Period Of Stable Disease Research Articles

Long-term response in advanced bladder cancer involving the use of temsirolimus and vinflunine after platin resistance

Relapse after initial first-line chemotherapy shows a poor prognosis in metastatic urothelial cancer. Currently, several chemotherapeutic agents and targeted drugs are under evaluation for platin-resistant advanced urothelial carcinoma. Vinflunine has been approved for second-line treatment in this indication. We present a patient with initial T4 advanced and subsequently metastasized bladder cancer, who has shown prolonged survival of 44 months after radical cystectomy. During her clinical course, the patient received two different platinum-containing therapies, temsirolimus within a phase II protocol and subsequent vinflunine chemotherapy. Treatment duration was 15 weeks with temsirolimus and 9 weeks with vinflunine, respectively, with a stable disease period of 3.8 months under temsirolimus therapy. This case is an example of how patients can derive a survival benefit from adequate sequencing of surgery and medical treatment including the newest therapies, even in advanced disease.

Desmoid Tumors: Clinical Features and Treatment Options for Advanced Disease

Desmoid tumors describe a rare monoclonal, fibroblastic proliferation characterized by a variable and often unpredictable clinical course. Although histologically benign, desmoids are locally invasive and associated with a high local recurrence rate, but lack metastatic potential. On the molecular level, desmoids are characterized by mutations in the β-catenin gene, CTNNB1, or the adenomatous polyposis coli gene, APC. Proof of a CTNNB1 mutation may be useful when the pathological differential diagnosis is difficult and location might be predictive for disease recurrence. Many issues regarding the optimal treatment of patients with desmoids remain controversial; however, surgery is the therapeutic mainstay, except if mutilating and associated with considerable function loss. Postoperative radiotherapy reduces the local recurrence rate, in cases of involved surgical margins. Because of the heterogeneity of the biological behavior of desmoids, including long periods of stable disease or even spontaneous regression, treatment needs to be individualized to optimize local tumor control and preserve patients' quality of life. Therefore, the application of a multidisciplinary assessment with multimodality treatment forms the basis of care for these patients. Watchful waiting may be the most appropriate management in selected asymptomatic patients. Patients with desmoids located at the mesentery or in the head and neck region could present with life-threatening complications and often need more aggressive treatment. This review describes treatment options and management strategies for patients with desmoid tumors with a focus on advanced disease.

Gastrointestinal Stromal Tumors: Disease and Treatment Update

Gastrointestinal Stromal Tumors: Disease and Treatment Update

First Case of A859T Epidermal Growth Factor Receptor Mutation Responding to Erlotinib

A 59-year-old smoker consulted for a pulmonary nodule. Computed tomography (CT) scan lung biopsy diagnosed a non-small cell lung cancer (NSCLC) of adenocarcinoma subtype. Positron emission tomography demonstrated a left adrenal metastasis. First-line chemotherapy with a combination of pemetrexed and carboplatin was performed. After four cycles, a partial response was observed according to RECIST 1.1 criteria. During the same period, epidermal growth factor receptor (EGFR) mutations were characterized according to a sensitive method based on high-performance liquid chromatography and sequencing (Figures 1A, B). The rare mutation A859T was observed. Erlotinib was introduced after a wash-out period of 4 weeks. Tolerance was excellent. Eight weeks later, CT scan demonstrated a partial response (criteria RECIST 1.1 = − 41%). Maximal standard uptakes of 18F-fluorodeoxyglucose (FDG) showed a reduction for primary and secondary tumors, 3.9 to 1.0 and 2.9 to 2.3, respectively (Figure 2). The radiographic response was confirmed with a CT scan 3 months later. To date, the duration of response is 3 months.FIGURE 2Computed tomography and positron emission tomography scans and fused images before and 8 weeks after erlotinib.View Large Image Figure ViewerDownload (PPT) Activating EGFR mutations are predictive responses for the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. The most frequent deletions and mutations, located in exon 19 and 21, are observed from 10% in Caucasian populations1Rosell R Moran T Queralt C et al.Screening for epidermal growth factor receptor mutations in lung cancer.N Engl J Med. 2009; 361: 958-967Crossref PubMed Scopus (1901) Google Scholar up to 40 to 60% in female, nonsmoking Asian populations.2Mok TS Wu YL Thongprasert S et al.Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.N Engl J Med. 2009; 361: 947-957Crossref PubMed Scopus (6514) Google Scholar Alongside the most frequent activating EGFR mutations, many other less frequent mutations have been described.3Avizienyte E Ward RA Garner AP Comparison of the EGFR resistance mutation profiles generated by EGFR-targeted tyrosine kinase inhibitors and the impact of drug combinations.Biochem J. 2008; 415: 197-206Crossref PubMed Scopus (73) Google Scholar In general, little is known about the sensitivity or the lack of sensitivity to TKIs in humans. A859T EGFR mutation has already been reported twice and has been associated with the absence of sensitivity to gefitinib.4Han SW Kim TY Hwang PG et al.Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib.J Clin Oncol. 2005; 23: 2493-2501Crossref PubMed Scopus (715) Google Scholar, 5Cappuzzo F Bemis L Varella-Garcia M HER2 mutation and response to trastuzumab therapy in non-small-cell lung cancer.N Engl J Med. 2006; 354: 2619-2621Crossref PubMed Scopus (183) Google Scholar Functional analysis of A859T EGFR mutation exposed to erlotinib based on a cellular assay concluded that this variant could be a silent polymorphism.6de Gunst MM Gallegos-Ruiz MI Giaccone G et al.Functional analysis of cancer-associated EGFR mutants using a cellular assay with YFP-tagged EGFR intracellular domain.Mol Cancer. 2007; 6: 56Crossref PubMed Scopus (19) Google Scholar To the contrary of all these published data, our case supports the evidence of a therapeutic effect of erlotinib in a NSCLC patient bearing A859T EGFR mutation. The proofs are a tumor size reduction and a decrease of the FDG maximal uptake after 8 weeks of treatment and confirmed 3 months later. Although the follow-up of our case is limited, our observation seems similar to patients with TKI-sensitive adenocarcinomas harboring a frequent EGFR mutation: significant shrinking tumor size after TKI introduction, long period of stable disease, and good tolerance. For all the reasons, we consider that A859T EGFR mutation could be an activating mutation-associated response to erlotinib. Because of the lack of a reliable tool to predict EGFR mutation sensitivity of current TKIs, we recommend that physicians test both/several TKIs for every NSCLC patient harboring a rare/new EGFR mutation.

Combination Biologic Therapy as Initial Treatment for Follicular Lymphoma: Initial Results From CALGB 50701 - a Phase II Trial of Extended Induction Epratuzumab (anti-CD22) and Rituximab (anti-CD20)

AbstractAbstract 427Rituximab is effective as single agent therapy in the treatment of follicular lymphoma (FL), and when combined with chemotherapy has extended remissions and survival. Epratuzumab (Immunomedics), a humanized anti-CD22 monoclonal antibody, also has single agent activity in FL, and in combination with rituximab led to durable complete responses in the treatment of patients (pts) with relapsed and refractory indolent NHL. To evaluate the hypothesis that combining a second biological agent with rituximab might improve efficacy with good tolerability, the CALGB treated 60 previously untreated pts with epratuzumab and rituximab in a multicenter phase II trial and we report here the preliminary response and toxicity findings. Rituximab was administered at 375 mg/m2 iv weekly for four weeks, then every 8 weeks for four additional doses for a total of 8 doses over 9 months. Epratuzumab, was given at 360 mg/m2 two days before the first rituximab dose to assess toxicity. From week 2 on, epratuzumab was given before the rituximab on the same day for a total of 8 doses over 9 months. Fifty-seven evaluable pts were enrolled between May 2008 and September 2009. FLIPI scores at study entry were 13 (22%) low; 28 (47.5%) intermediate; and 18 (30.5%) high. Fifty-three pts completed all therapy through month 9. One pt was taken off therapy due to progression after month 5. One pt died during induction from line sepsis. Two pts were taken off study due to adverse events, 1 during induction (grade 4 thrombosis and MI), 1 following month 5 (dyspnea, hypoxia and pulmonary NOS). All other toxicities were grade 3 or lower, including fatigue (grade 3 3%, grade 2 17%), nodal pain (grade 3 5%, grade 2 8%), and cytokine release and pruritis (grade 2, 5% each). To date, there have been 19 CRs (33.3%), 29 PRs (50.9%)(ORR 84.2%); 9 (15.8%) had stable disease. All 19 CR patients completed all treatment. The mean time to CR was 9 months. Two patients progressed after a period of stable disease, and 25 of the 29 patients who achieved PR remain in response. All 19 CRs also remain in remission at this point with a median follow-up of 0.82 years (range 0.52 to 2.0). FLIPI score was not predictive of response. The CR rate in low risk pts was 31%, 44% in intermediate risk and 18% in high risk pts. There was a trend toward higher CR rate among patients with FcgR2A His (n=10, CR 60%) and to a lower CR rate among those with FcgR2A Arg (n=14, CR 14.3%). Correlations with PET scan at week 3, with tissue biomarkers and to statin use are being analyzed. Rituximab and epratuzumab is an effective and very well tolerated regimen with an ORR of 84% in previously untreated patients with follicular lymphoma. Disclosures: Off Label Use:Use of Epratuzumab, a humanized antiCD22 monoclonal antibody in treatment of follicular lymphoma. Leonard:BiogenIDEC: Consultancy; Genentech: Consultancy; Immunomedics: Consultancy. Jones:Glaxo Smith-Kline: Consultancy; Abbott: Research Funding. Cheson:Genentech: Consultancy.

Abstract B16: Anti-angiogenic therapy using brivanib, a combined VEGF and FGF pathway inhibitor, in a mouse model of pancreatic neuroendocrine cancer (PNET), results in sustained vascular blockade, without evidence for evasive/acquired resistance in the form of VEGF-independent revascularization, in contrast to other VEGF inhibitors

Abstract Previous studies using a mouse model of PNET (RIP-Tag2) demonstrated that anti-angiogenic therapy using an antibody that specifically targets murine VEGFR-2, DC101, led to a transitory period of stable disease followed by VEGF-independent revascularization and relapse leading to tumor progression (Casanovas, et al. Cancer Cell. 2005; 8: 299–309). Profiling analysis indicated that FGF was strongly upregulated upon failure of anti- VEGF therapy. Addition of a recombinant adenovirus expressing an FGF-Trap near the end of the response phase impaired revascularization and slowed tumor growth, implicating the FGF family of ligands in evasion of VEGF-targeted anti-angiogenic therapy in this model of PNET. Brivanib, a selective small molecule inhibitor of VEGFR-2,3 and FGFR-1,2,3 (Cai, et al. J Med Chem. 2008; 51:1976–80), is currently being evaluated in clinical trials in CRC and HCC. Brivanib's activity against FGFR signaling prompted investigation of its effects on evasive/adaptive resistance to selective VEGF inhibition. In the work to be presented, the efficacy of brivanib has been characterized as a first line inhibitor versus two different VEGF inhibitors, DC101 and sorafenib, and as a second line inhibitor following the failure of the aforementioned compounds. DC101 is a pure VEGF inhibitor, while sorafenib is a multikinase RTK inhibitor of VEGFR-2, PBGFR , and RAF/MEK/ERK currently approved in renal and liver cancer, and in Phase 3 trials for multiple other indications. Brivanib was comparable to FGF-trap as a second line inhibitor following DC101 failure, reducing tumor size and vascularity compared to continued DC101 monotherapy. Brivanib also showed reasonable efficacy in second line following sorafenib in short term trials. Notably, however, it could not reverse revascularization and tumor growth when sorafenib was allowed to fail in longer term trials. In contrast, first line brivanib therapy over comparable time courses that produced failure of both VEGF inhibitors resulted in tumor stasis and, in some cases, regression. Additionally, first-line brivanib therapy produced sustained blockade of angiogenesis, exhibited a trend for reduced invasiveness and metastasis in comparison to anti-VEGFR2 therapy alone, and significantly extended the lifespan of treated animals. Thus, while brivanib has clear benefits in second line therapy following failure of VEGF inhibitors, it may in some indications, as illustrated by this PNET model, be even more efficacious when used in a first line setting. The results from this mouse model of cancer may inform and facilitate design of future clinical trials of brivanib and other inhibitors of FGFR signaling. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B16.

Concomitant renal cell carcinoma and chronic myelogenous leukemia: Utilization of a targeted approach

Numerous therapeutic options have been introduced for metastatic renal cell carcinoma (MRCC) in recent years, including monoclonal antibodies such as bevacizumab and small-molecule tyrosine kinase inhibitors such as sunitinib and sorafenib. Similarly, several other small-molecule inhibitors-including imatinib, dasatinib, and nilotinib-have been approved for the treatment of chronic myelogenous leukemia (CML). The combination of these targeted agents is an area of intense clinical investigation. Here, we describe a patient diagnosed with MRCC)while on imatinib therapy for cml. Treatment of this patient with the combination of bevacizumab and imatinib led to a 6-month period of stable disease, with no treatment-related adverse events. More extensive clinical exploration of this combination of agents may therefore be warranted.

Concomitant Renal Cell Carcinoma and Chronic Myelogenous Leukemia: Use of a Targeted Approach

The development of molecularly targeted agents that inhibit pathways critical to the development of renal cell carcinoma has significantly improved outcomes in patients with these cancers. Compelling scientific and phase iii data have made the use of molecularly targeted agents the standard of care in first-line treatment. Now, available data show that re-treating patients with other tyrosine kinase inhibitors after they progress on sunitinib or sorafenib, or both, is beneficial. A large phase iii trial recently showed that, as compared with placebo, treatment with everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), almost halved the risk of progression (37% vs. 65%) and doubled the median progression-free survival (4 months vs. 2 months). Overall survival was not improved in that study, likely reflecting treatment crossover in the placebo arm, but these data position everolimus as the second-line standard of care. A consistent and growing body of literature also suggests that re-treatment with other kinase inhibitors that the patient has not previously encountered is a reasonable option. Outcomes of initial treatment with sunitinib or sorafenib (or both) should not deter the use of second-line targeted therapy, because the first-line use of targeted agents does not appear to be predictive of outcomes with second-line therapy. However, in view of poor absolute outcomes after second-line treatment and the benefits seen with rationally developed targeted agents in the first-line setting, enrolment of second- and subsequent-line patients in further trials would be preferable.

A Randomized Phase 2 Trial of Bevacizumab with or without Daily Low-Dose Interferon Alfa-2b in Metastatic Malignant Melanoma

Vascular endothelial growth factor (VEGF) is a proangiogenic molecule produced by melanoma cells. We hypothesized that administration of bevacizumab (Bev), a monoclonal antibody that neutralizes VEGF, with low-dose interferon alfa-2b (IFN-alpha2b), an inhibitor of basic fibroblast growth factor (FGF), would lead to the regression of metastatic melanoma. Patients with metastatic melanoma were randomized to receive Bev (15 mg/kg intravenously every 2 weeks) with or without low-dose IFN-alpha2b (1 MU/m2 subcutaneously daily). Patients exhibiting a clinical response or stable disease after 12 weeks were treated until disease progression. Thirty-two patients (16 per arm) were accrued (18 male, 14 female; mean age 57.5 years). Both regimens were well tolerated. Six patients developed easily managed exacerbations of preexisting hypertension. Two patients developed grade 3 proteinuria that resolved after a treatment break. IFN-alpha2b therapy was associated with grade 1 to 2 constitutional symptoms. Arterial thromboembolic complications were observed in three patients (two mild myocardial infarctions, one transient ischemic attack), all of whom had risk factors. One patient (Bev plus IFN-alpha2b arm) had locally recurrent scalp disease that partially responded to therapy. Eight patients (five Bev, three Bev plus IFN-alpha2b) had prolonged disease stabilization (24 to 146 weeks). Plasma levels of VEGF and FGF did not correlate with any clinical parameter. The patient with the longest period of stable disease had the highest baseline VEGF and FGF. Bev was well tolerated at this dose and prolonged disease stabilization was achieved in one-quarter of metastatic melanoma patients. Low-dose IFN-alpha2b did not augment the activity of Bev.

MUC5AC and MUC5B Mucins Increase in Cystic Fibrosis Airway Secretions during Pulmonary Exacerbation

Cystic fibrosis (CF) is believed to be associated with mucus hypersecretion; thus, the principal airway gel-forming mucins, MUC5AC and MUC5B, are also expected to be increased relative to non-CF secretions. However, we have shown that these mucins are decreased during stable CF disease. In this study, we determine if these mucins increase during a pulmonary exacerbation of CF. Expectorated sputum was collected from 11 adults with CF during stable disease and then during a pulmonary exacerbation and from 12 healthy control subjects. MUC5AC and MUC5B proteins were measured by Western blot. DNA content was measured using microfluorimetry. MUC5AC protein increased by 908% and MUC5B by 59% (p < 0.05 for both) during an exacerbation compared with periods of stable disease. During stable disease, the vol/vol quantity of MUC5AC protein was 89% less than normal mucus, and the mucin-associated sugars, measured using a lectin binding assay, were 46% less compared with normal mucus. The concentration of DNA in CF sputum did not increase during an exacerbation. During a CF exacerbation, concentration of secreted mucin increased to the amount found in mucus from normal subjects, suggesting that the capacity to secrete mucin in response to an infection or inflammatory stimulus is preserved in CF airways. This might help to protect the airway from injury.

GCS-100, a galectin-3 antagonist, in refractory solid tumors: A phase I study

13023 Background: Galectin-3 is a galactoside-binding protein implicated in inhibition of apoptosis, and promotion of angiogenesis, metastasis, cellular proliferation by a direct association with oncogenic K-ras. Modified citrus pectin (MCP) is a complex carbohydrate derived from citrus fruit and is rich in galactoside residues. GCS-100 is an MCP capable of binding to and antagonizing galectin-3, resulting in anti-tumor activity in vitro and in vivo. Methods: GCS-100 was administered to patients with refractory solid tumors in a Phase I dose-escalating study using standard eligibility criteria. Objectives were to determine dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetics (PK) and efficacy. Study drug was delivered by IV infusion over 1–2 hours for 5 consecutive days of a 21 day cycle. Results: 24 patients (17 F, 7 M, age 45–80 yo) were enrolled at 6 dose levels between 30–200 mg/m2. DLT and MTD for this dosing regimen were established at 200 mg/m2 and 160 mg/m2, respectively. DLT was a Grade 3 erythematous, maculopapular rash, resolving with systemic steroid treatment. There were no associated systemic findings, and the rash did not preclude further GCS-100 therapy. Skin biopsy revealed a vasculitis similar to findings seen in dog models. 9 other patients experienced Grade 1–2 rashes that did not require systemic treatment. The majority of adverse events (AEs) were Grade 1 or 2; the most common being nausea, vomiting, diarrhea, fatigue, fever and hyperglycemia. AEs thought to be related to treatment were rash, nausea and fatigue. Linear PKs were observed with a terminal half-life (t1/2) between 30–40 h and an effective t1/2 of 36 h. Peak GCS-100 concentrations reached 424 μg/mL at MTD. The median number of cycles was 4 (range 1–17). Best overall response per RECIST was stable disease observed in 16 patients with 6 of these patients on study for ≥ 6 months. Conclusion: Overall tolerability of GCS-100 was excellent with serum concentrations at MTD reaching levels associated with preclinical activity. Sustained periods of stable disease were achieved in patients with previously treated advanced solid tumors warranting Phase II studies. [Table: see text]

Ranpirnase – an antitumour ribonuclease: its potential role in malignant mesothelioma

Ranpirnase (Onconase®) is a novel cytotoxic ribonuclease. In clinical development as a single agent in patients with malignant mesothelioma (MM), at 480 μg/m2 intravenously weekly, analysis of survival indicated prolonged periods of stable disease in Phase II trials and a potential survival benefit, compared with doxorubicin, in a small unpublished Phase III trial. In all clinical studies it has generally demonstrated a favourable safety profile except for easily controlled allergic reactions and dose modifications for renal impairment. Standard first-line treatment for MM has recently been established with an antifolate and cisplatin. At present, a Phase III trial of doxorubicin with or without ranpirnase is nearing completion in MM patients without prior chemotherapy or one prior chemotherapy regimen.

Stable disease for four years in metastatic malignant melanoma treated with the heat shock protein inhibitor 17-AAG

Heat shock proteins, including HSP90, contribute to the stabilization of a number of key molecules implicated in proliferative pathways in cancer. Geldanamycin and related compounds are competitive inhibitors of HSP90 at the N-terminal ATP binding site. The geldanamycin derivative 17-allylamino, 17-demethoxygeldanamycin (17-AAG) was the first HSP90 inhibitor to enter clinical development. Here we describe a patient with metastatic malignant melanoma treated with 17-AAG. She enjoyed a period of stable disease for a period of 49 months on treatment. Prolonged disease stabilization may prove to be a clinically meaningful outcome for many molecularly targeted agents and the design of phase II studies of these novel therapies needs to consider the use of progression-free survival as a valid endpoint.

A Phase II Study of Enzastaurin, a Protein Kinase C-β (PKCβ) Inhibitor, in the Treatment of Relapsed Diffuse Large B-Cell Lymphoma (DLBCL).

PKCβ was identified by gene expression profiling and confirmed by independent analysis as a possible rational therapeutic target for DLBCL. Therefore, we investigated the safety and anti-cancer activity of enzastaurin, an orally administered, potent inhibitor of PKCβ, in this disease. Patients (pts) with relapsed DLBCL, who progressed following CHOP-based (or equivalent) chemotherapy, were enrolled in this phase II, single-arm, US multicenter study. The primary objective was to determine the rate of freedom from progression ≥2 cycles (FFP). Secondary end-points included objective response rate (complete or partial response), and toxicity. Pts initially received an oral dose of 525 mg (capsules) enzastaurin, amended to 500 mg (tablets), once daily, until disease progression or unacceptable toxicity occurred. One cycle of therapy lasted for 28 days. All 55 enrolled pts received at least 1 dose of enzastaurin, and were included in the safety and efficacy analyses. Of these, 13 pts completed less than 1 cycle of therapy, which is noteworthy because enzastaurin must be administered for 14 days to achieve therapeutic levels. Of the 55 pts evaluated, 27 were men and 28 were women, 47 (85%) had an ECOG performance status of ≤1, and 28 pts had elevated LDH levels. The median age was 68 years (range: 31–87). Pts had received a median number of 2 prior therapies (range: 1–5); 6 pts had also received prior stem-cell transplantation. There were 11 dose omissions due to toxicities, 2 of which were possibly related to the study drug (fatigue and edema). There was only 1 grade 4 toxicity (hypomagnesemia), 1 grade 3 thrombocytopenia, and no grade 3 or 4 neutropenia. Other grade 3 toxicities were fatigue (2), edema (1), headache (1), and motor neuropathy (1). Twelve of 55 pts (21.8%, 95% CI: 11.8%–35.0%) were alive and free from progression at the end of 2 cycles. Two of these 12 pts had elevated LDH levels at baseline, which normalized after enzastaurin therapy. Nine pts had stable disease for at least 4 cycles, one of whom achieved a complete response; 2 of the 9 pts had relapsed after prior stem-cell therapy. Five pts with stable disease achieved a minor response (lesion shrinkage ≥25% and <50%). Three pts remain progression-free for ≥12 cycles (12+, 17+, and 32+ cycles, respectively).Pts enrolledPts on-study for ≥1 cyclePts with FFP for ≥2 cyclesPts with FFP for ≥4 cyclesPts with FFP for ≥12 cycles55421293In conclusion, several pts with multiple relapsed DLBCL achieved prolonged periods of stable disease following enzastaurin treatment, although the objective tumor response rate was low. In addition, enzastaurin was well tolerated. These results suggest that enzastaurin, an oral agent, has clinical activity in DLBCL that warrants further investigation.

Anaplastic large-cell lymphoma primarily infiltrating femoral muscles

Dear Sir, Primary extranodal lymphoma is known to occur in the gastrointestinal tract (so-called MALToma), orbit, skin, bone, and central nervous system. Among 7,000 cases of malignant lymphomas diagnosed at the Mayo Clinic between 1976 and 1986, only eight cases initially presented as soft tissue masses in the extremities [1]. Especially, primary muscular lymphoma is relatively rare, accounting for less than 1% of extranodal lymphoma [2]. Skeletal muscle can be involved in non-Hodgkin’s lymphoma as a part of disseminated disease, as a local extension from lymphomatous deposits in the adjacent lymph nodes or bones, or as a primary site of disease. Although anaplastic large cell lymphoma (ALCL), so-called Ki-1 lymphoma, frequently exhibits extranodal disease, primary muscular involvement is extremely rare. Recently, the anaplastic lymphoma kinase (ALK) protein was shown to identify a subgroup of nodal ALCL with an excellent prognosis. On the contrary, absence of ALK expression in tumor usually denotes resistance to treatment and unfavorable prognosis. A 21-year-old Asian male presented with a 2-month history of progressively painless swelling of the right thigh. There were no constitutional symptoms such as fever, weight loss, local heat, or skin erythema. Pertinent physical examination included significance for diffuse swelling of right thigh extending to right knee joint without significant skin change or adjacent lymphadenopathy. Computed tomography (CT) scan demonstrated swelling and edematous change of adductor muscular groups, including biceps femoris, gluteus intermedius muscle, and surrounding subcutaneous tissue. A venography of right lower extremity carried out in a regional hospital found a questionable filling defect at the right popliteo-femoral vein prompt to the diagnosis of deep venous thrombosis. However, the muscular swelling did not respond to subsequent anticoagulant therapy. He was then referred to our center, and a magnetic resonance imaging (MRI) scan demonstrated diffuse nodular masses infiltrating the posterior and medial compartments of the right thigh and vastus intermedialis muscle (Fig. 1a,b). Those masses were marked hyperintense on T2-weighted images (Fig. 1c) with enhancement after the gadolinium administration. Incisional biopsy of biceps femoris and histological examination disclosed diffuse infiltration of large pleomorphic cells with hyperchromatic nucleus and prominent nucleoli (Fig. 2a,b). Upon immunohistological staining, these atypical cells were positive for CD45 and CD30 (Ki1) and negative for CD3, CD5, CD15, CD19, CD20, CD56, and nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) protein (also named P80) (Fig. 2c). Further systemic staging work-up did not find any nodal and bone marrow involvement. Intensive chemotherapy, using cyclophosphamide, doxorubicin, vincristine, prednisolone, and etoposide (CHOP-E) was conducted, but his disease started to progress after completion of third cycle treatment. Subsequent salvage therapy including high-dose methotrexate followed by weekly vinblastine and external beam radiotherapy can only achieve stable disease. Nine months after diagnosis, progressive dyspnea developed, and the chest X-ray disclosed right massive pleural effusion containing CD30+ lymphoma cells. After obtaining a partial response to salvage regimen with mesna, ifosphamide, mitoxantrone, etoposide (MINE) and etoposide, methylprednisolone, cytarabine, cisplatin (ESHAP), he subsequently underwent high-dose chemotherapy (busulfan and cyclophosphamide) followed by autologous peripheral blood stem cell transplantation. Despite experiencing a brief period of stable disease, he finally succumbed to rapid systemic dissemination 2 months after PBSCT. W.-P. Liao . M.-S. Dai . N.-S. Yao (*) Division of Hematology/Oncology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan e-mail: nancynsy@yahoo.com.tw Tel.: +886-2-87927208 Fax: +886-2-87927209

Immunization With Mutantp53- andK-ras–Derived Peptides in Cancer Patients: Immune Response and Clinical Outcome

To determine the ability to induce tumor-specific immunity with individual mutant K-ras-or p53-derived peptides and to monitor clinical outcome. Patients in varying stages of disease underwent genetic analysis for mutations in K-ras and p53. Thirty-nine patients were enrolled. Seventeen-mer peptides were custom synthesized to the corresponding mutation. Baseline immunity was assessed for cytotoxic T-lymphocyte (CTL) response and interferon gamma (IFN-gamma) release from mutant peptide-primed lymphocytes. Patients' peripheral-blood mononuclear cells were pulsed with the corresponding peptide, irradiated, and applied intravenously. Patients were observed for CTL, IFN-gamma, interleukin (IL) -2, IL-5, and granulocyte-macrophage colony-stimulating factor responses, for treatment-related toxicity, and for tumor response. No toxicity was observed. Ten (26%) of 38 patients had detectable CTL against mutant p53 or K-ras, and two patients were positive for CTL at baseline. Positive IFN-gamma responses occurred in 16 patients (42%) after vaccination, whereas four patients had positive IFN-gamma reaction before vaccination. Of 29 patients with evident disease, five experienced a period of stable disease. Favorable prognostic markers were detectable CTL activity and a positive IFN-gamma reaction but not IL-5 release. Median survival times of 393 v 98 days for a positive versus negative CTL response (P = .04), respectively, and of 470 v 88 days for a positive versus negative IFN-gamma response (P = .02), respectively, were detected. Custom-made peptide vaccination is feasible without any toxicity. CTL and cytokine responses specific to a given mutation can be induced or enhanced with peptide vaccines. Cellular immunity to mutant p53 and K-ras oncopeptides is associated with longer survival.

Combination antiangiogenesis therapy with marimastat, captopril and fragmin in patients with advanced cancer

Marimastat, low molecular weight heparins and captopril have antiangiogenic activity in vitro and in animal models. We studied the safety and efficacy of the combination of these drugs in patients with advanced cancer. In all, 50 patients were enrolled. Captopril was given orally at a dose of 50 mg bd daily. Fragmin was administered as a daily subcutaneous injection of 200 units kg−1 for the first 28 days and 5000 units thereafter. Marimastat was given at 10 mg bd orally. Serum, plasma and urinary angiogenic factors were measured at baseline and after 1 month of treatment. Inhibition of release of tumour necrosis factor alpha (TNF-alpha) from peripheral lymphocytes was used as a surrogate pharmacodynamic end point. There was one case of haemorrhagic stroke and one upper gastrointestinal haemorrhage. The commonest toxicity was myalgia. One of 10 patients with renal cancer had a partial response, and three patients had a prolonged period of stable disease. The treatment significantly inhibited phytohaemagglutinin (PHA)-stimulated TNF-alpha release from patient's lymphocytes. The combination of marimastat, fragmin and captopril is well tolerated and has in vivo activity. Inhibition of PHA-stimulated TNF-alpha release from lymphocytes is a surrogate pharmacodynamic marker of metalloprotease inhibition.

Immunotherapy for renal carcinoma: theoretical basis and current standard of care.

Carcinoma of the kidney (a.k.a. ‘hypernephroma’ or renal cell cancer) accounts for 2–3% of all adult cancers, and over 4000 new cases are reported in the UK every year [1]. It occurs more commonly in men, and has a peak incidence around 60–70 years, although can occur at any age. The incidence is increasing [2]. If confined to the kidney, surgical resection is the treatment of choice, and cure can result. However, most patients with metastatic disease survive less than 1 year [3], and chemotherapeutic or hormonal approaches are generally ineffective. The natural history of renal cancer characteristically manifests an indolent course, with long periods of stable disease. In addition, the ‘spontaneous regression’ of metastases has often been reported in the literature, and Evenson & Cole [4] made the observation that renal cancer appeared to have the highest incidence of this controversial and intriguing phenomenon. The actual frequency of spontaneous regression in renal tumours is not known, but estimates put it at around 0.3% [5]. A higher frequency has been reported following nephrect-omy in patients with established metastatic disease [6]. The existence of spontaneous regression has been put forward as evidence that a form of innate ‘host factor’ or immunological response may be involved in its pathogen-esis. Such a hypothesis is supported by the increase in renal cancer cases observed in patients receiving long-term immunosuppressive therapy for organ transplantation [7].

Liver Metastases.

Liver metastases, especially from colorectal primary cancers, are treatable and potentially curable. Imaging techniques such as CT, MRI, and sonography have advanced in recent years and led to increased sensitivity and specificity in the diagnosis of liver metastases. Liver surgery also has been revolutionized in the past two decades. Dissections along nonanatomic lines have permitted the resection of multiple lesions that previously might have been considered unresectable. We regard resection of a solitary hepatic metastasis or up to four metastases from colorectal carcinoma as the best treatment for this condition. In patients over 70 years of age and those with medical conditions preventing surgery, we endorse expectant follow-up as long as the tumor remains stable. But if the tumor begins growing rapidly and local techniques cannot be used, we consider systemic chemotherapy. In patients with progressive metastatic liver disease, we initiate systemic therapy or hepatic arterial infusion. In young patients with metastatic disease, even when the disease is indolent or symptomatic, it may be difficult not to treat. We use either local regional therapy (resection or regional infusion) or systemic chemotherapy followed by regional therapy. In patients with neuroendocrine tumors metastatic to the liver, the first approach we use is not to treat because there may be a long period of stable disease. We use Sandostatin (Sandoz Pharmaceuticals, East Hanover, NJ) to treat symptoms. If the tumor progresses and symptoms cannot be controlled, these vascular tumors can be treated by embolization or chemoembolization, with high expectations of response. Newer approaches to liver metastases such as cryosurgery, chemoembolization, and interstitial radiation are also available. Cryosurgery is an ablative procedure that has not been proven yet to be as effective as surgical removal of metastases. However, in a situation where surgery cannot be performed, cryosurgery is an alternative. Chemoembolism has not been proven to be more effective than systemic therapy for liver metastases, but it allows another regional approach. External localized radiation can be used for patients who fail first-line treatment or in new protocols to delineate its value, perhaps in concert with chemotherapy. We also consider offering external localized radiation in patients who fail first-line treatment, perhaps in concert with chemotherapy. The usefulness of these techniques compared with surgery or regional therapy is being investigated.

Prolonged Survival of a Patient With Sickle Cell Trait and Metastatic Renal Medullary Carcinoma

The treatment and outcome of a patient with sickle cell trait and metastatic renal medullary carcinoma is described. A 12-year-old boy with sickle cell trait had metastatic renal medullary carcinoma. After surgical resection of the primary tumor, he received chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin. The carcinoma progressed after a 6-month period of stable disease. At that time, he received chemotherapy including ifosfamide, etoposide, carboplatin, and topotecan. The patient died of progressive disease 15 months from diagnosis. The patient's tumor in this report showed no progression while he was receiving methotrexate, vinblastine, doxorubicin, and cisplatin, but eventually became refractory to these and other cytotoxic agents. Renal medullary carcinoma is a highly chemotherapy-resistant tumor. Average survival after diagnosis is 15 weeks; the longest survival reported in the literature is 12 months from diagnosis. The patient in this report survived longer than the previously described patients before dying from progressive disease.