Avelumab Plus Intermittent Axitinib in Previously Untreated Patients with Metastatic Renal Cell Carcinoma. The Tide-A Phase 2 Study.

BACKGROUND: Combinations of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) plus immune checkpoint inhibitor (ICI) against PD1/PD-L1 are the standard first-line therapy for patients with metastatic renal cell carcinoma (mRCC), irrespective of the prognostic class. OBJECTIVE: To investigate the feasibility and safety of withdrawing VEGFR-TKI but continuing anti-PD1/PD-L1 in patients who achieve a response to their combination. DESIGN, SETTING, AND PARTICIPANTS: This was a single-arm phase 2 trial in patients with treatment-naïve mRCC with prior nephrectomy, without symptomatic/bulky disease and no liver metastases. INTERVENTION: Enrolled patients received axitinib + avelumab; after 36 wk of therapy those who achieved a tumour response interrupted axitinib and continued avelumab maintenance until disease progression. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the rate of patients without progression 8 wk after the axitinib interruption. The secondary endpoints were the median value for progression-free (mPFS) and overall (mOS) survival and the safety in the overall population. RESULTS AND LIMITATIONS: Seventy-nine patients were enrolled and 75 were evaluated for efficacy. A total of 29 (38%) patients had axitinib withdrawn, as per the study design, with 72% of them having no progression after 8 wk and thus achieving the primary endpoint. The mPFS of the overall population was 24 mo, while the mOS was not reached. The objective response rate was 76% (12% complete response and 64% partial response), with 19% of patients having stable disease. In the patients who discontinued axitinib, the incidence of adverse events of any grade was 59% for grade 3 and 3% for grade 4. This study was limited by the lack of a comparative arm. CONCLUSIONS: The TIDE-A study demonstrates that the withdrawal of VEGFR-TKI with ICI maintenance is feasible for selected mRCC patients with evidence of a response to the VEGFR-TKI + ICI combination employed in first-line therapy. Axitinib interruption with avelumab maintenance leads to decreased side effects and should be investigated further as a new strategy to delay tumour progression. PATIENT SUMMARY: We evaluated whether certain patients with advanced kidney cancer treated with the fist-line combination of axitinib plus avelumab can interrupt the axitinib in case of a tumour response after 36 wk of therapy. We found that axitinib interruption improved the safety of the combination, while the maintenance with avelumab might delay tumour progression.

Management of patients with extensive small-cell lung cancer in the immunotherapy era: an Italian consensus through a Delphi approach.

BACKGROUND: Immunotherapy represented a turning point for treating extensive small-cell lung cancer (ES-SCLC). Although, many issues remain debated. METHODS: A group of Italian medical and radiation oncologists with expertise in managing patients with ES-SCLC developed a list of statements divided in six areas of interest. The Delphi method was used to assess the consensus on the defined list of statements. RESULTS: 32 statements were included in the final list to be voted by the Delphi panel, and 26 reached a consensus on the agreement. A prompt involvement of a multidisciplinary team is a priority to provide an integrated treatment strategy. First-line recommended treatment is immunotherapy in combination with platinum-based chemotherapy and etoposide for four cycles followed by maintenance immunotherapy. CONCLUSIONS: While awaiting new data from clinical trials and real-world studies, these recommendations can represent a useful tool to guide the management of ES-SCLC patients in daily practice.

Pralsetinib in RET fusion-positive non-small-cell lung cancer: A real-world data (RWD) analysis from the Italian expanded access program (EAP).

OBJECTIVES: The selective RET-inhibitor pralsetinib has shown therapeutic activity in early clinical trials in patients with non-small cell lung cancer (NSCLC) harboring rearranged during transfection (RET) gene fusions. To date, the real-world efficacy of pralsetinib in this population is unknown. MATERIALS AND METHODS: A retrospective efficacy and safety analysis was performed on data from patients with RET-fusion positive NSCLC enrolled in the pralsetinib Italian expanded access program between July 2019 and October 2021. RESULTS: Overall, 62 patients with RET-fusion positive NSCLC received pralsetinib at 20 Italian centers. Next-generation sequencing was used to detect RET alterations in 44 patients (73 %). The most frequent gene fusion partner was KIF5B (75 % of 45 evaluable). Median age was 62 years (range, 36-90), most patients were female (57 %) and never smokers (53 %). Brain metastases were known in 18 patients (29.5 %) at the time of pralsetinib treatment. 13 patients were treatment naïve (unfit for chemotherapy), 48 were pretreated (median number of previous lines: 1, range, 1-4). The objective response rate (ORR) was 66 % [95 % confidence interval (CI), 53-81] in the evaluable population (n = 59). The disease control rate (DCR) was 79 %. After a median follow-up of 10.1 months, the median progression free survival was 8.9 months (95 %CI, 4.7-NA). In patients with measurable brain metastases (n = 6) intracranial ORR was 83 %, intracranial DCR was 100 %. Overall, 83.6 % of patients experienced any-grade treatment-related adverse events (TRAEs), 39 % grade 3 or greater (G ≥ 3). The most common G ≥ 3 TRAEs were neutropenia (9.8 %), dry mouth/oral mucositis (8.2 %), and thrombocytopenia (6.6 %). Seven patients (12 %) discontinued pralsetinib due to TRAEs, twenty-six had at least one dose level modification due to TRAEs. Two treatment-related deaths were observed (1 sepsis, 1 typhlitis). CONCLUSIONS: In the real-world setting, pralsetinib confirmed durable systemic activity and intracranial response in RET-fusion positive NSCLC. Toxicity profile was consistent with previous reports.

SARS-CoV-2 infection and adverse events in patients with cancer receiving immune checkpoint inhibitors: an observational prospective study.

BACKGROUND: In ambulatory patients with cancer with asymptomatic or pauci-symptomatic SARS-CoV-2 infection, the safety of targeted therapies (TTs), chemotherapy (CT) or immune checkpoint inhibitors (ICIs) therapy is still unknown. MATERIAL AND METHODS: From the start of the first epidemic wave of SARS-CoV-2 in Bergamo, Italy, we have prospectively screened all consecutive outpatients who presented for treatment to the Oncology Division of the Papa Giovanni XXIII Hospital, Bergamo for SARS-CoV-2 antigen expression. We identified patients treated with ICIs and compared these to patients with the same cancer subtypes treated with TTs or CT. RESULTS: Between March 5 and May 18, 293 consecutive patients (49% melanoma, 34% non-small cell lung cancer, 9% renal cell carcinoma, 8% other) were included in this study: 159 (54%), 50 (17%) and 84 (29%) received ICIs, CT or TTs, respectively. Overall 89 patients (30.0%) were SARS-CoV-2 positive. Mortality of SARS-CoV-2-positive patients was statistically significantly higher compared with SARS-CoV-2 negative patients (8/89 vs 3/204, respectively, Fisher's exact test p=0.004). All deaths were due to COVID-19. Serious adverse events (SAEs) were more frequent in SARS-CoV-2-positive patients compared with SARS-CoV-2-negative cases (Cochran-Mantel-Haenszel (CMH) test p=0.0008). The incidence of SAEs in SARS-CoV-2 positive compared with SARS-CoV-2 negative patients was similar in ICI and CT patients (17.3% and 3.7% for positive and negative patients in ICIs and 15.4% and 2.7% in CT, Breslow-Day test p=0.891). No COVID-19-related SAEs were observed in the TTs patients. CONCLUSIONS: The incidence of SAEs was higher for SARS-CoV-2-positive patients treated with ICIs and CT, mostly in advanced disease. No SAEs were observed in patients treated with TTs. SAEs were COVID-19 related rather than treatment related. Treatment with ICIs does not appear to significantly increase risk of SAEs compared with CT. This information should be considered when determining treatment options for patients.

Prevalence and Clinical Impact of SARS-CoV-2 Silent Carriers Among Actively Treated Patients with Cancer During the COVID-19 Pandemic.

INTRODUCTION: In Europe, the SARS-CoV-2 pandemic had its first epicenter in Italy. Despite a significant mortality rate, the severity of most cases of COVID-19 infection ranges from asymptomatic to mildly symptomatic, and silent infection affects a still-unknown proportion of the general population. No information is available on the prevalence and clinical impact of SARS-CoV-2 silent infection among patients with cancer receiving anticancer treatment during the pandemic. MATERIALS AND METHODS: From April 1, 2020, to the end of the same month, 560 consecutive patients with cancer, asymptomatic for COVID-19 and on anticancer treatment at Papa Giovanni XXIII Hospital in Bergamo, were evaluated and tested for SARS-CoV-2. We implemented a two-step diagnostics, including the rapid serological immunoassay for anti-SARS-CoV-2 immunoglobulin (Ig) G/IgM and the nasopharyngeal swab reverse transcriptase-polymerase chain reaction (RT-PCR) test in case of seropositivity to identify SARS-CoV-2 silent carriers. RESULTS: In 560 patients, 172 (31%) resulted positive for anti-SARS-CoV-2 IgM/IgG antibodies, regardless of different type of cancer, stage, and treatment. The Ig-seropositive patients were then tested with RT-PCR nasopharyngeal swabs, and 38% proved to be SARS-CoV-2 silent carriers. At an early follow-up, in the 97 SARS-CoV-2-seropositive/RT-PCR-negative patients who continued their anticancer therapies, only one developed symptomatic COVID-19 illness. CONCLUSION: Among patients with cancer, the two-step diagnostics is feasible and effective for SARS-CoV-2 silent carriers detection and might support optimal cancer treatment strategies at both the individual and the population level. The early safety profile of the different anticancer therapies, in patients previously exposed to SARS-CoV-2, supports the recommendation to continue the active treatment, at least in cases of RT-PCR-negative patients. IMPLICATIONS FOR PRACTICE: This is the first study evaluating the prevalence and clinical impact of SARS-CoV-2 silent infection in actively treated patients with cancer, during the epidemic peak in one of the worst areas of the COVID-19 pandemic. Lacking national and international recommendations for the detection of asymptomatic SARS-CoV-2 infection, a pragmatic and effective two-step diagnostics was implemented to ascertain SARS-CoV-2 silent carriers. In this series, consisting of consecutive and unselected patients with cancer, the prevalence of both SARS-CoV-2-seropositive patients and silent carriers is substantial (31% and 10%, respectively). The early safety profile of the different anticancer therapies, in patients previously exposed to SARS-CoV-2, supports the recommendation to continue the active treatment, at least in case of RT-PCR-negative patients.

High Prevalence and Early Occurrence of Skeletal Complications in EGFR Mutated NSCLC Patients With Bone Metastases.

OBJECTIVES: The prevalence of Skeletal Related Adverse Events (SREs) in EGFR mutated non-small cell lung cancer (NSCLC) patients with bone metastases, treated with modern tyrosine kinase inhibitors (TKIs), has been scarcely investigated. MATERIALS AND METHODS: We retrospectively evaluated the data of EGFR mutated NSCLC patients with bone metastases treated with TKIs in 12 Italian centers from 2014 to 2019, with the primary aim to explore type and frequency of SREs. RESULTS: Seventy-seven out of 274 patients enrolled (28%) developed at least one major SRE: 55/274 (20%) bone fractures, 30/274 (11%) spinal cord compression, 5/274 (2%) hypercalcemia. Median time to the onset of SRE was 3.63 months. Nine patients (3%) underwent bone surgery and 150 (55%) radiation therapy on bone. SREs were more frequently observed within the 12 months from TKI start than afterwards (71 vs 29%, p 0.000). Patient Performance Status and liver metastases where independently associated with the risk of developing SREs. Median TKI exposure and overall survival were 11 and 28 months, respectively. Bone resorption inhibitors were associated with a lower risk of death (HR 0.722, 95% CI: 0.504-1.033, p = 0.075) although not statistically significant at multivariate analysis. CONCLUSION: Bone metastatic NSCLC patients with EGFR mutated disease, treated with EGFR TKIs, have a relatively long survival expectancy and are at high risk to develop SREs. The early SRE occurrence after the TKI start provides the rationale to administer bone resorption inhibitors.

Nivolumab efficacy in leptomeningeal metastasis of renal cell carcinoma: a case report.

BACKGROUND: Meningeal carcinomatosis is rare in patients with kidney cancer and treatment options are limited. Few patients treated with systemic approaches have been reported. We describe a case of complete remission of leptomeningeal metastasis in a patient with renal cell carcinoma treated with nivolumab. To our knowledge, this is the first report of nivolumab safety and efficacy in this particular site of metastasis. CASE PRESENTATION: Our patient was a 60-year-old Caucasian man with bone and lung metastases from renal cell carcinoma. He developed leptomeningeal metastasis and progression of bone and lung lesions after only 2 months of his first-line treatment. He was then treated with nivolumab in second-line setting and experienced a rapid improvement of cancer-related symptoms, complete remission of leptomeningeal and lung lesions, and increased bone mineral density in bone metastasis. The patient did not experience any drug-related toxicity. CONCLUSIONS: Meningeal carcinomatosis metastasis from renal cancer is a rare condition. Diagnosis is often challenging: the onset of nonspecific presenting symptoms could be initially attributed to bone involvement, side effects of oncologic therapy, or paraneoplastic syndromes. Our case suggests that nivolumab could be an effective and safe treatment option in patients with pretreated renal cancer with leptomeningeal metastasis.

Second line therapy with axitinib after only prior sunitinib in metastatic renal cell cancer: Italian multicenter real world SAX study final results.

BACKGROUND: This multi-institutional retrospective real life study was conducted in 22 Italian Oncology Centers and evaluated the role of Axitinib in second line treatment in not selected mRCC patients. METHODS: 148 mRCC patients were evaluated. According to Heng score 15.5%, 60.1% and 24.4% of patients were at poor risk, intermediate and favorable risk, respectively. RESULTS: PFS, OS, DCR and ORR were 7.14 months, 15.5 months, 70.6% and 16.6%, respectively. The duration of prior sunitinib treatment correlated with a longer significant mPFS, 8.8 vs 6.3 months, respectively. Axitinib therapy was safe, without grade 4 adverse events. The most frequent toxicities of all grades were: fatigue (50%), hypertension (26%), and hypothyroidism (18%). G3 blood pressure elevation significantly correlated with longer mPFS and mOS compared to G1-G2 or no toxicity. Dose titration (DT) to 7 mg and 10 mg bid was feasible in 24% with no statistically significant differences in mPFS and mOS. The sunitinib-axitinib sequence was safe and effective, the mOS was 41.15 months. At multivariate analysis, gender, DCR to axitinib and to previous sunitinib correlated significantly with PFS; whereas DCR to axitinib, nephrectomy and Heng score independently affected overall survival. CONCLUSIONS: Axitinib was effective and safe in a not selected real life mRCC population. Trial registration INT - Napoli - 11/16 oss. Registered 20 April 2016. http://www.istitutotumori.na.it.

DNA repair gene polymorphisms in non-small-cell lung cancer patients treated with first-line platinum-containing chemotherapy.

PURPOSE: Single nucleotide polymorphisms (SNPs) in the DNA repair genes are believed to contribute to the clinical outcome of patients receiving platinum-based chemotherapy. We investigated the impact of 2 SNPs of excision repair cross-complementation group 1 and 2 of xeroderma pigmentosum complementation group G on the outcome in patients with non-small-cell lung cancer (NSCLC) treated with platinum-based chemotherapy. METHODS: Between October 2007 and March 2012, we collected 374 blood samples from consecutive patients registered in the TAILOR trial. Four SNPs (rs11615, rs3212986, rs17655, rs1047768) were genotyped using real-time polymerase chain reaction. RESULTS: The rs11615 polymorphism was associated with histotype (p = 0.0123). No other correlations were found with clinical variables or with EGFR or KRAS mutational status. None of the SNPs had any impact on overall survival or progression-free survival. CONCLUSIONS: The findings suggest that the investigated SNPs do not make any significant contribution to the outcome of NSCLC.

KRAS mutations affect prognosis of non-small-cell lung cancer patients treated with first-line platinum containing chemotherapy.

UNLABELLED: KRAS mutations seem to indicate a poor outcome in Non-Small-Cell Lung Cancer (NSCLC) but such evidence is still debated. The aim of this planned ancillary study within the TAILOR trial was to assess the prognostic value of KRAS mutations in advanced NSCLC patients treated with platinum-based first-line chemotherapy. Patients (N = 540), enrolled in the study in 52 Italian hospitals, were centrally genotyped twice in two independent laboratories for EGFR and KRAS mutational status.Of these, 247 patients were eligible and included in the present study. The primary endpoint was overall survival (OS) according to KRAS mutational status in patients harboring EGFR wild-type.Sixty (24.3%) out of 247 patients harbored KRAS mutations. Median OS was 14.3 months and 10.6 months in wild-type and mutated KRAS patients, respectively (unadjusted Hazard Ratio [HR]=1.41, 95%Confidence Interval [CI]: 1.03-1.94 P = 0.032; adjusted HR=1.39, 95%CI: 1.00-1.94 P = 0.050). This study, with all consecutive patients genotyped, indicates that the presence of KRAS mutations has a mild negative impact on OS in advanced NSCLC patient treated with a first-line platinum-containing regimen. TRIAL REGISTRATION: clinicaltrials.gov identifierNCT00637910.

Immunological stress in kidney cancer patients undergoing either open nephrectomy or nephron-sparing surgery: an immunophenotypic study of lymphocyte subpopulations and circulating dendritic cells.

Immunosuppression is a characteristic hallmark of renal cell carcinoma (RCC), with several complex immune defects, almost solely at the level of cell-mediated immune function, well evident even in patients at first diagnosis. The main circulating lymphocyte subsets and the total number of circulating dendritic cells were quantified in 47 RCC patients at diagnosis (T0), 12 h (T1), 24 h (T2) and 8 days following either radical nephrectomy or nephron-sparing surgery using flow cytometry. RCC patients presented, at baseline, (T0) a profound state of immunosuppression involving naïve T-cells, memory T-cells, CD16+ NK and total circulating dendritic cells, that worsened after 12 (T1) and 24 h (T2) from surgery, involving the majority of the analysed subsets; after 8 days (T3) from surgical removal of tumor, however, there was a return of all the analyzed parameters to the basal state. In conclusion, surgery causes transient but relevant immune suppression in RCC patients; even though, by day +8, this tends to return to baseline, immunostimulatory therapies could be considered in the peri-operative setting with the aim of reducing immunosuppression and, hopefully, also disease recurrence.

Cytokine-based immunotherapy for advanced kidney cancer: past results and future perspectives in the era of molecularly targeted agents.

Until recently, immunotherapy has been the only therapeutic option available for patients with advanced kidney cancer, even though different choices were often made on the two sides of the Atlantic Ocean. The absence of alternatives made different immunotherapeutic approaches common practice, even with few adequate randomized studies that addressed key questions, such as the best treatment and schedule, and so on. The recent registration of the first two, molecularly targeted, agents Sorafenib and Sunitinib could (and will) render many therapeutic approaches, e.g., single-agent Interferon, obsolete. In this review, we shall cover the past achievements obtained so far with cytokine-based immunotherapy and discuss the present role of immunotherapy in the era of molecularly targeted agents. In particular, specific indications for immunotherapy are emerging (e.g., the use of Interleukin-2 in patients with high CAIX expression), while new trials are ongoing to test immunotherapy in combination with molecularly targeted agents, such as Sorafenib, Sunitinib, or Bevacizumab.

Renal cell carcinoma-induced immunosuppression: an immunophenotypic study of lymphocyte subpopulations and circulating dendritic cells.

BACKGROUND: Renal cell carcinoma (RCC)-induced immune dysfunction in patients at first diagnosis was investigated. PATIENTS AND METHODS: The main circulating lymphocyte subsets, the total number of circulating and intratumor dendritic cells and the titers of circulating VEGF were quantified in 47 RCC patients, using flow cytometric, immunohistochemical and ELISA assays. RESULTS: Despite a significant activation of CD3/HLA-DR+ lymphocytes and of the CD56+ NK subset, RCC patients presented a marked immunosuppression of CD4/CD45RA naïve T-cells, CD4/CD45RO memory T-cells, CD16+ NK-cells, and total circulating dendritic cells, as well as a significant increase of lymphocytes co-expressing the CD4 and CD8 antigens. Finally, CD16+/CD56+ NK and DCs were poorly represented in tumor specimens. CONCLUSION: The complex immunological dysfunctions demonstrated involve different levels of immunocompetence and indicate a pattern of major disturbance of the immune system.

Raltitrexed-Oxaliplatin combination chemotherapy is inactive as second-line treatment for malignant pleural mesothelioma patients.

Within a single-institution phase II trial, we investigated the antitumor activity of the Raltitrexed-Oxaliplatin combination as second-line therapy for malignant pleural mesothelioma (MPM). Fourteen patients were enrolled and all were assessable for response. The trial was then closed because chemotherapy, though well tolerated, yielded no objective responses. The best response observed was disease stabilization in 4 patients only (28.57%), while the other 10 patients (71.42%) progressed despite treatment. Median time to progression (TTP) was 8 weeks (average: 9.85, range: 7-20), while median overall survival was just 14 weeks (average: 21.69, range: 9-66+).

Pro-neoangiogenic cytokines (VEGF and bFGF) and anemia in solid tumor patients.

Using a commercial ELISA assay, we evaluated circulating VEGF and bFGF levels in 203 consecutive patients with solid tumors, and sought a correlation between them and with the grade of anemia. Serum VEGF values were within the normal range in 128 patients (63.05%), with a mean value of 675.04 pg/ml (median, 571.00; range, 0-2796.54). The analysis of VEGF values per tumor group did not provide any statistically significant difference. Regarding bFGF, 143 patients (70.44%) had measurable, and thus abnormal, bFGF values. Overall, mean bFGF serum value was 57.14 pg/ml (median, 8.30; range, 0-4334.71), with the highest bFGF levels found in breast carcinoma patients. As expected, a large number of our patients was fairly anemic, mean hemoglobin level being 11.47 g/dl (median, 11.30; range, 7.1-19.20), the lowest titers being observed in prostate carcinoma patients. No statistically significant correlation was found between serum VEGF and hemoglobin values (r=0.004) but a significant negative correlation was seen between serum bFGF and hemoglobin (r=-0.22, p<0.05). Considering the different tumor groups, a statistically significant negative correlation between bFGF and hemoglobin becomes even more apparent in the subgroup of renal carcinoma patients (r=-0.55, p<0.05). In conclusion, our results demonstrate that there is a statistically significant correlation between systemic hypoxia (evaluated in terms of hemoglobin levels) and circulating bFGF values, but not VEGF; this correlation may lead to therapeutic interventions.

Comportamiento ultraestructural de la inervación de las células intersticiales durante la diferenciación del ovario del embrion de pollo cultivado con 17-beta-estradiol / Ultrastructural behavior of interstiTial cells innervation during the differentiation of the chick embryo ovary cultured with 17-beta-estradiol

En trabajos previos hemos demostrado la relación entre las fibras y terminaciones nerviosas y las células intersticiales (células productoras de estrógenos) en el ovario derecho atrófico y la médula del ovario izquierdo funcionante, in ovo. Además la producción local de neurotrofinas por la células esteroidogénicas está probablemente comprometida en el control de la inervación ovárica. El objetivo del presente estudio fue analizar ultraestructuralmente la inervación durante la diferenciación del ovario del embrión de pollo cultivado con 17- ß- estradiol. Explantos de ovarios derechos e izquierdos de 7 a 19 días de desarrollo in ovo fueron cultivados separadamente por cuatro días en MEM (controles) o en presencia de 17- ß- estradiol (problemas) . En los controles,con microscopía electrónica, el examen de la inervación de los explantos de los ovarios de embrión de pollo reveló que las células intersticiales están bien inervadas. Fibras y terminaciones nerviosas fueron observadas en íntimo contacto con las células productoras de esteroides, una estructura similar a la encontrada en la inervación de aquellos ovarios de quince días del desarrollo in ovo. Los cultivos problemas de 7 días cultivados por cuatro días mostraron fibras y terminaciones nerviosas a diferencias del control. Estos resultados in vitro sugieren que la inervación de los ovarios es controlada por mecanismos indirectos por vía del sistema hipotálamo-hipofisario y de la producción de factores locales. Más experimentos son necesarios para confirmar estos resultados.

Comportamiento ultraestructural de la inervación de las células intersticiales durante la diferenciación del ovario del embrion de pollo cultivado con 17-beta-estradiol / Ultrastructural behavior of interstiTial cells innervation during the differentiation of the chick embryo ovary cultured with 17-beta-estradiol

En trabajos previos hemos demostrado la relación entre las fibras y terminaciones nerviosas y las células intersticiales (células productoras de estrógenos) en el ovario derecho atrófico y la médula del ovario izquierdo funcionante, in ovo. Además la producción local de neurotrofinas por la células esteroidogénicas está probablemente comprometida en el control de la inervación ovárica. El objetivo del presente estudio fue analizar ultraestructuralmente la inervación durante la diferenciación del ovario del embrión de pollo cultivado con 17- ß- estradiol. Explantos de ovarios derechos e izquierdos de 7 a 19 días de desarrollo in ovo fueron cultivados separadamente por cuatro días en MEM (controles) o en presencia de 17- ß- estradiol (problemas) . En los controles,con microscopía electrónica, el examen de la inervación de los explantos de los ovarios de embrión de pollo reveló que las células intersticiales están bien inervadas. Fibras y terminaciones nerviosas fueron observadas en íntimo contacto con las células productoras de esteroides, una estructura similar a la encontrada en la inervación de aquellos ovarios de quince días del desarrollo in ovo. Los cultivos problemas de 7 días cultivados por cuatro días mostraron fibras y terminaciones nerviosas a diferencias del control. Estos resultados in vitro sugieren que la inervación de los ovarios es controlada por mecanismos indirectos por vía del sistema hipotálamo-hipofisario y de la producción de factores locales. Más experimentos son necesarios para confirmar estos resultados. (Au)