Clinical features and response to immune combinations in patients with renal cell carcinoma and sarcomatoid de-differentiation (ARON-1 study).

Metastatic renal cell carcinoma (mRCC) carrying sarcomatoid features (sRCC) has aggressive biology and poor prognosis. First-line immunotherapy (IO)-based combinations have improved the outcome of clear cell RCC patients, including that of sRCC. Real-world data confirming the adequate first-line management of sRCC is largely lacking. We investigated the clinical features and the outcome of sRCC patients treated with IO-based combinations within the ARON-1 study population (NCT05287464). The primary objective was to define the incidence and baseline clinical characteristics of sRCC compared with non-sRCC patients. The secondary objective was to describe the outcome of sRCC patients based on type of first-line treatment (IO + IO vs. IO + tyrosin kinase inhibitor [TKI]). We identified 1362 mRCC patients with IMDC intermediate or poor risk, 226 sRCC and 1136 non-sRCC. These two subgroups did not differ in terms of baseline characteristics. The median overall survival (OS) was 26.8 months (95%CI 21.6-44.2) in sRCC and 35.3 months (95%CI 30.2-40.4) in non-sRCC patients (p = .013). The median progression-free survival (PFS) was longer in non-sRCC patients compared to sRCC (14.5 vs. 12.3 months, p = .064). In patients treated with first-line IO + TKI the median OS was 34.4 months compared to 26.4 months of those who received IO + IO (p = .729). The median PFS was 12.4 months with IO + TKI and 12.3 months with IO + IO (p = .606). In conclusion, we confirm that sRCC are aggressive tumors with poor prognosis. IO-based combinations improve survival outcomes of sRCC patients, regardless from the type of strategy (IO + IO versus IO + TKI) adopted.

2024 ASCO genitourinary cancers symposium: a focus on renal cell carcinoma.

In this article, we report the breakthrough acquisitions for renal cell carcinoma (RCC) management presented at the 2024 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium. The results from Keynote 564 showed an impressive overall survival (OS) advantage for pembrolizumab, in patients at higher risk of relapse after surgery and confirmed the benefit in terms of disease-free survival (DFS). Until now, pembrolizumab is the only immune checkpoint inhibitor (ICI) to prove a survival advantage. On the contrary, the results from CheckMate 914 trial showed the lack of benefit of adjuvant nivolumab. In the metastatic setting, the longer-term follow-up data of the CheckMate 9ER and CheckMate 214 trials reassessed the undoubtable role of ICI-based combination in first-line treatment, with a clear survival advantage in the subgroup of patients at intermediate/poor IMDC prognosis. No OS advantage was seen in favorable IMDC risk group patients. This 2024 ASCO Genitourinary Cancer Symposium laid the foundations for further knowledge development necessary for an increasingly personalized therapy for RCC patients.

Symptomatic androgen deficiency and sexual dysfunctions in male patients receiving alectinib for ALK-positive advanced non-small cell lung cancer.

BACKGROUND: It is reported that treatment with anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) induces hypogonadism both in male patients with ALK-positive cancer and in murine models. METHODS: In this study, three groups, including an experimental group of male patients with ALK-positive, advanced non-small cell lung cancer (ANSCLC) who were receiving alectinib (cohort A), a control group of female patients with ALK-positive ANSCLC who were receiving alectinib (cohort B), and a control group of male patients with ALK-negative ANSCLC (cohort C), prospectively underwent a full hormone assessment for androgen deficiency at 8 weeks after the start of treatment and in case of reported suspected symptoms. Patients with major sexual dysfunctions were referred to an endocrinologist. RESULTS: Ninety-five patients were consecutively enrolled onto the study. Among sixty-eight male patients, both median total testosterone levels (2.93 vs. 4.92 ng/ml; p = .0001) and free testosterone levels (0.11 vs. 0.17 pg/ml; p = .0002) were significantly lower in ALK-positive ANSCLC patients in cohort A compared with ALK-negative patients in cohort C; conversely, median FSH (10.32 vs. 17.52 mUI/ml; p = .0059) and LH levels (4.72 vs. 7.49 mUI/ml; p = .0131) were significantly higher in cohort C compared to cohort A. Median inhibin B levels were higher in ALK-positive male patients (74.3 vs. 44.24 pg/ml; p = .0038), but all patients had inhibin B values within the normal range. The percentage of male patients who had positive scores on the Androgen Deficiency in Aging Males (ADAM) questionnaire was 62% in cohort A and 26.8% in cohort C, including eight patients who reported at least one major symptom and were referred to Andrology Unit. No significant differences in the endocrine assessment were reported between cohorts A and B. CONCLUSIONS: Symptoms of androgen deficiency should be tracked in male patients with ALK-positive ANSCLC who are receiving alectinib, and testosterone replacement should be considered, as appropriate.

2023 ASCO genitourinary cancers symposium: focus on renal cell carcinoma.

This article describes the main acquisitions of renal cell carcinoma (RCC) management presented during the 2023 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium. In particular, the efficacy of adjuvant pembrolizumab in patients with resected renal cell carcinoma (RCC) at increased risk of recurrence was confirmed through a subgroup analysis. In the metastatic setting, the updated analysis of the CheckMate 9ER study confirmed the efficacy in terms of overall survival (OS) of the combination of nivolumab plus cabozantinib; of note, this survival advantage was clear in the subgroup of patients at poor IMDC prognosis, but not in favorable IMDC risk group patients. As concern the triplet therapy (i.e. nivolumab+ipilumumab+cabozantinib), the updated analysis of the COSMIC-313 study confirmed a significant PFS advantage in the subgroup of mRCC patients at intermediate IMDC risk, while the lack of benefit in the poor risk group supports the critical role of immunotherapy (but not of VEGFR-TKIs) in this poor prognosis subgroup of patients. Finally, the activity of cabozantinib as second-line therapy after progression to ICI-based combinations was prospectively assessed. This 2023 ASCO Genitourinary Cancer Symposium laid the foundations for further knowledge development necessary for an increasingly personalized management of mRCC.

Multimodality treatment in recurrent/metastatic squamous cell carcinoma of head and neck: current therapy, challenges, and future perspectives.

Squamous cell carcinoma of the head and neck is a complex group of diseases that presents a challenge to the clinician. The prognosis in the recurrent/metastatic disease is particularly dismal, with a median survival of approximately 12 months. Recently, the personalized and multimodal approach has increased prognosis by integrating locoregional strategies (salvage surgery and stereotactic radiotherapy) and systemic treatments (chemotherapy, immunotherapy, and target therapy). Malnutrition is a significant clinical problem that interferes with dose intensity, and thus, feeding supplementation is critical not only to increase the quality of life but also to improve overall survival. With this review, we want to emphasize the importance of the multidisciplinary approach, quality of life, and nutritional supportive care and to integrate the latest updates of predictive biomarkers for immunotherapy and future therapeutic strategies.

The role of immune profile in predicting outcomes in cancer patients treated with immunotherapy.

Background: Despite the efficacy of immunotherapy, only a small percentage of patients achieves a long-term benefit in terms of overall survival. The aim of this study was to define an immune profile predicting the response to immune checkpoint inhibitors (ICIs). Methods: Patients with advanced solid tumors, who underwent ICI treatment were enrolled in this prospective study. Blood samples were collected at the baseline. Thirteen soluble immune checkpoints, 3 soluble adhesion molecules, 5 chemokines and 11 cytokines were analyzed. The results were associated with oncological outcomes. Results: Regardless of tumor type, patients with values of sTIM3, IFNα, IFNγ, IL1ß, IL1α, IL12p70, MIP1ß, IL13, sCD28, sGITR, sPDL1, IL10 and TNFα below the median had longer overall survival (p<0.05). By using cluster analysis and grouping the patients according to the trend of the molecules, two clusters were found. Cluster A had a significantly higher mean progression free survival (Cluster A=11.9 months vs Cluster B=3.5 months, p<0.01), a higher percentage of disease stability (Cluster A=34.5% vs. Cluster B=0%, p<0.05) and a lower percentage of disease progression (Cluster A=55.2% vs. Cluster B = 94.4%, p=0.04). Conclusion: The combined evaluation of soluble molecules, rather than a single circulating factor, may be more suitable to represent the fitness of the immune system status in each patient and could allow to identify two different prognostic and predictive outcome profiles.

Sequential healing of the elevated sinus floor with different size of antrostomy: a histomorphometric study in rabbits.

PURPOSE: To study the influence of the access window dimensions on the healing at the antrostomy and within the augmented maxillary sinus. MATERIAL AND METHODS: A maxillary sinus augmentation was performed in twenty-four albino New Zealand rabbits. Antrostomies of 3 × 6 mm (small) or 5 × 6 mm (large) in dimensions were randomly prepared in each animal. A collagenated cortico-cancellous porcine bone was used to fill the elevated region, and an equine collagen membrane was placed on the antrostomies. Three different groups were formed, based on the time of euthanasia, i.e., 2, 4, and 8 weeks from surgery. RESULTS: No relevant changes of the height of the augmented sinus were detected over time. Mineralized bone increased between 2 and 4 weeks of healing while remained stable between 4 and 8 weeks. The highest amounts of new bone were found close to the sinus bone walls. No antrostomies were found healed with an even layer of corticalized bone, while large amounts of connective tissue were occupying the antrostomy in both groups. CONCLUSION: Antrostomies of different dimensions resulted in similar outcome in bone formation both in the antrostomy regions and within the elevated sinus.

Sequential healing of the elevated sinus floor after applying autologous bone grafting: an experimental study in minipigs.

AIM: To describe the sequential healing after elevation of the maxillary sinus mucosa applying the lateral access technique with the use of autogenous bone grafting without membrane to occlude the osteotomy access. MATERIAL AND METHODS: Immediately after the elevation of the maxillary sinus Schneiderian membrane, applying the lateral access technique in 10 minipigs, autologous bone was harvested from the lateral aspect of the mandibular molar region and ground into particles with a bone mill. The space under the Schneiderian membrane was filled with this graft. No membranes were placed onto the access osteotomy. The healing was evaluated after 15, 30, 90 and 180 days. Paraffin sections were prepared and analyzed histologically. RESULTS: After 15 days of healing, the elevated area was mainly filled with provisional matrix, newly formed bone and some remnants of bone chips, and appeared reduced in volume compared with that at the time of surgery. After 30 days of healing, further shrinkage of the height of the elevated space was found, with similar percentages of the different tissue components. After 90 and 180 days, the area underneath the Schneiderian membrane appeared reduced in volume and condensed toward the base of the sinus. The bone tissues appeared to be more mature, both for the mineralized and the non-mineralized portions, while connective tissue occupied 20% of the space, most likely related to the lack of the use of a membrane occluding the access at the time of surgery. CONCLUSIONS: Suboptimal healing outcomes with respect to augmentation of the space under the sinus floor membrane were documented when autologous bone chips were used as a filler and no membrane was applied to cover the access.

Healing outcomes at implants installed in grafted sites: an experimental study in dogs.

AIM: To evaluate the integration of implants installed using a surgical guide in augmented sites with autologous bone or deproteinized bovine bone mineral (DBBM) blocks, concomitantly with a collagen membrane. MATERIAL AND METHODS: Mandibular molars were extracted bilaterally in six Labrador dogs, the buccal bony wall was removed, and a box-shaped defect was created. After 3 months, flaps were elevated, a bony graft was harvested from the ascending ramus, and secured to the lateral wall of the defect by means of screws. In the left mandibular side, a DBBM block was fixed into the defect. A resorbable membrane was applied at both sides, and the flaps were sutured. After 3 months, flaps were elevated, and a customized device was used as surgical guide to prepare the recipient sites in the interface between grafts and parent bone. One implant was installed in each side of the mandible. After 3 months, biopsies were harvested, and ground sections were prepared for histologic evaluation. RESULTS: One autologous bone block graft was lost before implant installation. The width of the alveolar crest at the test sites (DBBM) was 5.4 ± 1.2 mm before, 9.4 ± 1.2 mm immediately after grafting, and 9.3 ± 1 mm at implant installation. At the control sites (autologous bone), the corresponding values were: 5.2 ± 1, 9 ± 1.2, and 8.7 ± 0.9 mm, respectively. All implants installed were available for histologic evaluation (n = 5). The autologous bone grafts, rich in vessels and cells, were integrated in the parent bone, and only little non-vital bone was found. The BIC% was 56.7 ± 15.6% and 54.2 ± 13.2% at the buccal and lingual aspects, respectively. At the test sites, the DBBM appeared to be embedded into connective tissue, and very little newly formed bone was encountered within the grafts. The BIC% was 5.8 ± 12.3% and 51.3 ± 14.2% at the buccal and lingual aspects, respectively. CONCLUSIONS: Autologous bone blocks used to augment the alveolar bony crest horizontally allowed the complete osseointegration of implants installed after 3 months of healing. However, similar blocks of DBBM did not promote osseointegration, although the installed implants were stable owing to the osseointegration in the sites of the parent bone.

Efeito da plataforma Switching sobre os tecidos peri-implantares: estudo experimental em cães / Effect of plataform Switching on peri-implant tissues: an experimental study in dogs

Objetivo: Avaliar a influência da plataforma Switching sobre a remodelação dos tecidos peri-implantares. Material e métodos: Em 6 cães labradores, foram extraídos os pré-molares e primeiro molares inferiores bilateralmente. Após 3 meses de cicatrização, na região correpondente ao 1º molar, foi instalado um implante cônico em cada lado da mandíbula, com o ombro do mesmo posicionado ao nível da crista óssea alveolar vestibular. No lado direito da mandíbula, foi utilizado um pilar de diâmetro reduzido em relação à plataforma do implante, criando uma incompatibilidade de 0,85 milímetros (grupo teste), enquanto no lado esquerdo selecionou-se um pilar do mesmo diâmetro da plataforma do implante (grupo controle). Os retalhos foram suturados permitindo a cicatrização não-submersa. Após 4 meses, os animais foram eutanasiados para obtenção dos cortes histológicos para avaliação histométrica. Resultados: Todos os implantes apresentaram-se completamente osseointegrados. No grupo teste foram observados que os níveis ósseos apresentaram-se superiores ao grupo controle. No entanto, a diferença estatisticamente significativa foi encontrada apenas na região vestibular e na região proximal. A dimensão vertical dos tecidos moles foi maior no grupo controle em comparação ao grupo teste. No entanto, foi encontrada diferença estatisticamente significativa apenas na vestibular. Conclusões: O presente estudo demonstrou diferenças nas dimensões dos tecidos duros e moles peri-implantares (vestibular e proximal) como resultado da incompatibilidade do implante / pilar de 0,85 milímetros, quando o ombro do implante foi posicionado ao nível da crista óssea vestibular.

Aim: to evaluate the effect of platform switching on the peri-implant tissue remodeling. Material & methods: Mandibular premolars and first molars of 6 Labrador dogs were extracted bilaterally. After 3 months of healing, 1 tapered implant was installed on each side of the mandibular molar region with the implant shoulder placed at the level of the alveolar buccal bony crest. On the right side of the mandible, an abutment of reduced diameter in relation to the platform of the implant was used creating a mismatch of 0.85mm (test), while an abutment of the same diameter of the implant platform was affixed in the left side of the mandible (control). The flaps were sutured to allow a non-submerged healing. After 4 months, the animals were sacrificed and ground sections were obtained for histometric assessment. Results: All implants were completely osseointegrated. Bone levels were superior at the test than at the control sites. However, statistically significant differences were found only at the buccal and proximal aspects. The soft tissue vertical dimension was higher at the control compared to the test sites. However, statistically significant differences were demonstrated only or at the buccal aspects. Conclusions: The present study demonstrated differences in peri-implant (buccal and proximal) hard and soft tissue dimensions as a result of an implant/abutment mismatch of 0.85mm, when the implant shoulder was placed at the level of the buccal bony crest.

Efeito da plataforma Switching sobre os tecidos peri-implantares: estudo experimental em cães / Effect of plataform Switching on peri-implant tissues: an experimental study in dogs

Objetivo: Avaliar a influência da plataforma Switching sobre a remodelação dos tecidos peri-implantares. Material e métodos: Em 6 cães labradores, foram extraídos os pré-molares e primeiro molares inferiores bilateralmente. Após 3 meses de cicatrização, na região correpondente ao 1º molar, foi instalado um implante cônico em cada lado da mandíbula, com o ombro do mesmo posicionado ao nível da crista óssea alveolar vestibular. No lado direito da mandíbula, foi utilizado um pilar de diâmetro reduzido em relação à plataforma do implante, criando uma incompatibilidade de 0,85 milímetros (grupo teste), enquanto no lado esquerdo selecionou-se um pilar do mesmo diâmetro da plataforma do implante (grupo controle). Os retalhos foram suturados permitindo a cicatrização não-submersa. Após 4 meses, os animais foram eutanasiados para obtenção dos cortes histológicos para avaliação histométrica. Resultados: Todos os implantes apresentaram-se completamente osseointegrados. No grupo teste foram observados que os níveis ósseos apresentaram-se superiores ao grupo controle. No entanto, a diferença estatisticamente significativa foi encontrada apenas na região vestibular e na região proximal. A dimensão vertical dos tecidos moles foi maior no grupo controle em comparação ao grupo teste. No entanto, foi encontrada diferença estatisticamente significativa apenas na vestibular. Conclusões: O presente estudo demonstrou diferenças nas dimensões dos tecidos duros e moles peri-implantares (vestibular e proximal) como resultado da incompatibilidade do implante / pilar de 0,85 milímetros, quando o ombro do implante foi posicionado ao nível da crista óssea vestibular...

Aim: to evaluate the effect of platform switching on the peri-implant tissue remodeling. Material & methods: Mandibular premolars and first molars of 6 Labrador dogs were extracted bilaterally. After 3 months of healing, 1 tapered implant was installed on each side of the mandibular molar region with the implant shoulder placed at the level of the alveolar buccal bony crest. On the right side of the mandible, an abutment of reduced diameter in relation to the platform of the implant was used creating a mismatch of 0.85mm (test), while an abutment of the same diameter of the implant platform was affixed in the left side of the mandible (control). The flaps were sutured to allow a non-submerged healing. After 4 months, the animals were sacrificed and ground sections were obtained for histometric assessment. Results: All implants were completely osseointegrated. Bone levels were superior at the test than at the control sites. However, statistically significant differences were found only at the buccal and proximal aspects. The soft tissue vertical dimension was higher at the control compared to the test sites. However, statistically significant differences were demonstrated only or at the buccal aspects. Conclusions: The present study demonstrated differences in peri-implant (buccal and proximal) hard and soft tissue dimensions as a result of an implant/abutment mismatch of 0.85mm, when the implant shoulder was placed at the level of the buccal bony crest