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Biomedical subjects

P B Chapman

Publications and source records attributed to P B Chapman.

At least 19 recordsLinked to original sources
PubMed2002

Clinical results using biochemotherapy as a standard of care in advanced melanoma.

Phase II studies of biochemotherapy in metastatic melanoma patients have reported response rates of 47-63%. Even though these were highly selected patients, we were intrigued by these promising response rates and began using this regimen as standard care in advanced melanoma patients. We report the results of the first 65 patients with AJCC stage IV melanoma (n = 57) or unresectable stage III (n = 8) melanoma treated with concurrent biochemotherapy at Memorial Hospital. Treatment was repeated every 3 weeks and patients were assessed for antitumour effects after every other cycle. The overall response rate among the 63 patients evaluable for response was 29% (three complete responses, 15 partial responses). The median duration of responses was 3.7 months. The response rate among previously treated and previously untreated patients was 6% and 38%, respectively. The estimated median survival for all patients was 8.5 months; the median survival for previously untreated patients was 9.2 months. Tumour response did not correlate with survival. Our experience, which is a retrospective evaluation, does not provide support for the routine use of biochemotherapy as standard treatment. The low response rate among previously treated patients indicates that biochemotherapy is not useful as second-line therapy.

Adolescent↗
PubMed2001

High-dose interferon alfa-2b does not diminish antibody response to GM2 vaccination in patients with resected melanoma: results of the Multicenter Eastern Cooperative Oncology Group Phase II Trial E2696.

PURPOSE: High-dose interferon alfa-2b (IFNalpha2b) is the only established adjuvant therapy of resectable high-risk melanoma. GM2-KLH/QS-21 (GMK) is a chemically defined vaccine that is one of the best developed of a range of vaccine candidates for melanoma. A single-institution phase III trial conducted at Memorial Hospital served as the impetus for an intergroup adjuvant E1694/S9512/C509801 trial, which recently completed enrollment of 880 patients. To build on the apparent benefit of IFNalpha2b in resectable high-risk American Joint Committee on Cancer (AJCC) stage IIB or III melanoma, this phase II study was designed to evaluate the combination of GMK and IFNalpha2b. The E2696 trial was undertaken to evaluate the toxicity and other effects of the established adjuvant high-dose IFNalpha2b regimen in relation to immune responses to GMK and to evaluate the potential clinical and immunologic effects of the combined therapies. PATIENTS AND METHODS: This trial enrolled 107 patients with resectable high- or very high-risk melanoma (AJCC stages IIB, III, and IV). RESULTS: The results demonstrate that IFNalpha2b does not significantly inhibit immunoglobulin M or G serologic responses to the vaccine and that the combination of high-dose IFNalpha2b and GMK is well tolerated in this patient population. CONCLUSION: Cox analysis of the results of the combination with IFNalpha2b show improvement in the relapse-free survival of patients with very high-risk melanoma (including those with resectable M1 disease).

Adult↗
PubMed2000

Evaluation of CD8(+) T-cell frequencies by the Elispot assay in healthy individuals and in patients with metastatic melanoma immunized with tyrosinase peptide.

The lack of reproducible, quantitative assays for T-cell responses has been a limitation in the development of cancer vaccines to elicit T-cell immunity. We utilized the Elispot assay, which allows a quantitative and functional assessment of T cells directed against specific peptides after only brief in vitro incubations. CD8(+) T-cell reactivity was determined with an interferon (IFN)-gamma Elispot assay detecting T cells at the single cell level that secrete IFN-gamma. We studied both healthy individuals and patients with melanoma. Healthy HLA-A*0201-positive individuals showed a similar mean frequency of CD8(+) cells recognizing a tyrosinase peptide, YMDGTMSQV, when compared with melanoma patients prior to immunization. The frequencies of CD8(+) cells recognizing the tyrosinase peptide remained relatively constant over time in healthy individuals. Nine HLA-A*0201-positive patients with stage IV metastatic melanoma were immunized intradermally with the tyrosinase peptide together with the immune adjuvant QS-21 in a peptide dose escalation study with 3 patients per dose group. Two patients demonstrated a significant increase in the frequency of CD8(+) cells recognizing the tyrosinase peptide during the course of immunization, from approx. 1/16,000 CD8(+) T cells to approx. 1/4,000 in the first patient and from approx. 1/14,000 to approx. 1/2,000 in the second patient. These results demonstrate that modest expansion of peptide-specific CD8(+) T cells can be generated in vivo by immunization with peptide plus QS-21 in at least a subset of patients with melanoma.

Adult↗
PubMed2000

Induction of antibodies against GM2 ganglioside by immunizing melanoma patients using GM2-keyhole limpet hemocyanin + QS21 vaccine: a dose-response study.

In a previous randomized Phase III trial (P. O. Livingston et al, J. Clin. Oncol., 12: 1036-1044, 1994), we demonstrated that immunization with GM2 and bacille Calmette-Guerin reduced the risk of relapse in stage III melanoma patients who were free of disease after surgical resection and who had no preexisting anti-GM2 antibodies. That vaccine formulation induced IgM anti-GM2 antibodies in 74% but induced IgG anti-GM2 antibodies in only 10% of the patients. To optimize the immune response against GM2, a reformulated vaccine was produced conjugating GM2 to keyhole limpet hemocyanin (KLH) and using the adjuvant QS21 (GM2-KLH/QS21). In pilot studies, 70 microg of vaccine induced IgG anti-GM2 antibodies in 76% of the patients. We wished to define the lowest vaccine dose that induced consistent, high-titer IgM and IgG antibodies against GM2. Fifty-two melanoma patients who were free of disease after resection but at high risk for relapse were immunized with GM2-KLH/QS21 vaccine at GM2 doses of 1, 3, 10, 30, or 70 ILg on weeks 1, 2, 3, 4, 12, 24, and 36. Serum collected at frequent and defined intervals was tested for anti-GM2 antibodies. Overall, 88% of the patients developed IgM anti-GM2 antibodies; 71% also developed IgG anti-GM2 antibodies. GM2-KLH doses of 3-70 microg seemed to be equivalent in terms of peak titers and induction of anti-GM2 antibodies. At the 30-microg dose level, 50% of the patients developed complement fixing anti-GM2 antibodies detectable at a serum dilution of 1:10. We conclude that the GM2-KLH/QS21 formulation is more immunogenic than our previous formulation and that 3 microg is the lowest dose that induces consistent, high-titer IgM and IgG antibodies against GM2.

Adult↗
PubMed2000

Systemic chemotherapy.

The main use of systemic chemotherapy in metastatic melanoma remains palliative. Dacarbazine (dimethyl-1-triazeno imidazole-4-carboxamide [DTIC]) is the standard chemotherapy agent for advanced disease. The combination chemotherapy and biochemotherapy regimens have achieved higher response rates, but have not led to durable remission or improved survival. The field of systemic therapy remains in need of a more effective and less toxic treatment strategy.

Antineoplastic Agents↗
PubMed2000

Vaccination with a bivalent G(M2) and G(D2) ganglioside conjugate vaccine: a trial comparing doses of G(D2)-keyhole limpet hemocyanin.

Immunization with GMK vaccine (G(M2) ganglioside conjugated to keyhole limpet hemocyanin mixed with QS-21 adjuvant) induces anti-G(M2) antibodies in close to 100% of patients. We found previously that anti-G(D2) antibodies could be induced in some patients using G(D2)-keyhole limpet hemocyanin + QS-21 (GDK). In this trial, we wished: (a) to determine whether immunization with both GMK and GDK vaccines could induce antibodies against both G(M2) and G(D2); and (b) to determine the optimal dose of GDK. Thirty-one patients with melanoma or sarcoma who had no evidence of disease after complete surgical resection were immunized with both GMK (30 microg of G(M2)) and GDK on weeks 1, 2, 3, 4, 12, 24, and 36. Patients were assigned to one of five GDK dose levels (3, 10, 30, 70, or 130 microg of G(D2)). Anti-G(M2) IgM or IgG were induced in 97% of patients. The dose of GDK did not affect the anti-G(M2) response, although at the highest GDK dose level, 3 of 7 patients did not make anti-G(M2) IgG. GDK was less immunogenic; overall 45% of patients developed either IgM or IgG against G(D2). At GDK doses of 30 or 70 microg, 8 of 11 patients (73%) made either IgM or IgG anti-G(D2) antibodies. We conclude that both GMK and GDK vaccines can induce antibodies against G(M2) and G(D2) in a majority of patients and are safe. The optimal dose of GDK appears to be either 30 or 70 microg when administered with GMK vaccine.

Cancer Vaccines↗
PubMed2000

Paucity of functional T-cell memory to melanoma antigens in healthy donors and melanoma patients.

The functional characteristics of CD8+ T cells specific for melanoma antigens (MAs) have often been defined after in vitro culture using nonprofessional antigen-presenting cells. We have examined CD8+ T-cell immunity to MAs and a viral antigen (influenza) in uncultured T cells of healthy donors and melanoma patients using autologous, mature, monocyte-derived dendritic cells (DCs) pulsed with peptide antigens and viral vectors. Antigen-specific IFN-gamma-producing T cells reactive with HLA-A*0201-restricted peptides from four melanoma antigens (MelanA/MART-1, MAGE-3, tyrosinase, and gp100) were detected only at low frequencies (<30 per 2 x 10(5) peripheral blood mononuclear cells for each of the MAs) from HLA-A2.1-positive healthy donors (n = 12) and patients with stages III/IV melanoma (n = 8). Detection of MA-specific, but not influenza matrix peptide (Flu-MP)-specific, T cells required a high concentration (10 microg/ml) of the peptide in this assay. Furthermore, these T cells did not recognize endogenously processed antigen on tumor cell lines or cells infected with viral vectors capable of expressing MAs. The use of autologous, mature DCs led to a significant increase in the number of Flu-MP, but not MA-specific, T cells in 16-h ELISPOT assays for both melanoma patients and healthy donors. In 1-week cocultures with DCs pulsed with 10 microg/ml peptide, MelanA/MART-1-specific T cells did not readily proliferate or differentiate into lytic effectors, in contrast to strong influenza-specific lytic responses. Therefore, despite distinct memory responses to influenza antigens, melanoma patients and healthy controls have a paucity of MA-reactive memory T cells, failing to rapidly generate IFN-gamma-secreting lytic effectors in short-term assays, even when stimulated by DCs.

Antigens↗
PubMed1999

The role of homophilic binding in anti-tumor antibody R24 recognition of molecular surfaces. Demonstration of an intermolecular beta-sheet interaction between vh domains.

The murine antibody R24 and mouse-human Fv-IgG1(kappa) chimeric antibody chR24 are specific for the cell-surface tumor antigen disialoganglioside GD3. X-ray diffraction and surface plasmon resonance experiments have been employed to study the mechanism of "homophilic binding," in which molecules of R24 recognize and bind to other molecules of R24 though their heavy chain variable domains. R24 exhibits strong binding to liposomes containing disialoganglioside GD3; however, the kinetics are unusual in that saturation of binding is not observed. The binding of chR24 to GD3-bearing liposomes is significantly weaker, suggesting that cooperative interactions involving antibody constant regions contribute to R24 binding of membrane-bound GD3. The crystal structures of the Fabs from R24 and chR24 reveal the mechanism for homophilic binding and confirm that the homophilic and antigen-binding idiotopes are distinct. The homophilic binding idiotope is formed largely by an anti-parallel beta-sheet dimerization between the H2 complementarity determining region (CDR) loops of two Fabs, while the antigen-binding idiotope is a pocket formed by the three CDR loops on the heavy chain. The formation of homophilic dimers requires the presence of a canonical conformation for the H2 CDR in conjunction with participation of side chains. The relative positions of the homophilic and antigen-binding sites allows for a lattice of GD3-specific antibodies to be constructed, which is stabilized by the presence of the cell membrane. This model provides for the selective recognition by R24 of cells that overexpress GD3 on the cell surface.

Animals↗
PubMed1999

Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma.

PURPOSE: Several single-institution phase II trials have reported that the Dartmouth regimen (dacarbazine, cisplatin, carmustine, and tamoxifen) can induce major tumor responses in 40% to 50% of stage IV melanoma patients. This study was designed to compare the overall survival time, rate of objective tumor response, and toxicity of the Dartmouth regimen with standard dacarbazine treatment in stage IV melanoma patients. PATIENTS AND METHODS: In this multicenter phase III trial, 240 patients with measurable stage IV melanoma were randomized to receive the Dartmouth regimen (dacarbazine 220 mg/m(2) and cisplatin 25 mg/m(2) days 1 to 3, carmustine 150 mg/m(2) day 1 every other cycle, and tamoxifen 10 mg orally bid) or dacarbazine 1, 000 mg/m(2). Treatment was repeated every 3 weeks. Patients were observed for tumor response, survival time, and toxicity. RESULTS: Median survival time from randomization was 7 months; 25% of the patients survived > or = 1 year. There was no difference in survival time between the two treatment arms when analyzed on an intent-to-treat basis or when only the 231 patients who were both eligible and had received treatment were considered. Tumor response was assessable in 226 patients. The response rate to dacarbazine was 10.2% compared with 18.5% for the Dartmouth regimen (P =.09). Bone marrow suppression, nausea/vomiting, and fatigue were significantly more common in the Dartmouth arm. CONCLUSION: There was no difference in survival time and only a small, statistically nonsignificant increase in tumor response for stage IV melanoma patients treated with the Dartmouth regimen compared with dacarbazine. Dacarbazine remains the reference standard treatment for stage IV melanoma.

Adult↗
PubMed1999

Long survival of patients with small cell lung cancer after adjuvant treatment with the anti-idiotypic antibody BEC2 plus Bacillus Calmette-Guérin.

Despite active therapies for small cell lung cancer (SCLC), most patients relapse and die of the disease. The present study evaluates immunization using the anti-idiotypic antibody BEC2, which mimics the ganglioside GD3 expressed on the surface of most SCLC tumors, combined with Bacillus Calmette-Guérin (BCG) as an immune adjuvant. We hypothesized that active immunization could alter the natural history of the disease. Fifteen patients who had completed standard therapy for SCLC received a series of five intradermal immunizations consisting of 2.5 mg of BEC2 plus BCG over a 10-week period. Blood was collected for serological analysis, and outcome was monitored. All patients developed anti-BEC2 antibodies, despite having received chemotherapy with or without thoracic radiation. We detected anti-GD3 antibodies in five patients, including those with the longest relapse-free survival. The median relapse-free survival for patients with extensive stage disease is 11 months and has not been reached for patients with limited stage disease (>47 months), with only one of seven patients having relapsed after a median follow-up of 47 months. Immunization of patients with SCLC after standard therapy using BEC2 plus BCG can induce anti-GD3 antibodies and is safe. The survival and relapse-free survival in this group of patients are substantially better than those observed in a prior group of similar patients. A Phase III trial is being conducted to evaluate BEC2 plus BCG as adjuvant therapy after chemotherapy and irradiation.

Adjuvants, Immunologic↗
PubMed1999

Intradermal injection of granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with metastatic melanoma recruits dendritic cells.

Dendritic cells (DCs) are the main antigen-presenting cells in the skin. We hypothesized that intradermal (i.d.) injection of granulocyte-macrophage colony-stimulating factor (GM-CSF) would recruit DCs into melanoma skin metastases and enhance autologous melanoma antigen presentation to host T cells. Sixteen patients with cutaneous or subcutaneous melanoma metastases were treated with GM-CSF injected i.d. into a single dermal metastasis and into a normal skin site for 10 consecutive days at one of four dose levels (10, 20, 40, or 80 microg/injection). Pretreatment and post-treatment skin and tumor biopsies were stained for a panel of T-cell, B-cell, macrophage, and DC immunohistochemical markers. Positive cells were quantitated in a blinded fashion. There was a significant increase in the number of DCs (HLA-DR+, S100+, factor XIIIa+) and CD45R0+ T cells in the skin and in the tumors Injected with GM-CSF at all dose levels. Uninjected control tumors showed no increase in HLA-DR+ cells or T-cell infiltrate, but did show an Increase in S100+ and factor XIIIa+ cells, suggesting a non-DC population. ID GM-CSF administered in this manner recruited DCs into melanoma tumors and normal skin. Although no antitumor effects were seen, this represents a potential method of preparing skin sites for vaccine delivery.

Antigen Presentation↗
PubMed1999

Immunization of melanoma patients with BEC2-keyhole limpet hemocyanin plus BCG intradermally followed by intravenous booster immunizations with BEC2 to induce anti-GD3 ganglioside antibodies.

BEC2 is an anti-idiotypic mouse monoclonal antibody that mimics GD3 ganglioside. Previous clinical trials demonstrated that intradermal immunization using 2.5 mg of BEC2 with BCG or i.v. immunization with 10 mg of BEC2 can induce anti-GD3 antibodies in a subset of patients. We hypothesized that combining these two immunization strategies might be more effective in inducing anti-GD3 antibodies and that conjugation of BEC2 to keyhole limpet hemocyanin (KLH) would further enhance the immunogenicity of BEC2. In this clinical trial, 18 melanoma patients who were free of disease after complete surgical resection within 1-6 months received intradermal immunizations on weeks 0, 2, 4, 6, and 10 with 2.5 mg of BEC2 conjugated to KLH and mixed with BCG (BEC2-KLH/BCG). Booster immunizations of 10 mg of unconjugated BEC2 were administered i.v. on weeks 24, 37, and 50. Four of 18 patients (22%) developed IgM anti-GD3 antibodies. No IgG anti-GD3 antibodies were detected. All four responding patients developed anti-GD3 IgM during immunization with BEC2-KLH/BCG; only one patient demonstrated a reboost of the IgM anti-GD3 titer during the i.v. immunizations. Thirteen of the patients are free of melanoma (3 after undergoing re-resection for local relapse); 14 patients (78%) remain alive with a median follow-up of 28 months. These results confirm our previous trial, showing that BEC2 with BCG can induce anti-GD3 antibodies in patients. The data do not provide evidence that conjugation to KLH increases the immunogenicity of BEC2 when it is administered with BCG.

Adjuvants, Immunologic↗
PubMed1998

Phase I study of R24 in patients with metastatic melanoma including evaluation of immunologic parameters.

R24 is a mouse IgG3 monoclonal antibody with specificity for the disialoganglioside GD3. Most human melanomas have substantial surface GD3; in addition, a significant proportion of T lymphocytes display surface GD3. In a phase I study, we have investigated the toxicity and effect on selected immunological parameters of three dose levels of R24 given intravenously daily for five days (10 mg/m2/d, 30 mg/m2/d and 50 mg/m2/d) to patients with advanced melanoma. R24 administration neither consistently diminished nor augmented expression of delayed type hypersensitivity (DTH) skin reactions to anergy panel antigens or to a contact allergen dinitrofluorobenzene. R24 was infrequently found on tumor cells, or on lymphocytes from DTH biopsies, despite measurable serum levels of R24. The 30 mg/m2/d dose of R24 produced a statistically significant drop in peripheral blood lymphocytes on treatment Day 5. Likewise, on Day 5 there was a modest but statistically significant decrement in the proportion of circulating cells which were R24+. While there was one mixed response, there were no complete or partial tumor regressions in the R24 treated patients; there was no evident clinical benefit from the R24 therapy. The toxicity of the R24 at the higher dose levels can be very substantial. One patient, on the highest dose level, died on the 4th day of R24 treatment; in the absence of a plausible alternative explanation, a relationship of the death to the administered R24 must be considered. A precipitous drop in serum albumin coincident with R24 administration was found in all cases; this effect has not been previously reported with R24.

Animals↗
PubMed1997

Anti-melanoma effects of R24, a monoclonal antibody against GD3 ganglioside.

R24, a mouse monoclonal antibody against GD3 ganglioside, is potent at mediating in vitro effector functions such as human complement-mediated cytotoxicity and antibody-dependent cellular cytotoxicity, and can block melanoma tumor growth in animal models. Because of these properties and the fact that GD3 is abundantly expressed on virtually all melanomas but is found on few normal tissues, R24 has been tested in a series of clinical trials in patients with metastatic melanoma. As a single agent, R24 can induce responses in patients treated with metastatic melanoma. Overall, there have been 10 responders out of 103 patients reported; two responses have been complete responses. Responses have largely occurred in patients treated with intermediate doses of R24 and have included complete responses. Combining R24 with either cytotoxic drugs or cytokines has not increased this response rate, although one trial with R24 and interleukin-2 resulted in a 43% response rate and merits further investigation. Local-regional treatments R24 (intratumor injections, regional limb perfusion, intrathecal administration) have also been attempted in a small number of patients and responses have been described. Taken together, multiple centers have reported responses in patients with metastatic melanoma treated with R24.

Animals↗
PubMed1997

Administration of R24 monoclonal antibody and low-dose interleukin 2 for malignant melanoma.

R24 is a monoclonal antibody that recognizes the disialoganglioside GD3 expressed on the surface of malignant melanoma cells. Once bound, it can mediate destruction of these cells through both complement-mediated lysis and antibody-dependent cellular cytotoxicity. Agents such as interleukin 2 (IL-2), which can augment effector cell function and promote destruction of antibody-coated tumor cells, might produce improved antitumor responses when combined with R24. In this series, we evaluated the combination of R24 and IL-2 in a Phase 1b study in patients with metastatic melanoma. Twenty-eight patients with metastatic melanoma were entered into the protocol at two institutions. Patients received 8 weeks of IL-2 by continuous i.v. infusion at a dose (4.5 x 10(5) Amgen units/m2/day) designed to selectively expand natural killer (NK) cells. In weeks 5 and 6, patients received R24 for a total of four doses. Twenty-four h after each R24 infusion, patients received a 2-h bolus dose of IL-2 to help promote activity of NK effectors against antibody-coated melanoma targets. Additional IL-2 boluses were administered in weeks 7 and 8. Doses were escalated through two bolus doses of R24 (5 or 15 mg/m2) and two bolus doses of IL-2 (2.5 or 5.0 x 10(5) units/m2). Although one patient experienced severe capillary leak syndrome during IL-2, therapy was otherwise well tolerated. At the higher dose level of R24, two of four patients experienced transient but severe abdominal and chest discomfort, necessitating dose reduction. One patient with ocular melanoma and liver metastases had a partial response. Two additional patients had minor responses. A dramatic increase in NK cell number was noted as a result of treatment, as was augmentation of cytolytic activity against cultured NK-sensitive targets. Antibody-dependent cellular cytotoxicity against cultured melanoma cells in the presence of exogenous R24 or in the presence of serum obtained from patients following R24 infusion also increased during treatment. Our experience indicates that R24 and low-dose IL-2 can be safely combined in patients with metastatic melanoma and that this combination can promote destruction of cultured melanoma cells. The clinical activity of this combination against ocular melanoma may merit further investigation.

Adult↗
PubMed1996

Characterization of an Ig VH idiotope that results in specific homophilic binding and increased avidity for antigen.

mAb against GD3 ganglioside demonstrate homophilic binding in which soluble anti-GD3 mAb bind, through the GD3 binding site, to a VH idiotope (designated IdHOM) on solid phase anti-GD3 mAb. In this way, homophilic binding provides a mechanism for amplifying the binding of mAb to cell surface GD3. We show that serine 52a, within CDR2, is required for IdHOM expression, homophilic binding, and high avidity binding to cell surface GD3. Computer modeling based on the crystal structure of anti-GD3 mAb R24 showed serine 52a situated at the mouth of the GD3 binding pocket, but not directly involved with GD3 binding. Substitutions at position 52a predicted to maintain the GD3 binding pocket (e.g., threonine) resulted in the loss of IdHOM expression and homophilic binding and markedly decreased binding to cell surface GD3, but maintained low avidity GD3 binding as measured by ELISA. All other substitutions at position 52a were predicted to significantly distort the GD3 binding pocket and resulted in the loss of both homophilic binding and any detectable avidity for GD3. We have structurally defined IdHOM and conclude that this idiotope is not required for the GD3 binding pocket, but that the idiotope is necessary for homophilic binding, which is required for high avidity binding to cell surface GD3. We speculate that selection of certain VH genes may result in the expression of idiotopes that allow homophilic binding, and this may represent a general mechanism for increasing the avidity of Abs against T cell-independent Ags.

Amino Acid Sequence↗
PubMed1996

Medical treatment of metastatic melanoma.

The role of combination chemotherapy in the treatment of metastatic melanoma is still a matter of controversy because of the lack of prospective trials directly demonstrating increased response rates and improved survival compared with DTIC alone. Nevertheless, several three-drug regimens have reported response rates between 30% and 50% in single-institution studies. The duration of response medians of these regimens ranges between 6 and 9 months. However, the survival medians of 6 to 11 months are not substantially better than those of DTIC alone. However, survival at 1 and 2 years following initiation of therapy may more clearly demonstrate an impact of therapies for metastatic melanoma.

Antineoplastic Combined Chemotherapy Protocols↗