Six-month humoral and cellular immune response to the third dose of BNT162b2 anti-SARS-CoV-2 vaccine in patients with solid tumors: a longitudinal cohort study with a focus on the variants of concern.

BACKGROUND: The role and the durability of the immunogenicity of the third dose of vaccine against COVID-19 variants of concern in cancer patients have to be elucidated. PATIENTS AND METHODS: We have prospectively evaluated the immunogenicity of the third dose of the SARS-CoV-2 BNT162b2 messenger RNA vaccine in triggering both humoral and cell-mediated immune response in patients with solid tumors undergoing active treatment 6 months after the booster. Neutralizing antibody (NT Ab) titers and total anti-spike immunoglobulin G concentrations were measured in serum. Heparinized whole blood samples were used for the SARS-CoV-2 interferon-γ release assay (IGRA). RESULTS: Six months after the third dose only two patients (2.4%) showed negative spike-specific immunoglobulin G antibody levels (<33.8 BAU/ml). The median level of SARS-CoV-2 NT Abs decreased and only 39/83 (47%) subjects showed maximum levels of NT Abs. T-cellular positive response was observed in 38/61 (62.3%) patients; the highest median level of response was observed 21 days after the third dose (354 mIU/ml, interquartile range 83.3-846.3 mIU/ml). The lowest median level of NT Ab response was observed against the Omicron variant (1 : 10, interquartile range 1 : 10-1 : 40) with a significant reduced rate of responder subjects with respect to the wild-type strain (77.5% versus 95%; P = 0.0022) and Delta variant (77.5% versus 93.7%; P = 0.0053). During the follow-up period, seven patients (8%) had a confirmed post-vaccination infection, but none of them required hospitalization or oxygen therapy. CONCLUSIONS: Our work highlights a significant humoral and cellular immune response among patients with solid tumors 6 months after the third BNT162b2 vaccine dose, although a reduction in neutralizing activity against Omicron was observed.

Immunogenicity and safety after the third dose of BNT162b2 anti-SARS-CoV-2 vaccine in patients with solid tumors on active treatment: a prospective cohort study.

BACKGROUND: Although a full course of coronavirus disease 2019 (COVID-19) vaccine is effective in cancer patients, the duration of the protection and the efficacy of a booster dose against the new variants remain unknown. We prospectively evaluated the immunogenicity of the third dose of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) BNT162b2 messenger RNA vaccine in cancer patients undergoing active treatment. PATIENTS AND METHODS: Patients with solid cancer, vaccinated with a booster dose during active treatment, were enrolled in this study. Patients were classified into SARS-CoV-2 naïve (without previous COVID-19 infection) and SARS-CoV-2 experienced (with previous COVID-19 infection). Neutralizing antibody (NT Ab) titer and total anti-Spike immunoglobulin G (IgG) concentration were quantified in serum. Heparinized whole blood samples were used for SARS-CoV-2 Interferon Gamma Release Assay (IGRA). The primary endpoint was to assess the increase of IgG antibody level between baseline and 3 weeks after the booster. RESULTS: One hundred and forty-two consecutive patients were recruited. In SARS-CoV-2-naïve subjects, the median level of IgG was 157 BAU/ml [interquartile range (IQR) 62-423 BAU/ml] at T0 and reached a median of 2080 BAU/ml (IQR 2080-2080 BAU/ml) at 3 weeks after booster administration (T1; P < 0.0001). A median 16-fold increase of SARS-CoV-2 NT Ab titer (IQR 4-32) was observed in naïve subjects (from median 20, IQR 10-40, to median 640, IQR 160-640; P < 0.0001). Median interferon-γ level at T1 was significantly higher than that measured at T0 in SARS-CoV-2-naïve subjects (P = 0.0049) but not in SARS-CoV-2-experienced patients. The median level of SARS-CoV-2 NT Abs was 32-fold lower against Omicron compared to the wild-type strain (P = 0.0004) and 12-fold lower compared to the Delta strain (P = 0.0110). CONCLUSIONS: The third dose is able to trigger both the humoral and the cell-mediated immune response in cancer patients on active treatment. Our preliminary data about the neutralization of the SARS-CoV-2 vaccine against variants of concern seem to confirm the lower vaccine activity.

Analysis of the humoral and cellular immune response after a full course of BNT162b2 anti-SARS-CoV-2 vaccine in cancer patients treated with PD-1/PD-L1 inhibitors with or without chemotherapy: an update after 6 months of follow-up.

BACKGROUND: The durability of immunogenicity of SARS-CoV-2 vaccination in cancer patients remains to be elucidated. We prospectively evaluated the immunogenicity of the vaccine in triggering both the humoral and the cell-mediated immune response in cancer patients treated with anti-programmed cell death protein 1/programmed death-ligand 1 with or without chemotherapy 6 months after BNT162b2 vaccine. PATIENTS AND METHODS: In the previous study, 88 patients were enrolled, whereas the analyses below refer to the 60 patients still on immunotherapy at the time of the follow-up. According to previous SARS-CoV-2 exposure, patients were classified as SARS-CoV-2-naive (without previous SARS-CoV-2 exposure) and SARS-CoV-2-experienced (with previous SARS-CoV-2 infection). Neutralizing antibody (NT Ab) titer against the B.1.1 strain and total anti-spike immunoglobulin G concentration were quantified in serum samples. The enzyme-linked immunosorbent spot assay was used for quantification of anti-spike interferon-γ (IFN-γ)-producing cells/106 peripheral blood mononuclear cells. Fifty patients (83.0%) were on immunotherapy alone, whereas 10 patients (7%) were on chemo-immunotherapy. We analyzed separately patients on immunotherapy and patients on chemo-immunotherapy. RESULTS: The median T-cell response at 6 months was significantly lower than that measured at 3 weeks after vaccination [50 interquartile range (IQR) 20-118.8 versus 175 IQR 67.5-371.3 IFN-γ-producing cells/106 peripheral blood mononuclear cells; P < 0.0001]. The median reduction of immunoglobulin G concentration was 88% in SARS-CoV-2-naive subjects and 2.1% in SARS-CoV-2-experienced subjects. SARS-CoV-2 NT Ab titer was maintained in SARS-CoV-2-experienced subjects, whereas a significant decrease was observed in SARS-CoV-2-naive subjects (from median 1 : 160, IQR 1 : 40-1 : 640 to median 1 : 20, IQR 1 : 10-1 : 40; P < 0.0001). A weak correlation was observed between SARS-CoV-2 NT Ab titer and spike-specific IFN-γ-producing cells at both 6 months and 3 weeks after vaccination (r = 0.467; P = 0.0002 and r = 0.428; P = 0.0006, respectively). CONCLUSIONS: Our work highlights a reduction in the immune response in cancer patients, particularly in SARS-CoV-2-naive subjects. Our data support administering a third dose of COVID-19 vaccine to cancer patients treated with programmed cell death protein 1/programmed death-ligand 1 inhibitors.

A snapshot of the immunogenicity, efficacy and safety of a full course of BNT162b2 anti-SARS-CoV-2 vaccine in cancer patients treated with PD-1/PD-L1 inhibitors: a longitudinal cohort study.

BACKGROUND: Very few cancer patients were enrolled in coronavirus disease-2019 vaccine studies. In order to address this gap of knowledge, real-world studies are mandatory. The aim of this study was to assess both humoral and cellular response after a messenger RNA vaccination schedule. PATIENTS AND METHODS: Eighty-eight consecutive cancer patients treated with programmed cell death protein 1/programmed death-ligand 1 inhibitors were enrolled from the beginning of the vaccination campaign for frail patients. Blood samples for humoral and cell-mediated immune response evaluation were obtained before vaccination (T0), before the second administration (T1) and 21 days after the second dose (T2). The primary endpoint was the evaluation of the percentage of participants showing a significant increase in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells, measured by an enzyme-linked immunospot assay, after the second dose of BNT162b2 vaccine. The proportion of patients who reached the primary endpoint is computed together with its exact binomial 95% confidence interval. RESULTS: In SARS-CoV-2-naïve subjects, spike-specific T-cell response was almost undetectable at T0 [median 0.0 interferon-γ (IFN-γ) spot forming units (SFU)/million peripheral blood mononuclear cell (PBMC) interquartile range (IQR) 0-7.5] and significantly increased at T1 and T2 (median 15.0 IFN-γ SFU/million PBMC, 25th-75th 0-40 versus 90 IFN-γ SFU/million PBMC, 25th-75th 32.5-224, respectively) (P < 0.001). Focusing on naïve and experienced SARS-CoV-2 subjects, no differences were reported both in terms of CD4- and CD8-specific T-cell response, suggesting that BNT162b2 is able to elicit both adaptive responses after complete vaccination schedule, regardless of previous SARS-CoV-2 exposure. The level of SARS-CoV-2 neutralizing antibodies was low at T1 in SARS-CoV-2-naïve subjects [median 1 : 5 (IQR 1 : 5-1 : 20)] but reached a significantly higher median of 1 : 80 (25th-75th 1 : 20-1 : 160) at T2 (P < 0.0001). Moreover, no COVID-19 cases were documented throughout the period of study. CONCLUSIONS: Our data have demonstrated that the administration of a full course of BNT162b2 vaccine elicited a sustained immune response against SARS-CoV-2 regardless of the type of cancer and/or the type of immune checkpoint inhibitors.

Development of adaptive immune effector therapies in solid tumors.

State-of-the-art treatment strategies have drastically ameliorated the outcome of patients affected by cancer. However, resistant and recurrent solid tumors are generally nonresponsive to conventional therapies. A central factor in the sequence of events that lead to cancer is an alteration in antitumor immune surveillance, which results in failure to recognize and eliminate the transformed tumor cell. A greater understanding of the dysregulation and evasion of the immune system in the evolution and progression of cancer provides the basis for improved therapies. Targeted strategies, such as T-cell therapy, not only generally spare normal tissues, but also use alternative antineoplastic mechanisms that synergize with other therapeutics. Despite encouraging success in hematologic malignancies, adaptive cellular therapies for solid tumors face unique challenges because of the immunosuppressive tumor microenvironment, and the hurdle of T-cell trafficking within scarcely accessible tumor sites. This review provides a brief overview of current cellular therapeutic strategies for solid tumors, research carried out to increase efficacy and safety, and results from ongoing clinical trials.

Multimodal Approach of Pulmonary Artery Intimal Sarcoma: A Single-Institution Experience.

INTRODUCTION: Pulmonary artery sarcoma (PAS) is a rare tumor, whose therapeutic approach is mainly based on surgery, either pneumonectomy or pulmonary endarterectomy (PEA). The prognosis reported in published series is very poor, with survival of 1.5 months without any kind of treatment. PATIENTS AND METHODS: From January 2010 to January 2016, 1027 patients were referred to our hospital for symptoms of acute or chronic pulmonary thromboembolic disease. Twelve patients having a confirmed diagnosis of PAS underwent PEA. Median age was 64.5 years. Most patients had a long history of symptoms, having a median time of 7.5 months from onset of symptoms to surgery. RESULTS: Following PEA and cardiopulmonary rehabilitation, 10 patients received conventional chemotherapy with doxorubicin and ifosfamide, starting at a median of 42 days from surgery. Four patients also received radiotherapy. Four patients have died due to disease progression, while 7 are still alive, with 5 being disease-free at 4-55+ months from diagnosis. CONCLUSIONS: In patients with PAS, a multimodal approach including PEA, CT, and RT is feasible but it should be evaluated individually, according to the tumor extension and the patient's clinical condition. Apart from improving quality of life mainly by reducing or delaying symptoms due to PH, it may improve life expectancy.

Prognostic impact of progression to induction chemotherapy and prior paclitaxel therapy in patients with germ cell tumors receiving salvage high-dose chemotherapy in the last 10 years: a study of the European Society for Blood and Marrow Transplantation Solid Tumors Working Party.

Little is known about the prognostic impact of prior paclitaxel therapy and response to induction chemotherapy defined as the regimen preceding high-dose chemotherapy (HDCT) for the salvage therapy of advanced germ cell tumors. Twenty European Society for Blood and Marrow Transplantation centers contributed data on patients treated between 2002 and 2012. Paclitaxel used in either prior lines of therapy or in induction-mobilization regimens was considered. Multivariable Cox analyses of prespecified factors were undertaken on PFS and overall survival (OS). As of October 2013, data for 324 patients had been contributed to this study. One hundred and ninety-two patients (59.3%) had received paclitaxel. Sixty-one patients (19%) had a progression to induction chemotherapy, 234 (72%) a response (29 (9%) missing or granulocyte colony-stimulating factor without chemotherapy). Both progression to induction chemotherapy and prior paclitaxel were significantly associated with shorter OS univariably (P<0.001 and P=0.032). On multivariable analysis from the model with fully available data (N=216) progression to induction was significantly prognostic for PFS and OS (P=0.003), but prior paclitaxel was not (P=0.674 and P=0.739). These results were confirmed after multiple imputation of missing data. Progression to induction chemotherapy could be demonstrated as an independent prognostic factor, in contrast to prior paclitaxel.

Long-term survival in patients with metastatic breast cancer receiving intensified chemotherapy and stem cell rescue: data from the Italian registry.

The median survival of women with metastatic breast cancer (MBC) is 18-24 months, and fewer than 5% are alive and disease free at 5 years. We report toxicity and survival in a cohort of MBC patients receiving high-dose chemotherapy (HDC) with autologous hematopoietic SCT (AHSCT) in Italy between 1990 and 2005. Data set for survival analysis has been obtained for 415 patients. Clinical parameters including probability of transplant-related mortality (TRM), PFS and OS. With a median follow-up of 27 months (range 0-172), OS and PFS at 5 and 10 years in the whole population were 47/23 and 32/14%, respectively. A total 239 patients are alive with a median follow-up of 33 months (range 2-174). Survival was significantly more pronounced in patients harboring hormone receptor positive tumors (P=0.028), without visceral metastases (P=0.009) and in women with chemosensitive disease (P<0.0001). Sixty eight patients (20.4%) who received HDC in partial response, stable or progressive disease underwent conversion to CR. TRM was 2.5% overall and 1.3% since 2000. Our findings suggest that could be a role for HDC and AHSCT in delaying disease progression and possibly cure a subset of MBC patient harboring chemosensitive tumors.

T-cell therapy for EBV-associated nasopharyngeal carcinoma: preparative lymphodepleting chemotherapy does not improve clinical results.

BACKGROUND: We and others have demonstrated that adoptive cell therapy with Epstein-Barr virus (EBV)-specific autologous cytotoxic T lymphocytes (CTLs) may control disease progression in patients with EBV-associated nasopharyngeal carcinoma (NPC). With the aim of favoring in vivo T-cell expansion, we optimized our cell therapy approach by administering higher doses of EBV-specific CTLs, following lymphodepleting chemotherapy. PATIENTS AND METHODS: Eleven patients with EBV-related NPC in whom conventional treatment failed have been enrolled. Patients received nonmyeloablative lymphodepleting chemotherapy consisting of cyclophosphamide and fludarabine. Two doses of autologous EBV-specific CTLs were subsequently infused, 2 weeks apart. Study end points were feasibility and clinical outcome. RESULTS: All patients enrolled completed the treatment and were assessable for analysis. The median dose of CTLs per infusion was 3.7 × 10(8). Therapy was well tolerated, with no severe adverse events ascribable to either chemotherapy or cell therapy. Disease control (defined as either tumor regression or disease stabilization lasting >4 months) was obtained in 6 of 11 patients, in keeping with previously published results. CONCLUSIONS: Our data confirm that EBV-specific CTL therapy is safe and associated with antitumor activity in patients with advanced NPC. The use of lymphodepleting chemotherapy before high-dose CTL infusion did not enhance the clinical benefit observed in our previous series.

T cell therapy for nasopharyngeal carcinoma.

Among the novel biologic therapeutics that will increase our ability to cure human cancer in the years to come, T cell therapy is one of the most promising approaches. However, with the possible exception of tumor-infiltrating lymphocytes therapy for melanoma, clinical trials of adoptive T-cell therapy for solid tumors have so far provided only clear proofs-of-principle to build on with further development. Epstein-Barr virus (EBV)-associated malignancies offer a unique model to develop T cell-based immune therapies, targeting viral antigens expressed on tumor cells. In the last two decades, EBV-specific cytotoxic T-lymphocytes (CTL) have been successfully employed for the prophylaxis and treatment of EBV-related lymphoproliferative disorders in immunocompromised hosts. More recently, this therapeutic approach has been applied to the setting of EBV-related solid tumors, such as nasopharyngeal carcinoma. The results are encouraging, although further improvements to the clinical protocols are clearly necessary to increase anti-tumor activity. Promising implementations are underway, including harnessing the therapeutic potential of CTLs specific for subdominant EBV latent cycle epitopes, and delineating strategies aimed at targeting immune evasion mechanisms exerted by tumor cells.

High dose chemotherapy with autologous hematopoietic stem cell support for solid tumors other than breast cancer in adults.

Since the early 1980s high dose chemotherapy with autologous hematopoietic stem cell support was adopted by many oncologists as a potentially curative option for solid tumors, supported by a strong rationale from laboratory studies and apparently convincing results of early phase II studies. As a result, the number and size of randomized trials comparing this approach with conventional chemotherapy initiated (and often abandoned before completion) to prove or disprove its value was largely insufficient. In fact, with the possible exception of breast carcinoma, the benefit of a greater escalation of dose of chemotherapy with stem cell support in solid tumors is still unsettled and many oncologists believe that this approach should cease. In this article, we critically review and comment on the data from studies of high dose chemotherapy so far reported in adult patients with small cell lung cancer, ovarian cancer, germ cell tumors and sarcomas.

Second-line chemotherapy with bleomycin, methotrexate, and vinorelbine (BMV) for patients with squamous cell carcinoma of the head, neck and esophagus (SCC-HN&E) pretreated with a cisplatin-containing regimen: a phase II study.

We evaluated the toxicity and activity of bleomycin, methotrexate and vinorelbine (BMV) combination chemotherapy in cisplatin-pretreated patients with squamous cell carcinoma of the head, neck and esophagus (SCC-HN&E) with the aim of identifying a second-line therapy combination and schedule that might offer an improved therapeutic index. BMV (bleomycin 15 I.U., total dose, methotrexate 30 mg/m2, and vinorelbine 30 mg/m2) was administered intravenously every 2 weeks until disease progression, to 26 consecutive patients. Clinical and CT-scan evaluations revealed 7 partial responses (PR) 127%, 95% confidence interval: 9.6%-44.4%], and 13 patients with stable disease (SD) [50%]. The mean progression-free survival for patients who achieved a PR or SD was 6.47 months (range 4-13 months), with 75% of these patients experiencing partial relief of symptoms, mainly pain and dysphagia. BMV, administered second-line in an outpatient setting, has activity similar to that of the taxanes, but with a more acceptable toxicity profile including an absence of alopecia.

An analysis of p53, BAX and vascular endothelial growth factor expression in node-positive rectal cancer. Relationships with tumour recurrence and event-free survival of patients treated with adjuvant chemoradiation.

Tumours of patients with node-positive rectal cancer were studied by immunohistochemistry for p53, BAX and vascular endothelial growth factor expressions. Results were correlated to the relapse rate, the pattern of relapse and the event-free survival after radical surgery and adjuvant chemoradiation. After a median follow-up of 60 months, 39 patients remained disease-free and 40 patients relapsed (18 local relapses and 22 distant metastases). The majority of disease-free patients showed p53 negative and vascular endothelial growth factor negative tumours. Local relapses occurred more frequently in patients with p53 overexpressing tumours (P<0.01), while distant metastases were in patients with vascular endothelial growth factor positive tumours (P<0.003). Patients with p53 negative or vascular endothelial growth factor negative tumours showed better event-free survival than patients with p53 positive or vascular endothelial growth factor positive tumours. BAX analysis did not show any association with patients' outcome and it was unrelated to the p53 status. Adjuvant treatment strategies for node-positive rectal cancer may be improved by identifying categories of high-risk patients. In this study, vascular endothelial growth factor and p53 expressions correlated with recurrent disease, pattern of relapse and poor event-free survival.

Abnormally enhanced blood concentrations of vascular endothelial growth factor (VEGF) in metastatic cancer patients and their relation to circulating dendritic cells, IL-12 and endothelin-1.

Elevated VEGF blood concentrations have been proven to be associated with poor prognosis in human neoplasms. This finding is generally explained as a consequence of the potential angiogenic properties of VEGF itself. However, preliminary experimental studies suggest that VEGF, in addition to its angiogenic activity, may also play an immunosuppressant role by inhibiting dendritic cell (DC) maturation. The present study was performed to analyze blood levels of VEGF in cancer patients in relation to those of another potentially angiogenic tumor growth factor, endothelin-1 (ET-1), and to the absolute number of circulating immature and mature DC, and serum levels of the best known antitumor cytokine, IL-12. The study was performed in 100 healthy controls and in 80 solid tumor patients (colorectal cancer: 24; gastric cancer: 17; cancer of pancreas: 4; lung cancer: 13; breast cancer: 11; renal cell cancer: 6; gynecologic tumors: 5), 48 of whom showed distant organ metastases. In each patient, we have evaluated serum concentrations of VEGF-165, total VEGF, ET-1, IL-12 and the circulating number of immature (CD123+) and mature (CD11c+) DC. Mean serum levels of VEGF-165 were significantly higher in metastatic patients than in controls or in non-metastatic patients, whereas the total amounts of VEGF were not significantly higher. Moreover, it has been observed that patients with abnormally elevated blood concentrations of VEGF-165 showed significantly lower mean values of immature DC, mature DC and IL-12 and significantly higher mean levels of ET-1 than those with normal concentrations. This study, by confirming that advanced neoplastic disease may be associated with increased endogenous secretion of VEGF, seems to suggest that the association between high blood levels of VEGF and poor prognosis in cancer does not depend only on VEGF-induced stimulation of the neovascularization, but also on VEGF-related immunosuppression.

Serum concentrations of interleukin-18 in early and advanced cancer patients: enhanced secretion in metastatic disease.

The recent availability of adequate methods for cytokine measurement could contribute to better understanding the immunophysiopathology of neoplastic disease. Unfortunately, very little data is available about cytokine secretion in cancer patients. At present, IL-2, IL-12 and IL-15 represent the major antitumor cytokines in humans. Preliminary clinical studies have shown a progressive decline in IL-2 levels with cancer progression, whereas IL-12 seems to increase in the advanced disease. IL-18 is the latest cytokine discovered by potential anticancer and anti-angiogenetic activity, and it has effects similar to those of IL-12. This preliminary study was carried out to analyze IL-18 secretion in early or advanced cancer patients. The study included 40 cancer patients (lung cancer, 21; gastrointestinal tumors, 19), 17 of whom had metastatic disease, and 50 healthy controls. Serum levels of IL-18 were measured by ELISA. No significant difference in IL-18 mean levels was seen between controls and non-metastatic patients. In contrast, metastatic patients showed significantly higher IL-18 mean values with respect to both healthy controls and non-metastatic patients. This preliminary study seems to suggest that metastatic disease may be characterized by enhanced IL-18 secretion the biological and prognostic significance to be established by successive clinical investigation.

Chemotherapy and angiogenesis in advanced cancer: vascular endothelial growth factor (VEGF) decline as predictor of disease control during taxol therapy in metastatic breast cancer.

Angiogenesis is essential for tumor growth. Since vascular endothelial growth factor (VEGF) represents the main angiogenic factor, the control of VEGF secretion could constitute the most important mechanism to achieve the inhibition of angiogenesis-related processes. High blood concentrations have been proven to correlate with poor prognosis in advanced cancer. In experimental conditions, chemotherapeutic agents such as taxol appeared to inhibit VEGF-induced angiogenesis, while at present there are no data about the influence of chemotherapy on VEGF secretion in cancer patients. This preliminary study was performed to evaluate the effect of taxol therapy on VEGF secretion in advanced cancer patients in relation to the clinical response. The study included 14 patients with metastatic breast cancer who were treated with taxol monochemotherapy (175 mg/m2 i.v. every 21 days for three cycles). Serum levels of VEGF were measured by ELISA in blood samples collected before therapy and at 21-day intervals. The clinical response consisted of partial response (PR) in three and stable disease (SD) in six patients, whereas the other five patients had progressive disease (PD). Abnormally high pre-treatment levels of VEGF were seen in 8/14 patients. VEGF mean values significantly decreased during taxol therapy in patients with PR or SD, whereas no decline was observed in patients with PD. Moreover, the percent of normalization or decline greater than 50% in VEGF levels was significantly higher in patients with PR or SD than in those with PD (5/9 vs. 0/5). This preliminary study would suggest that the efficacy of taxol therapy in metastatic breast cancer - at least in terms of disease stabilization - may be associated with a decrease in VEGF blood levels followed by potential inhibition of cancer-related neovascularization.