Evaluation of Prostate-Specific Membrane Antigen (PSMA) Immunohistochemical Expression in Early-Stage Breast Cancer Subtypes.

Breast cancer, known for its diverse subtypes, ranks as one of the leading causes of cancer-related deaths. Prostate-specific membrane antigen (PSMA), primarily associated with prostate cancer, has also been identified in breast cancer, though its role remains unclear. This study aimed to evaluate PSMA expression across different subtypes of early-stage breast cancer and investigate its correlation with clinicopathological factors. This retrospective study included 98 breast cancer cases. PSMA expression was examined in both tumor cells and tumor-associated blood vessels. The analysis revealed PSMA expression in tumor-associated blood vessels in 88 cases and in tumor cells in 75 cases. Ki67 expression correlated positively with PSMA expression in blood vessels (p < 0.0001, RSpearman 0.42) and tumor cells (p = 0.010, RSpearman 0.26). The estrogen and progesterone receptor expression correlated negatively with PSMA levels in blood vessels (p = 0.0053, R Spearman -0.26 and p = 0.00026, R Spearman -0.347, respectively). Human epidermal growth factor receptor 2 (HER2) status did not significantly impact PSMA expression. We did not detect any statistically significant differences between breast cancer subtypes. These findings provide evidence for a heterogenous PSMA expression in breast cancer tissue and suggest its correlation with tumor aggressiveness. Despite the limited sample size, the study provides valuable insights into the potential of PSMA as a prognostic, diagnostic, and therapeutic target in the management of breast cancer.

Glioblastoma Multiforme: The Latest Diagnostics and Treatment Techniques.

BACKGROUND: Glioblastoma multiforme (GBM) is a WHO grade 4 glioma and the most common malignant primary brain tumour. Recently, there has been outstanding progress in the treatment of GBM. In addition to the newest form of GBM removal using fluorescence, three-dimensional (3D) imaging, tomoradiotherapy, moderate electro-hyperthermia, and adjuvant temozolomide (post-operative chemotherapy), new developments have been made in the fields of immunology, molecular biology, and virotherapy. An unusual and modern treatment has been created, especially for stage 4 GBM, using the latest therapeutic techniques, including immunotherapy and virotherapy. Modern oncological medicine is producing extraordinary and progressive therapeutic methods. Oncological therapy includes individual analysis of the properties of a tumour and targeted therapy using small-molecule inhibitors. Individualised medicine covers the entire patient (tumour and host) in the context of immunotherapy. An example is individualised multimodal immunotherapy (IMI), which relies on individual immunological tumour-host interactions. In addition, IMI is based on the concept of oncolytic virus-induced immunogenic tumour cell death. SUMMARY: In this review, we outline current knowledge of the various available treatment options used in the therapy of GBM including both traditional therapeutic strategy and modern therapies, such as tomotherapy, electro-hyperthermia, and oncolytic virotherapy, which are promising treatment strategies with the potential to improve prognosis in patients with GBM. KEY MESSAGES: This newest therapy, immunotherapy combined with virotherapy (oncolytic viruses and cancer vaccines), is displaying encouraging signs for combating GBM. Additionally, the latest 3D imaging is compared to conventional two-dimensional imaging.

Differences between TNM classification and 2-[18F]FDG PET parameters of primary tumor in NSCLC patients.

BACKGROUND: The aim of the study was to compare the TNM classification with 2-[18F]FDG PE T biological parameters of primary tumor in patients with NSCLC. MATERIALS AND METHODS: Retrospective analysis was performed on a group of 79 newly diagnosed NSCLC patients. PET scans were acquired on Gemini TF PET/CT scanner 60-70 min after injection of 2-[18F]FDG with the mean activity of 364 ± 75 MBq, with the area being examined from the vertex to mid-thigh. The reconstructed PET images were evaluated using MIM 7.0 Software for SUVmax, MTV and TLG values. RESULTS: The analysis of the cancer stage according to TNM 8th edition showed stage IA2 in 8 patients, stage IA3 - 6 patients, stage IB - 4 patients, IIA - 3 patients, 15 patients with stage IIB, stage IIIA - 17 patients, IIIB - 5, IIIC - 5, IVA in 7 patients and stage IVB in 9 patients. The lowest TLG values of primary tumor were observed in stage IA2 (11.31 ± 15.27) and the highest in stage IIIC (1003.20 ± 953.59). The lowest value of primary tumor in SUVmax and MTV were found in stage IA2 (6.8 ± 3.8 and 1.37 ± 0.42, respectively), while the highest SUVmax of primary tumor was found in stage IIA (13.4 ± 11.4) and MTV in stage IIIC (108.15 ± 127.24). CONCLUSION: TNM stages are characterized by different primary tumor 2-[18F]FDG PET parameters, which might complement patient outcome.

Predictive factors determining incomplete response to radioiodine therapy in patients with differentiated thyroid cancer.

BACKGROUND: Although differentiated thyroid cancer (DTC) has relatively favorable course, factors predicting the course of the disease are intensively searched. The aim of the study was to identify the clinical factors determining incomplete response to radioiodine therapy in patients with DTC. METHODS: We retrospectively analyzed 385 consecutive patients with DTC treated and followed-up at a single tertiary reference center. We investigated clinical factors detectable during first hospitalization 3-6 months following total thyroidectomy due to DTC, which may serve as prognostic factors determining response to DTC therapy in a long-term follow-up. RESULTS: Stimulated thyroglobulin (sTg) was the only parameter significantly correlated with the cumulative radioiodine activity (r=0.247, P<0.001). The need for repeated radioiodine administration (≥3 doses) was best predictable on the basis of sTg concentration assessed at the moment of qualification to radioiodine therapy (P=0.003). Predictive value of the sTg for incomplete response to radioiodine has been confirmed with the ROC curve analysis and the best proposed cut-off value was 8.17 ng/mL (sensitivity 55%, specificity 77%, positive predictive value 42.1%, negative predictive value 84.7%); sTg over 8.17 ng/mL increases the risk of incomplete response to therapy 2.5-folds (P=0.002). CONCLUSIONS: sTg, assessed at the moment of qualification to radioiodine therapy, as the most important factor determining incomplete response to radioiodine therapy in patients with DTC, should be particularly taken into consideration in predicting the future course of the disease as well as treatment and follow-up planning. Radical thyroidectomy may help to increase the effectiveness of treatment.

Clinical significance of nestin and its association with survival in neuroendocrine lung tumours.

Nestin is considered to be a cancer stem cell marker. Nestin expression in neuroendocrine tumours might be useful to predict prognosis and facilitate treatment planning. 88 patients with neuroendocrine lung tumours operated in the Department of Thoracic Surgery from 2007 to 2015 were included into the study. Immunohistochemical staining for nestin was performed. Clinicopathological and survival data were retrospectively analyzed. Nestin expression was detected in 15 (17%) specimens. Multivariate analysis showed that lymph node metastases (p = 0.0001; hazard ratio (HR) = 3.93; confidence interval (CI) 95%: 1.96-7.87), nestin expression (p = 0.034; HR = 2.30; CI 95%: 1.06-4.99) and patient's age (p = 0.024; HR = 1.04; CI 95%: 1.00-1.09) were independent negative prognostic factors. Nestin expression was significantly higher in large cell neuroendocrine carcinoma when compared with carcinoids (p = 0.001). Collected data support the thesis that nestin can be regarded as a biomarker in patients with neuroendocrine lung tumours.

Metabolic activity in bone metastases of breast and prostate cancer were similar as studied by 18F-FDG PET/CT. The role of 99mTc-MDP.

OBJECTIVE: The aim of this study was to compare the metabolic activity of metastatic foci from breast and prostate cancer patients as scanned by fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and by technetium-99m methyl diphosphonate (99mTc-MDP) bone scan (BS). SUBJECTS AND METHODS: Forty one patients were studied, divided into 2 groups based on histologically confirmed diagnosis: a) Breast cancer group, 23 women, mean age: 61±12 years, range: 37-79 years and, b) Prostate cancer group, 18 men, mean age 68±8 years, range: 52-82 years. Another group of 17 non cancer atherosclerotic subjects 9 women and 8 men, of mean age and age range similar to the above were also studied for comparison. The R index (the total count rate in bone metastases divided by the total count rate in a contralateral area), the maximum semi-quantitative standardized uptake value (SUVmax) of BS lesions and the mean number of metastases were evaluated. For the metastatic findings in the PET/CT scans the automatic method of contouring with 50% background cut-off was used, while for the 99mTc-MDP BS metastases were delineated manually. RESULTS: The mean R index of the bone metastatic foci studied by 18F-FDG PET/CT was 1.89±0.69 for Groups I and II patients. There was no significant difference of the R index between prostate cancer and breast cancer metastases (1.95±0.86 vs 1.83±0.52). The average SUVmax value was significantly higher in breast cancer patients than in prostate cancer patients (5.15±2.54 vs 4.01±1.71; P<0.05). There was no significant correlation in both cancer groups between R index and SUVmax values. The number of metastatic foci diagnosed by the 99mTc-MDP BS scan was much less than by the 18F-FDG PET/CT. CONCLUSION: No significant correlation was noticed in the metabolic activity-glucose utilization of metastatic bone foci between breast and prostate cancer cases. This observation validates the independent value of analyzed diagnostic methods and suggests negligible influence of glucose utilization in bone re-modeling in the above metastatic cancer cells. The 18F-FDG PET/CT bone scan was much better in diagnosing metastases compared to the 99mTc-MDP scan.

Application of positron emission tomography (PET/CT) in diagnosis of breast cancer. Part I. Diagnosis of breast cancer prior to treatment.

Positron emission tomography with computed tomography (PET/CT) is gaining popularity as a method for overall staging assessment of breast cancer. Currently, it is not a part of the routine workup before the beginning of treatment, because of insufficient sensitivity for the detection of small tumors (due to its limited spatial resolution), the heterogeneity of radiotracer uptake by the primary tumor, and unsatisfactory sensitivity in detection of lymph node metastases (particularly when they are small). Nevertheless, it should be considered when there is a high risk of metastases, because then initial PET/CT examination allows for accurate staging and may change the treatment algorithm in up to almost 50% of stage III patients, due to detection of distant and lymph node metastases throughout the whole body. Despite the discussed limitations of PET/CT, there is ongoing research concerning the recommendations for the examination prior to treatment. For a particular group of patients with high risk of metastases, PET/CT may be expected to become a part of the routine workup as the most appropriate staging method.

The application of positron emission tomography (PET/CT) in diagnosis of breast cancer. Part II. Diagnosis after treatment initiation, future perspectives.

Similarly to the applications described in the first part of this publication, positron emission tomography with computed tomography (PET/CT) is also gaining importance in monitoring a tumour's response to therapy and diagnosing breast cancer recurrences. This is additionally caused by the fact that many new techniques (dual-time point imaging, positron emission tomography with magnetic resonance PET/MR, PET/CT mammography) and radiotracers (16α-18F-fluoro-17ß-estradiol, 18F-fluorothymidine) are under investigation. The highest sensitivity and specificity when monitoring response to treatment is achieved when the PET/CT scan is made after one or two chemotherapy courses. Response to anti-hormonal treatment can also be monitored, also when new radiotracers, such as FES, are used. When monitoring breast cancer recurrences during follow-up, PET/CT has higher sensitivity than conventional imaging modalities, making it possible to monitor the whole body simultaneously. New techniques and radiotracers enhance the sensitivity and specificity of PET and this is why, despite relatively high costs, it might become more widespread in monitoring response to treatment and breast cancer recurrences.

Head-to-Head Comparison of [18F]PSMA-1007 and [18F]FDG PET/CT in Patients with Triple-Negative Breast Cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) exhibits high aggressiveness and a notably poorer prognosis at advanced stages. Nuclear medicine offers new possibilities, not only for diagnosis but also potentially promising therapeutic strategies. This prospective study explores the potential of prostate-specific membrane antigen (PSMA) as a diagnostic and therapeutic target in TNBC. METHODS: the research investigates PSMA expression in vivo among TNBC patients using [18F]PSMA-1007 PET/CT and compares it head-to-head with the standard-of-care [18F]FDG PET/CT. RESULTS: The study involves 10 TNBC patients, revealing comparable uptake of [18F]PSMA-1007 and [18F]FDG in primary and metastatic lesions. Nodal metastases were found in eight patients, showing similar SUVmax values in both modalities. Two patients had uncountable lung metastases positive in both [18F]FDG and [18F]PSMA-1007 scans. PET-positive bone metastases were identified by 18F-PSMA in four patients, while elevated [18F]FDG uptake was found only in three of them. Distant metastases displayed higher SUVmax values in the [18F]PSMA-1007 PET/CT, as compared to [18F]FDG. Additionally, brain metastases were exclusively detected using [18F]PSMA-1007. CONCLUSIONS: the findings provide valuable insights into the expression of PSMA in TNBC and underscore the potential clinical significance of [18F]PSMA-1007 PET/CT in enhancing both diagnostic and therapeutic approaches for this aggressive breast cancer subtype.

Expression of semaphorin 3A (SEMA3A) in breast cancer subtypes.

Breast cancer is a major health concern, and its accurate diagnosis and management depend on identifying its histological type and biological subtype. Semaphorin-3A (SEMA3A) is a membrane protein with diverse roles in cellular processes, including cancer progression and angiogenesis regulation. However, its role in breast cancer remains poorly understood. This study aimed to evaluate SEMA3A expression in breast cancer and investigate its distribution across breast cancer subtypes: luminal A, luminal B, HER2-positive, and triple-negative breast cancer (TNBC). Immunohistochemical evaluation was performed on 98 breast cancer patients' tumor specimens, and SEMA3A expression was assessed in tumor cells and vessels. The study included the analysis of the Ki67 proliferation index, estrogen receptor (ER) expression, progesterone receptor (PR) expression, and HER2 status in conjunction with SEMA3A expression. Analysis indicated positive expression of SEMA3A in breast cancer cells in 60 out of 98 cases. SEMA3A expression correlated positively with Ki67 levels in tumor cells (p = 0.0005, R Spearman 0.338). Notably, a negative correlation was found between SEMA3A expression and ER and PR levels in tumor cells (p = 0.04, Spearman's R = - 0.21 and p = 0.016, Spearman's R = - 0.25 respectively). HER2 status did not significantly influence SEMA3A expression. The study demonstrated positive SEMA3A expression in tumor vessels across all subtypes in 91 out of 98 cases, suggesting its involvement in endothelial cell function. However, no significant differences in SEMA3A expression were observed between breast cancer subtypes either in vessels or tumor cells. These findings suggest that elevated SEMA3A expression may be associated with worse prognosis in breast cancer, especially in ER- and PR-negative tumors. Further investigations are warranted to fully comprehend the role of SEMA3A in breast cancer biology, which may lead to the identification of novel therapeutic targets and personalized treatment strategies for breast cancer patients.

Tumour-Induced Osteomalacia-A Long Way to the Diagnosis Facilitated by [68Ga]Ga-DOTATATE PET/CT.

Background: Tumour-induced osteomalacia (TIO) is a rare paraneoplastic syndrome. Detecting the primary tumour in TIO is challenging using conventional imaging methods. This study assesses the efficacy of [68Ga]Ga-DOTATATE PET/CT in identifying the primary tumour. Methods: Six patients with suspected TIO underwent [68Ga]Ga-DOTATATE PET/CT. The patients' clinical history and biochemical parameters were analysed. Results: [68Ga]Ga-DOTATATE PET/CT successfully identified primary tumours in four patients (femoral bones for two, iliac bone for one, subcutaneous tissue of pubic region for one). Tumour removal led to clinical and laboratory improvement. In one patient, PET/CT showed rib uptake, but the biopsy was negative. One patient showed no tumour lesions on PET/CT despite clinical evidence. Two patients had focal recurrence at the primary tumour site, detected by follow-up PET/CT. Conclusions: [68Ga]Ga-DOTATATE PET/CT is a valuable tool for detecting primary tumours in TIO, aiding in accurate diagnosis and guiding surgery, leading to improved outcomes. Further research is needed to validate these findings and explore [68Ga]Ga-DOTATATE PET/CT in other paraneoplastic syndromes.

Patients with chronic hepatitis type C and interferon-alpha-induced hyperthyroidism in two-years clinical follow-up.

OBJECTIVES: Interferon-α (IFN-α) is a gold standard in the therapy of viral chronic hepatitis type C (CHC). However, such treatment might lead to thyroid dysfunction. Patients usually present hypothyroidism, but rarely also hyperthyroidism may develop. The aim of the study is to present two-year clinical follow-up of patients with CHC and IFN-α-induced hyperthyroidism (IIH), with special regard to the methods and efficacy of the therapy. METHODS: A group of 106 patients with CHC and IIH were analyzed. Subjects were divided into two groups according to etiology: group 1, with Graves' disease (GD) and group 2, with Hashitoxicosis (HT). The diagnosis of GD and HT was based on: clinical signs of hyperthyroidism, hormonal profile (TSH, fT4, fT3), level of thyroid autoantibodies (Tg-Abs, TPO-Abs, TSHRAbs). Treatment of hyperthyroidism was monitored by repeated clinical assessment and laboratory tests. RESULST: 28 patients (26 with GD of which 5 exhibited mild orbitopathy and 2 with HT) were treated with radioiodine [the average dose of was 17 mCi [668 MBq]. In adition 78 out of 80 patients with HT mostly ß-blocker therapy was successful (transient hyperthyroidism). At the end of the observation period, in group 1 remission was achieved in 17 (65.4%) cases, 6 (23.1%) patients showed hypothyroidism and 3 (11.5%) presented recurrence of hyperthyroidism. CONCLUSIONS: Most patients with IIH present Hashitoxicosis, while a minority of them develop Graves' disease. In a majority of patients with HT spontaneous remission of disease occurs. In patients with long-term hyperthyroidism, radioiodine therapy is an effective and well-tolerated.

[Positron emission tomography (PET) in malignant ovarian tumors]. / Pozytonowa tomografia emisyjna (PET) w nowotworach zlosliwych jajnika.

Accessibility of positron emission tomography integrated with computed tomography (PET/CT) has improved significantly in recent years. PET/CT with the use of 18F-deoxyglucose (FDG) is widely used in patients with ovarian malignancies at different stages of the management. FDG PET/CT shows high diagnostic accuracy in the differentiation of benign and malignant ovarian lesions with the exception of borderline tumors that may cause false negative results. Moreover FDG PET/CT is used in some centers for preoperative staging and determining the prognosis of ovarian cancer However further studies including larger groups of patients are needed to confirm the applicability of FDG PET/CT in case of the two abovementioned indications. Until now, the best documented indication for FDG PET/ CT in patients with ovarian cancer has been the detection of recurrence, especially in subjects with elevated CA 125 marker and negative results of other imaging techniques. This review focuses on the applicability of PET with the use of FDG in ovarian malignancies and points out to the limitations of this method.

Performance of a deep learning enhancement method applied to PET images acquired with a reduced acquisition time.

BACKGROUND: This study aims to evaluate the performance of a deep learning enhancement method in PET images reconstructed with a shorter acquisition time, and different reconstruction algorithms. The impact of the enhancement on clinical decisions was also assessed. MATERIAL AND METHODS: Thirty-seven subjects underwent clinical whole-body [18F]FDG PET/CT exams with an acquisition time of 1.5 min per bed position. PET images were reconstructed with the OSEM algorithm using 66% counts (imitating 1 min/bed acquisition time) and 100% counts (1.5 min/bed). Images reconstructed from 66% counts were subsequently enhanced using the SubtlePET™ (SP) deep-learning-based software, (Subtle Medical, USA) - with two different software versions (SP1 and SP2). Additionally, images obtained with 66% counts were reconstructed with QClear™ (GE, USA) algorithm and enhanced with SP2. Volumes of interest (VOI) of the lesions and reference VOIs in the liver, brain, bladder, and mediastinum were drawn on OSEM images and copied on SP images. Quantitative SUVmax values per VOI of OSEM or QClear™ and AI-enhanced 'shortened' acquisitions were compared. RESULTS: Two hundred and fifty-two VOIs were identified (37 for each reference region, and 104 for the lesions) for OSEM, SP1, SP2, and QClear™ images AI-enhanced with SP2. SUVmax values on SP1 images were lower than standard OSEM, but on SP2 differences were smaller (average difference for SP1 11.6%, for SP2 -4.5%). For images reconstructed with QClear™, SUVmax values were higher (average +8.9%, median 6.1%, SD 18.9%). For small lesions with SUVmax values range 2.0 to 4.0 decrease of measured SUVmax was much less significant with SP2 (for liver average -6.5%, median -5.6% for lesions average -5.6%, median - 6.0, SD 5.2%) and showed the best correlation with original OSEM. While no artifacts and good general diagnostic confidence were found in AI-enhanced images, SP1, the images were not equal to the original OSEM - some lesions were hard to spot. SP2 produced images with almost the same quality as the original 1.5 min/bed OSEM reconstruction. CONCLUSIONS: The studied deep learning enhancement method can be used to accelerate PET acquisitions without compromising quantitative SUVmax values. AI-based algorithms can enhance the image quality of accelerated PET acquisitions, enabling the dose reduction to the patients and improving the cost-effectiveness of PET/CT imaging.

[131I]I-MIBG-negative metastases of a recurrent sporadic paraganglioma in a female with achondroplasia.

Not required for Clinical Vignette.

Asphericity derived from [18F]FDG PET as a new prognostic parameter in cervical cancer patients.

The objective of this study was to assess the prognostic value of asphericity (ASP) and standardized uptake ratio (SUR) in cervical cancer patients. Retrospective analysis was performed on a group of 508 (aged 55 ± 12 years) previously untreated cervical cancer patients. All patients underwent a pretreatment [18F]FDG PET/CT study to assess the severity of the disease. The metabolic tumor volume (MTV) of the cervical cancer was delineated with an adaptive threshold method. For the resulting ROIs the maximum standardized uptake value (SUVmax) was measured. In addition, ASP and SUR were determined as previously described. Univariate Cox regression and Kaplan-Meier analysis with respect to event free survival (EFS), overall survival (OS), freedom from distant metastasis (FFDM) and locoregional control (LRC) was performed. Additionally, a multivariate Cox regression including clinically relevant parameters was performed. In the survival analysis, MTV and ASP were shown to be prognostic factors for all investigated endpoints. Tumor metabolism quantified with the SUVmax was not prognostic for any of the endpoints (p > 0.2). The SUR did not reach statistical significance either (p = 0.1, 0.25, 0.066, 0.053, respectively). In the multivariate analysis, the ASP remained a significant factor for EFS and LRC, while MTV was a significant factor for FFDM, indicating their independent prognostic value for the respective endpoints. The alternative parameter ASP has the potential to improve the prognostic value of [18F]FDG PET/CT for event-free survival and locoregional control in radically treated cervical cancer patients.

Clinical, Biochemical, and Sonographic Factors Influencing Performance of Parathormone Washout Measurement vs. 99mTc-MIBI Scintigraphy in the Preoperative Diagnostics of Parathyroid Adenomas.

The purpose of the study was to assess the clinical, biochemical, and sonographic factors influencing the performance of parathormone washout measurement (PTHw) vs. MIBI in the preoperative localization of parathyroid adenoma (PA). The studied group consisted of 39 patients with primary or tertiary hyperparathyroidism. The measurement of PTH concentrations was performed using an electro-chemiluminescence immunoassay. Scintigraphic localization of PA was carried out using dual-tracer planar neck scintigraphy, using 74 MBq 99mTc-pertechnetate and 740 MBq of 99mTc-MIBI. MIBI was unambiguously positive in 74% of patients. Among patients with negative or inconclusive MIBI, 90% had a positive PTHw result. Among patients with negative PTHw, two out of three had a positive MIBI result. The PTHw of lesions <10 mm in their largest diameter yielded positive results in 95%, compared to 75% for MIBI. For lesions ≥10 mm in largest diameter, 88% were visualised using MIBI. In conclusion, PTHw is a highly effective, easy, quick, safe, and relatively cheap procedure which might be considered for PA localisation, especially in patients with lesions presenting typical ultrasound features and a size below 10 mm. MIBI remains a useful procedure in specialized centres, particularly for patients in whom PTHw failed, larger lesions, and in cases of the ectopic location of PA.

Immunotherapy in Ovarian Cancer.

Despite advances in surgery and chemotherapy, ovarian cancer remains one of the most lethal malignancies. Hence, the implementation of novel treatment approaches is required to improve the outcomes of the disease. Immunotherapy has been proven to be effective in many tumors and has already been incorporated into clinical practice. In this review, we describe key strategies in immunotherapy of ovarian cancer and summarize data from clinical studies assessing immunological prospects which could improve ovarian cancer treatment approaches in the future. The most notable current strategies include checkpoint blockade agents, the use of vaccines, adoptive cell transfer, as well as various combinations of these methods. While several of these options are promising, large controlled randomized studies are still needed to implement new immunotherapeutic options into clinical practice.