for ULM development among surgically treated women. The higher prevalence of this genotype in blacks might explain the increased occurrence of this tumor among black women.

Single-Dose Rasburicase 6 mg in the Management of Tumor Lysis Syndrome in Adults

Rasburicase is currently approved at a dosage of 0.15-0.2 mg/kg once/day for 5 days in pediatric patients with cancer to lower plasma uric acid concentrations and manage tumor lysis syndrome (TLS). Information on rasburicase dosing in adults is limited, with some data on using rasburicase as a single dose instead of multiple daily doses. Therefore, we evaluated the efficacy of a single dose of rasburicase for preventing or managing TLS in adults. We collected retrospective data for 11 adults with hematologic malignancies who received a single 6-mg dose of rasburicase. All patients received intravenous hydration with urinary alkalinization and allopurinol; however, due to adverse reactions, two patients received short courses of allopurinol. Only patients at high risk for TLS (e.g., large tumor burden, increasing uric acid concentration) or those with TLS received rasburicase. The single dose of rasburicase 6 mg resulted in a median 0.0773-mg/kg dose (range 0.0232-0.1361 mg/kg). The single 6-mg dose rapidly lowered uric acid concentrations in 10 of the 11 patients. The median uric acid concentration of 11.7 mg/dl (range 7.4-17.4 mg/dl) declined to 2.0 mg/dl (range 0.5-15.4 mg/dl) within a day after rasburicase administration (p=0.022). In these 10 patients, uric acid concentrations remained low despite subsequent chemotherapy, and none required additional rasburicase doses. The only patient who did not respond to the single 6-mg rasburicase dose was a morbidly obese man (259 kg, body mass index 87 kg/m2) who subsequently responded to an additional dose of rasburicase 12 mg. These results warrant further investigation of a single 6-mg dose of rasburicase in adults with TLS or at high-risk for developing TLS.

DC-based vaccine loaded with acid-eluted peptides in acute myeloid leukemia: the importance of choosing the best elution method.

Tumor-associated peptides isolated by acid elution are frequently used for therapeutic immunization against various tumors both in mice and in humans. In acute myeloid leukemia (AML), the frequent accessibility of a large tumor burden allows for extraction of peptides from leukemia cells by using either citrate-phosphate (CP) or trifluoroacetic acid (TFA) buffer. To develop an optimal immunotherapeutic protocol for AML patients, we evaluated both in mice and in humans, the immunogenicity of peptides eluted from leukemia cells with the two acids (TFA or CP). Although ex vivo studies in mice showed that both prophylactic immunizations with mature dendritic cells (DC) loaded with TFA-peptides (DC/TFA), or CP-peptides (DC/CP), were able to stimulate specific antileukemia immune responses, only vaccination with DC/TFA was able to prevent leukemia outgrowth. Moreover, in humans, only DC/TFA generated significant antileukemia CD4(+) and cytotoxic CD8(+) T cell responses in vitro. In summary, these data demonstrate that the choice of the acid elution procedure to isolate immunogenic peptides strongly influences the efficacy of the antileukemia immune responses. These finding raise essential considerations for the development of immunotherapeutic protocols for cancer patients. In our model, our results argue for the use of the TFA elution method to extract immunogenic AML-associated peptides.