Neoadjuvant chemotherapy with or without radiotherapy versus upfront surgery for resectable pancreatic adenocarcinoma: a meta-analysis of randomized clinical trials.

BACKGROUND: The role of neoadjuvant chemotherapy (NC) in resectable pancreatic cancer (RPC) has yet to be defined. This review aims to analyze the benefit of NC in RPC compared with upfront surgery (US) in terms of overall survival (OS) and disease-free survival (DFS). PATIENTS AND METHODS: PubMed, CENTRAL (The Cochrane Library), and Embase were systematically reviewed until 3 November 2021. Abstract proceedings and virtual meeting presentations from the American Society of Clinical Oncology and the European Society of Medical Oncology conferences, reference articles of published clinical trials, and review articles were considered. Only randomized clinical trials (RCTs) comparing NC administration with or without radiotherapy previous with surgery (experimental arm) versus US followed by adjuvant chemotherapy with or without radiotherapy (control arm) for RPC were included. RESULTS: A total of 1135 studies were screened. Of these, 1117 studies were primarily excluded. Of the remaining 18 studies, 5 were excluded because of no adequate trial design for this work and 7 others had no available results. Finally, 6 trials with 469 patients with pancreatic cancer randomized to NC (n = 212) or US (n = 257) were selected. Compared with US, NC significantly improved OS [hazard ratio (HR) 0.75; 95% confidence interval (CI) 0.58-0.98; P = 0.033] and DFS (HR 0.73; 95% CI 0.59-0.89; P = 0.002). While the NC approach was not significantly associated with lower resection rate [relative risk (RR) 0.92; 95% CI 0.84-1.01; P = 0.069], the R0 resection rate was significantly higher for NC than for US (RR 1.31; 95% CI 1.13-1.52; P = 0.0004). CONCLUSION: This is the first meta-analysis of RCTs showing that NC improves OS for RPC compared with US followed by adjuvant therapy. Ongoing RCTs should confirm these findings with FOLFIRINOX to generalize the indication of NC.

Results from the INMUNOSUN-SOGUG trial: a prospective phase II study of sunitinib as a second-line therapy in patients with metastatic renal cell carcinoma after immune checkpoint-based combination therapy.

BACKGROUND: The INMUNOSUN trial had the objective of prospectively evaluating the efficacy and safety of sunitinib as a pure second-line treatment in patients with metastatic renal cell carcinoma (mRCC) who have progressed to first-line immune checkpoint inhibitor (ICI)-based therapies. PATIENTS AND METHODS: A multicenter, phase II, single-arm, open-label study was carried out in patients with a histologically confirmed diagnosis of mRCC with a clear-cell component who had progressed to a first-line regimen of ICI-based therapies. All patients received sunitinib 50 mg once daily orally for 4 weeks, followed by a 2-week rest period following package insert instructions. The primary outcome was the objective response rate. RESULTS: Twenty-one assessable patients were included in the efficacy and safety analyses. Four patients [19.0%, 95% confidence interval (CI) 2.3% to 35.8%] showed an objective response (OR), and all of them had partial responses. Additionally, 14 (67%) patients showed a stable response, leading to clinical benefit in 18 patients (85.7%, 95% CI 70.7% to 100%). Among the four assessable patients who showed an OR, the median duration of the response was 7.1 months (interquartile range 4.2-12.0 months). The median progression-free survival (PFS) was 5.6 months (95% CI 3.1-8.0 months). The median overall survival (OS) was 23.5 months (95% CI 6.3-40.7 months). Patients who had better antitumor response to first-line ICI-based treatment showed a longer PFS and OS with sunitinib. The most frequent treatment-emergent adverse events were diarrhea (n = 11, 52%), dysgeusia (n = 8, 38%), palmar-plantar erythrodysesthesia (n = 8, 38%), and hypertension (n = 8, 38%). There was 1 patient who exhibited grade 5 pancytopenia, and 11 patients experienced grade 3 adverse events. Eight (38%) patients had serious adverse events, four of which were considered to be related to sunitinib. CONCLUSION: Although the INMUNOSUN trial did not reach the pre-specified endpoint, it demonstrated that sunitinib is active and can be safely used as a second-line option in patients with mRCC who progress to new standard ICI-based regimens.

SAUL, a single-arm study of atezolizumab for chemotherapy-pretreated locally advanced or metastatic carcinoma of the urinary tract: outcomes by key baseline factors, PD-L1 expression and prior platinum therapy.

BACKGROUND: The impact of pretreatment factors on immune checkpoint inhibition in platinum-refractory advanced urothelial cancer (aUC) deserves further evaluation. The aim was to study the association of Bellmunt risk factors, time from last chemotherapy (TFLC), previous therapy and PD-L1 expression with atezolizumab efficacy in platinum-refractory aUC. PATIENTS AND METHODS: This was a post-hoc analysis of patients who had received prior cisplatin or carboplatin in the prospective, single-arm, phase IIIb SAUL study (NCT02928406). Patients were treated with 3-weekly atezolizumab 1200 mg intravenously. The primary outcome was overall survival (OS). Relationships were analysed using Cox regression and long-rank test. RESULTS: Of 997 patients in SAUL, 969 were eligible for this analysis. The number of Bellmunt risk factors was associated with OS (P < 0.001); median OS (mOS) for 0, 1 and 2-3 risk factors was 17.9, 8.9 and 3.3 months, respectively. Significant associations were also observed between OS and TFLC (P < 0.001), programmed death-ligand 1 (PD-L1) expression (P = 0.002), and prior perioperative chemotherapy (P = 0.013); mOS was 6.97 versus 11.63 months for TFLC ≤6 versus >6 months, 7.75 versus 11.6 months for PD-L1 expression on <1% of tumour-infiltrating immune cells (ICs) (IC0)/expression on 1% to <5% of tumour-infiltrating ICs (IC1) versus expression on ≥5% of tumour-infiltrating ICs (IC2/3) and 10.2 versus 7.8 months for prior versus no prior perioperative chemotherapy, respectively. The type of platinum compound and number of previous treatment lines were not associated with outcomes. CONCLUSIONS: Post-platinum atezolizumab is active in aUC, irrespective of previous platinum compound and lines of therapy. Bellmunt risk stratification, PD-L1 expression, TFLC and perioperative chemotherapy were identified as prognostic factors for OS with second-line atezolizumab, indicating the need for novel prognostic signatures for immunotherapy-treated patients with aUC.

Pneumatosis intestinalis in a radioactive iodine-refractory metastasic thyroid papillary carcinoma with BRAFV600E mutation treated with dabrafenib-trametinib: a case report.

BACKGROUND: Pneumatosis intestinalis (PI) is a rare entity which refers to the presence of gas within the wall of the small bowel or colon which is a radiographic sign. The etiology and clinical presentation are variable. Patients with PI may present either with chronic mild non-specific symptoms or with acute abdominal pain with peritonitis. Some cases of intestinal pneumatosis have been reported as adverse events of new oncological treatments such as targeted therapies that are widely used in multiple tumors. CASE PRESENTATION: A 59-year-old caucasian female with radioactive iodine-refractory metastatic thyroid papillary carcinoma with BRAFV600E mutation was treated with dabrafenib and trametinib as a compassionate use. After 4 months treatment, positron emission tomography-computed tomography (PET-CT) showed PI. At the time of diagnosis, the patient was asymptomatic without signs of peritonitis. The initial treatment was conservative and no specific treatment for PI was needed. Unfortunately, after dabrafenib-trametinib withdrawal, the patient developed tumor progression with significant clinical worsening. CONCLUSIONS: This case report is, in our knowledge, the first description of PI in a patient treated with dabrafenib-trametinib. Conservative treatment is feasible if there are no abdominal symptoms.

Recent advances in neoadjuvant immunotherapy for urothelial bladder cancer: What to expect in the near future.

Urothelial bladder cancer (UC) is the most common malignancy involving the urinary system and represents a significant health problem. Immunotherapy has been used for decades for UC with intravesical bacillus Calmette-Guérin (BCG) set as the standard of care for non-muscle-invasive bladder cancer (NMIBC). The advent of immune checkpoint inhibitors (ICIs) has completely transformed the treatment landscape of bladder cancer enabling to expand the treatment strategies. Novel ICIs have successfully shown improved outcomes on metastatic disease to such an extent that the standard of care paradigm has changed leading to the development of different trials with the aim of determining whether ICIs may have a role in early disease. The localized muscle-invasive bladder cancer (MIBC) scenario remains challenging since the recurrence rate continues to be high despite all therapeutic efforts. This article will review the current experience of ICIs in the neoadjuvant setting of UC, the clinical trials landscape and finally, an insight of what to expect in the immediate and mid-term future.

Complete response to immune checkpoint inhibitors-based therapy in advanced renal cell carcinoma patients. A meta-analysis of randomized clinical trials.

BACKGROUND: A major breakthrough with immunotherapy is its potential to achieve complete responses (CR) in a subset of advanced renal cell carcinoma (RCC) patients. We aim at evaluating the incidence and relative risk (RR) of CR in RCC patients treated with immune checkpoint inhibitors (ICIs). MATERIALS AND METHODS: Searching the MEDLINE/PubMed, Cochrane Library and ASCO Meeting abstracts prospective studies were identified. The proportion of patients with CR events and the derived 95% confidence intervals (CIs) were calculated for each study. Combined relative risks (RRs) and 95% CIs were calculated using fixed- or random-effects methods. The analysis was performed in the intention to treat population, in the PD-L1 expressing (≥1%) RCC tumors and in patients treated with the combination of ICIs and anti-VEGFR tyrosine kinase inhibitors. RESULTS: Six articles were considered for final analysis (total of 4.531 patients). The incidence of CR was 6.2% with ICIs and 2.6% with SOC. Treatment with ICIs significantly increased the risk of achieving CR compared to SOC (RR = 2.40; P = 0.001). This data was confirmed for patients treated with the combination of ICIs plus anti-VEGFR tyrosine kinase inhibitors (RR = 2.50; P = 0.002). In PD-L1 positive tumors, the incidence of CR was 10.0% with ICIs and 4.0% in the SOC arm (RR = 2.49; P < 0.0001). CONCLUSIONS: ICIs provide higher rates of CR compared to SOC, even higher in patients with PD-L1 positive tumors.

Combination of statin/vitamin D and metastatic castration-resistant prostate cancer (CRPC): a post hoc analysis of two randomized clinical trials.

In castration-resistant prostate cancer (CRPC) patients, observational studies have reported that statins may boost the antitumor activity of abiraterone (AA) and data suggest an improvement in efficacy; conclusions with vitamin D are less clear but an eventual benefit has been pointed. We conducted a post hoc analysis of individual patient data of CRPC patients treated with prednisone and/or AA with or without statins/vitamin D on randomized clinical trials. In the COU-AA-301 trial, use of AA with statin and vitamin D reduced the risk of death by 38% (p = 0.0007) while AA alone was associated with a decrease of 10% (p = 0.025), compared to prednisone alone. Meanwhile, in the COU-AA-302 trial, use of AA plus statin plus vitamin D was associated with a reduced risk of death of 26% (p = 0.0054). In this data analysis from two prospective randomized clinical trials, statin and vitamin D use was associated with superior overall survival in metastatic CRPC patients treated with AA and prednisone. To our knowledge, this is the first report suggesting the impact of statin plus vitamin D in this population. New strategies using big data may help to clarify these questions easily and in a most cost-effective approach.

SEOM clinical guideline for treatment of kidney cancer (2019).

In this article, we review de state of the art on the management of renal cell carcinoma (RCC) and provide recommendations on diagnosis and treatment. Recent advances in molecular biology have allowed the subclassification of renal tumours into different histologic variants and may help to identify future prognostic and predictive factors. For patients with localized disease, surgery is the treatment of choice with nephron-sparing surgery recommended when feasible. No adjuvant therapy has demonstrated a clear benefit in overall survival. Considering the whole population of patients with advanced disease, the combination of axitinib with either pembrolizumab or avelumab increase response rate and progression-free survival, compared to sunitinib, but a longer overall survival has only been demonstrated so far with the pembrolizumab combo. For patients with IMDC intermediate and poor prognosis, nephrectomy should not be considered mandatory. In this subpopulation, the combination of ipilimumab and nivolumab has also demonstrated a superior response rate and overall survival vs. sunitinib. In patients progressing to one or two antiangiogenic tyrosine-kinase inhibitors, both nivolumab and cabozantinib in monotherapy have shown benefit in overall survival compared to everolimus. Although no clear sequence can be recommended, medical oncologists and patients should be aware of the recent advances and new strategies that improve survival and quality of life in patients with metastatic RCC.

Correlation of radiological and immunochemical parameters with clinical outcome in patients with recurrent glioblastoma treated with Bevacizumab.

BACKGROUND: Some phase 2 trials had reported encouraging progression-free survival with Bevacizumab in monotherapy or combined with chemotherapy in glioblastoma. However, phase 3 trials showed a significant improvement in progression free survival without a benefit in overall survival. To date, there are no predictive biomarker of response for Bevacizumab in glioblastoma. METHODS: We used Immunochemical analysis on tumor samples and pretreatment and post-treatment perfusion-MRI to try to identify possible predictive angiogenesis-related biomarkers of response and survival in patients with glioblastoma treated with bevacizumab in the first recurrence. We analyzed histological parameters: vascular proliferation, mitotic number and Ki-67 index; molecular factors: MGMT promoter methylation, EGFR amplification and EGFR variant III; immunohistochemical: MET, Midkine, HIF1, VEGFA, VEGF-R2, CD44, Olig2, microvascular area and microvascular density; and radiological: rCBV. RESULTS: In the statistical analysis, no significant correlation of any histological, molecular, microvascular or radiological parameters could be demonstrated with the response rate, PFS or OS with bevacizumab treatment. CONCLUSION: Unfortunately, in this histopathological, molecular, immunohistochemical and neuroradiological study we did not find any predictive biomarker of response or survival benefit for Bevacizumab in glioblastoma.

SEOM clinical guideline for treatment of muscle-invasive and metastatic urothelial bladder cancer (2018).

The goal of this article is to provide recommendations about the management of muscle-invasive (MIBC) and metastatic bladder cancer. New molecular subtypes of MIBC are associated with specific clinical-pathological characteristics. Radical cystectomy and lymph node dissection are the gold standard for treatment and neoadjuvant chemotherapy with a cisplatin-based combination should be recommended in fit patients. The role of adjuvant chemotherapy in MIBC remains controversial; its use must be considered in patients with high-risk who are able to tolerate a cisplatin-based regimen, and have not received neoadjuvant chemotherapy. Bladder-preserving approaches are reasonable alternatives to cystectomy in selected patients for whom cystectomy is not contemplated either for clinical or personal reasons. Cisplatin-based combination chemotherapy is the standard first-line protocol for metastatic disease. In the case of unfit patients, carboplatin-gemcitabine should be considered the preferred first-line chemotherapy treatment option, while pembrolizumab and atezolizumab can be contemplated for individuals with high PD-L1 expression. In cases of progression after platinum-based therapy, PD-1/PD-L1 inhibitors are standard alternatives. Vinflunine is another option when anti-PD-1/PD-L1 therapy is not possible. There are no data from randomized clinical trials regarding moving on to immuno-oncology agents.

Specific IgE induced by Kudoa sp. (Myxosporea: Multivalvulida) antigens in BALB/c mice.

The majority of Kudoa species infect the somatic muscle of fish establishing cysts. As there is no effective method to detect infected fish without destroying them, these parasited fish reach the consumer. We have developed this work to determine whether this parasite contains antigenic compounds capable of provoking an immune response in laboratory animals, in order to consider the possible immunopathological effects in man by the ingestion of Kudoa infected fish. BALB/c mice were injected by the subcutaneous route with the following extracts suspended in aluminium hydroxide: Group 1 (black Kudoa sp. pseudocyst extract), group 2 (white Kudoa sp. pseudocyst extract). Specific IgE levels were measured by ELISA. IgE detected in both groups 1 and 2 showed the possible allergenic nature of some of the components of the parasitic extracts.

Humoral immune responses induced by Kudoa sp. (Myxosporea: Multivalvulida) antigens in BALB/c mice

The majority of Kudoa species infect the somatic muscle of fish establishing cysts. As there is no effective method to detect infected fish without destroying them these parasited fish reach the consumer. This work was developed to determine whether this parasite contains antigenic compounds capable of provoking an immune response in laboratory animals, in order to consider the possible immunopathological effects in man by the ingestion of Kudoa infected fish. BALB/c mice were injected by the subcutaneous route with the following extracts suspended in aluminium hydroxide: group 1 (black Kudoa sp. pseudocyst extract), group 2 (white Kudoa sp. pseudocyst extract), and group 3 (non-infected hake meat extract). Specific antibody levels were measured by ELISA against homologous and heterologous antigens. The highest responses were obtained from the black Kudoa sp. pseudocyst extract (group 1).The low optic density levels detected in group 3 proved that the results obtained in groups 1 and 2 were a consequence of the parasitic extract injection. The IgG1 was the predominant subclass. IgE detected in groups 1 and 2 showed the possible allergenic nature of some of the components of the parasitic extract. High IgA levels and medium IgG2a and IgG3 levels were obtained in groups 1 and 2. Low IgG2b responses were shown. No cross-reactions between Kudoa sp. pseudocyst extracts and the non-infected hake meat extract were observed

Humoral immune responses induced by Kudoa sp. (Myxosporea: Multivalvulida) antigens in BALB/c mice.

The majority of Kudoa species infect the somatic muscle of fish establishing cysts. As there is no effective method to detect infected fish without destroying them these parasited fish reach the consumer. This work was developed to determine whether this parasite contains antigenic compounds capable of provoking an immune response in laboratory animals, in order to consider the possible immunopathological effects in man by the ingestion of Kudoa infected fish. BALB/c mice were injected by the subcutaneous route with the following extracts suspended in aluminium hydroxide: group 1 (black Kudoa sp. pseudocyst extract), group 2 (white Kudoa sp. pseudocyst extract), and group 3 (non-infected hake meat extract). Specific antibody levels were measured by ELISA against homologous and heterologous antigens. The highest responses were obtained from the black Kudoa sp. pseudocyst extract (group 1). The low optic density levels detected in group 3 proved that the results obtained in groups 1 and 2 were a consequence of the parasitic extract injection. The IgG1 was the predominant subclass. IgE detected in groups 1 and 2 showed the possible allergenic nature of some of the components of the parasitic extract. High IgA levels and medium IgG2a and IgG3 levels were obtained in groups 1 and 2. Low IgG2b responses were shown. No cross-reactions between Kudoa sp. pseudocyst extracts and the non-infected hake meat extract were observed.