SPONTANEOUS REGRESSION OF HEPATOCELLULAR CARCINOMA: FOCUSING IN THE ASSOCIATED RISK FACTORS.

BACKGROUND: Spontaneous regression (SR) is defined as the partial or complete disappearance of a tumor, in the absence of a specific treatment. Evidence of the SR in hepatocellular carcinoma (HCC) is rare. OBJECTIVE: The authors aimed to review all the cases of SR of HCC in two reference centers of Southern Brazil, highlighting the main characteristics. METHODS: Data of all patients with HCC were retrospectively reviewed looking for the occurrence of SR in patients from two tertiary centers in Southern Brazil, in the last five years. The diagnosis of cirrhosis was established according to clinical, laboratory and imaging data, as well as upper endoscopy or histopathological examination when necessary. The diagnosis of HCC was based on typical findings according to radiologic criteria (LIRADS) or histopathological examination. Spontaneous regression was defined as a partial or complete involution of a HCC in the absence of a specific therapy. RESULTS: From all cases of HCC in the last 5 years (n=433), there were five cases of SR. Three (60%) were men, the mean age was 62.6 (50.0-76.0) years, and the etiology was HCV in 3 (60%). Complete regression was observed in three patients (60%), one patient (20%) presented partial regression, and one (20%) relapesed and died. The time of follow-up varied between 12 and 21 months. In this presentation, it was highlighted one case of SR observed after COVID-19 infection in a patient with cirrhosis. The possible mechanisms involved in this situation were reviewed, emphasizing the most common like hypoxia and immunological. There were also one patient submitted to a surgical procedure as a possible fator involved and three patients without obvious risk factors. CONCLUSION: This phenomenon will possibly contribute to a better understanding of the pathophysiological mechanisms of HCC.

Malignant features of minipig melanomas prior to spontaneous regression.

In MeLiM minipigs, melanomas develop around birth, can metastasize, and have histopathologic characteristics similar to humans. Interestingly, MeLiM melanomas eventually regress. This favorable outcome raises the question of their malignancy, which we investigated. We clinically followed tens of tumors from onset to first signs of regression. Transcriptome analysis revealed an enrichment of all cancer hallmarks in melanomas, although no activating or suppressing somatic mutation were found in common driver genes. Analysis of tumor cell genomes revealed high mutation rates without UV signature. Canonical proliferative, survival and angiogenic pathways were detected in MeLiM tumor cells all along progression stages. Functionally, we show that MeLiM melanoma cells are capable to grow in immunocompromised mice, with serial passages and for a longer time than in MeLiM pigs. Pigs set in place an immune response during progression with dense infiltration by myeloid cells while melanoma cells are deficient in B2M expression. To conclude, our data on MeLiM melanomas reveal several malignancy characteristics. The combination of these features with the successful spontaneous regression of these tumors make it an outstanding model to study an efficient anti-tumor immune response.

Progression to Lymph Node Metastasis After Spontaneous Regression of Pulmonary Adenocarcinoma Following Biopsy.

BACKGROUND/AIM: Spontaneous regression (SR) of cancer, which indicates the natural disappearance of malignant tumors, is rare. Little is known about the mechanisms underlying SR; however, immunological reactions, infections, injuries, and medications have been presumed. Among previously reported cases of SR, lung cancer cases have been extremely limited. CASE REPORT: Here, we present a case of lymph node metastasis exacerbation after SR of a primary adenocarcinoma following a biopsy. After complete disappearance of the primary site tumor, metastatic lymph nodes in the mediastinum gradually increased in size as a single lesion. Local treatment with resection and radiotherapy was effective for this metastasis, without recurrence for >3 years. CONCLUSION: This is an interesting case of SR of pulmonary adenocarcinoma with inconsistent features in the primary and metastatic lesions. When physicians encounter exacerbation of metastatic sites with SR of the primary site in lung cancer, local intervention may be considered as a curative treatment.

Resolução espontânea de osteocondroma de fêmur distal: relato de caso / Spontaneous resolution of osteochondroma of the distal femur: case report

Introdução: o osteocondroma é o tumor ósseo benigno mais comum. Normalmente são assintomáticos e diagnosticados incidentalmente. Sua localização mais comum é no fêmur distal e raramente sofrem resolução espontânea. Objetivo: relatar um caso de osteocondroma do ambulatório de especialidades do Hospital do Servidor Público Municipal que foi acompanhado por três anos e evoluiu com resolução espontânea. Ainda, buscar na literatura casos que sejam semelhantes a procura de justificativas para esta evolução que não é comum. Método: relato de caso de paciente do Ambulatório de Especialidade do Hospital do Servidor Público Municipal, de 12 anos de idade, que foi acompanhado por três anos apresentando um tumor ósseo no fêmur distal compatível com diagnóstico de osteocondroma, que ao longo dos três anos evoluiu com resolução espontânea. Conclusão: osteocondromas raramente evoluem com resolução espontânea, quando isso ocorre geralmente são pacientes que ainda não atingiram a maturidade esquelética, apesar de algumas teorias sobre os mecanismos dessa evolução ainda são necessários mais estudos para conclusões mais definitivas. Palavras-chave: Resolução espontânea de tumor ósseo. Osteocondroma. Tumor Ósseo.

Spontaneous Volumetric Tumor Regression During Wait-and-Scan Management of 952 Sporadic Vestibular Schwannomas.

OBJECTIVE: Spontaneous tumor shrinkage during wait-and-scan management of sporadic vestibular schwannoma is generally considered an uncommon phenomenon. However, most data informing this understanding stem from single-slice linear tumor measurements taken in the axial imaging plane. The objective of the current work was to characterize the regression capacity of sporadic vestibular schwannomas using volumetric tumor measurements. STUDY DESIGN: Retrospective cohort study using slice-by-slice, three-dimensional volumetric tumor measurements. SETTING: Three tertiary referral centers. PATIENTS: Patients with sporadic vestibular schwannoma. INTERVENTIONS: Wait-and-scan. MAIN OUTCOME MEASURES: Regression-free survival rates with regression defined as a decrease of at least 20% of the tumor volume. RESULTS: Among 952 patients undergoing a total of 3,505 magnetic resonance imaging studies during observation, 123 experienced volumetric tumor regression after diagnosis at a median of 1.2 years (interquartile range, 0.6-2.9 yr). Volumetric regression-free survival rates (95% confidence interval; number still at risk) at 1, 3, and 5 years after diagnosis were 94% (92-95%; 662), 86% (83-89%; 275), and 78% (73-82%; 132), respectively. Among 405 patients who demonstrated an initial period of tumor growth but continued wait-and-scan management, 48 experienced volumetric regression at a median of 1.2 years (interquartile range, 0.8-2.6 yr) after initial growth. Volumetric regression-free survival rates at 1, 3, and 5 years after initial growth were 94% (92-97%; 260), 84% (79-89%; 99), and 75% (67-83%; 43), respectively. Ultimately, only 82 of the 952 patients studied showed exclusively volumetric tumor regression (i.e., without any periods of tumor growth) by the time of last follow-up. CONCLUSION: Spontaneous volumetric tumor shrinkage during wait-and-scan management occurs more frequently than suggested by previous studies using linear tumor measurements and can even occur after previous episodes of documented tumor growth. These data further highlight the dynamic nature of vestibular schwannoma growth. To this end, the application of natural history data to patient management requires a nuanced approach that parallels the complex tumor behavior of vestibular schwannoma.

Spontaneous Regression of Laryngeal Squamous Cell Carcinoma After Biopsy.

Approximately 7 cases of spontaneous regression of adult laryngeal carcinoma have been published in the literature since 1900. This case presents a 62-year-old male with a 6-month history of hoarseness who was subsequently diagnosed with a T1aN0M0 left true vocal fold squamous cell carcinoma (SCC) after biopsy. One month following the initial biopsy, histopathological findings on repeat biopsy revealed absence of malignancy and regression of the tumor without radiation. There has been no evidence of tumor recurrence. This case exemplifies how innate immune modulation may play a role in the spontaneous regression of laryngeal SCC, although the mechanism remains unknown.

Role of FoxP3-positive regulatory T-cells in regressive and progressive cervical dysplasia.

PURPOSE: Forkhead Box Protein 3 (FoxP3) is known as a key mediator in the immunosuppressive function of regulatory T-cells (Tregs). The aim of our study was to investigate whether FoxP3-positive Tregs have the potential to act as an independent predictor in progression as well as in regression of cervical intraepithelial neoplasia, especially in patients with intermediate cervical intraepithelial neoplasia (CIN II). METHODS: Nuclear FoxP3 expression was immunohistochemically analysed in 169 patient samples (CIN I, CIN II with regressive course, CIN II with progressive course, CIN III). The median numbers were calculated for each slide and correlated with the histological CIN grade. Statistical analysis was performed by SPSS 26 (Mann-Whitney U test, Spearman's rank correlation). RESULTS: An increased FoxP3 expression in CIN II with progression could be detected in comparison to CIN II with regression (p = 0.003). Total FoxP3 expression (epithelium and dysplasia-connected stroma) was higher in more advanced CIN grades (p < 0.001 for CIN I vs. CIN II; p = 0.227 for CIN II vs. CIN III). A positive correlation could be detected between FoxP3-positive cells in epithelium and total FoxP3 expression (Spearman's Rho: 0,565; p < 0.01). CONCLUSION: Expression of FoxP3 could be a helpful predictive factor to assess the risks of CIN II progression. As a prognosticator for regression and progression in cervical intraepithelial lesions it might thereby help in the decision process regarding surgical treatment vs. watchful waiting strategy to prevent conisation-associated risks for patients in child-bearing age. In addition, the findings support the potential of Tregs as a target for immune therapy in cervical cancer patients.

Predicting regression of cervical intraepithelial neoplasia grade 2 in women under 25 years.

BACKGROUND: A number of retrospective and prospective studies have documented substantial rates of regression in cervical intraepithelial neoplasia grade 2 lesions in young women. Initial observational management of cervical intraepithelial neoplasia grade 2 is increasingly accepted as appropriate for women under 25 years of age with screen-detected abnormalities and is included in a number of clinical guidelines. However, there has been a paucity of large prospective studies on observational management with strict inclusion criteria. A number of important questions remain, specifically regarding the clinical variables that are associated with the risk of progression or persistence of disease. To investigate these factors and to ensure that young women with cervical intraepithelial neoplasia grade 2 undergoing observational management were being managed in a well-monitored and an appropriately informed fashion, we conducted a large, multicenter prospective study on observational management of cervical intraepithelial neoplasia grade 2 in women under 25 years. OBJECTIVE: This study aimed to determine the regression rates and clinical, cytologic, and pathologic predictors of regression of cervical intraepithelial neoplasia grade 2 in women under 25 years undergoing observational management over 24 months. STUDY DESIGN: This study was a multicenter prospective study on observational management of cervical intraepithelial neoplasia grade 2 (ie, repeat colposcopy, cytology, and cervical biopsy every 6 months) for up to 24 months. A total of 615 consenting women under 25 years with newly-diagnosed, biopsy-proven cervical intraepithelial neoplasia grade 2 were recruited (from 2010 to 2016) through 16 hospital-based colposcopy units in New Zealand and Australia. RESULTS: At completion, 326 women had confirmed regression, 156 had persistent high-grade cervical intraepithelial neoplasia grade 2 or 3 or adenocarcinoma in situ, and 24 had unconfirmed regression (ie, first regression at the 24-month follow-up). A total of 109 women did not complete the protocol (41 because of delayed follow-up, 41 lost to follow-up, 22 elected treatment, 4 refused a biopsy, and 1 died of an unrelated cause). Confirmed regression was observed in 53% (326 of 615) of all women enrolled in the study and, when missing data were imputed, it was estimated that 64% of women (95% confidence interval, 60%-68%) would have experienced regression. Similarly, lesions regressed in 64% (326 of 506) of women who completed the observational protocol. Based on a multivariable analysis, detection of human papillomavirus 16 in a liquid-based cytology sample at the time of initial colposcopy decreased the chance of regression by 31% (risk ratio, 0.69; 95% confidence interval, 0.56-0.86; P<.001). In addition, at initial colposcopy, low-grade or normal colposcopic impression, later year of diagnosis, low-grade or normal cytology, and being a nonsmoker were all independently associated with an increased chance of regression. CONCLUSION: More than half of women under 25 years with cervical intraepithelial neoplasia grade 2 will regress to cervical intraepithelial neoplasia grade 1 or normal within 24 months without destructive treatment. The absence of human papillomavirus 16 is the most important predictor of regression.

Spontaneous regression of solitary osteochondromas in children: An option to consider in clinical practice.

Osteochondromas are neoplasm that belong to the family of cartilaginous histogenesis tumors and represent 90% of all forms of exostoses. As most osteochondromas are asymptomatic, underdiagnosis is frequent. Symptomatic forms usually manifest before the age of 20 years, and the most common symptoms are pain and the detection of a bony mass. Herein, we report four cases of spontaneous regression of solitary osteochondromas in the light of literature. We consider that orthopedic surgeons should take into account the possibility of spontaneous regression of these tumors, before recommending surgery. Symptoms are usually mild and we recommend following these patients with X-ray and physical examination annually.

Regression is significantly associated with outcomes for patients with melanoma.

BACKGROUND: The prognostic significance of regression in melanoma is debated. We present a large multicenter study correlating regression with sentinel lymph node metastasis and melanoma-specific survival. METHODS: The Sentinel Lymph Node Working Group database was reviewed from 1993 to 2018. Patients with known regression and sentinel lymph node status were included. Clinicopathologic factors were correlated with regression, sentinel lymph node status, and melanoma-specific survival. RESULTS: There were 4,790 patients; median follow-up was 39.6 months. Regression was present in 1,081 (22.6%) cases, and 798 (16.7%) patients had sentinel lymph node metastases. On multivariable analysis, male sex, truncal tumors, and decreasing thickness were significantly associated with regression (P < .05), whereas head/neck or leg tumors had lower rates of regression (P < .05). Regression was significantly correlated with a decreased risk of sentinel lymph node disease on multivariable analysis (odds ratio 0.68, 95% confidence interval 0.54-0.85; P = .0008). Multivariable analysis also showed that increasing age, male sex, increasing thickness, ulceration, lymphovascular invasion, microsatellitosis, and sentinel lymph node metastasis were significantly (P < .05) associated with worse melanoma-specific survival, while regression was significantly associated with better melanoma-specific survival (hazard ratio 0.75, 95% confidence interval 0.57-0.99; P = .043). CONCLUSION: This large study shows that regression is significantly associated with better outcomes in patients with melanoma and is correlated with a lower risk of sentinel lymph node metastasis and a better melanoma-specific survival.

Five-year follow-up and clinical outcome in euthyroid patients with thyroid nodules.

BACKGROUND: Thyroid nodule diagnosis has become increasingly frequent. Defining optimum surveillance intervals for patients with unsuspicious thyroid nodules remains a challenge. This was a single centre cohort study in which patients diagnosed with unsuspicious thyroid nodules in whom no treatment was indicated were invited for re-evaluation 5 years after the diagnosis. The primary end point of the study was to estimate the change in nodule size with thyroid ultrasound (US) and the secondary end point was to assess the need for clinical management 5 years after the diagnosis. PATIENTS AND METHODS: Baseline patient parameters and ultrasound characteristics of the nodules were retrospectively collected. At follow-up, thyroid ultrasound was performed. RESULTS: A hundred and eighteen (107 women / 11 men, aged 56.8 ± 13.4 years) patients were included in the study having 203 nodules at baseline, with mean largest nodule diameter 10.5 ± 7.4 mm. After 5 years, 58 (28.6%) nodules significantly increased in size, 27 (13.3%) decreased, and for 104 (51.2%) of nodules, no change in size was noted. Fourteen (6.9%) nodules disappeared. Additional 26 new nodules (mean largest diameter 7.7 ± 5.0 mm) in 16 patients were identified at follow-up. Regarding the clinical outcome, no new thyroid cancers were found. For 107 (90.7%) patients no further management was indicated. Five (4.2%) patients were referred to thyroidectomy because of the growth of the nodules. Two (1.7%) patients were treated for hyperthyroidism. Four (3.4%) patients did not complete the study. CONCLUSIONS: We report a single centre experience of the natural history of unsuspicious thyroid nodules. Our results showed that 71.4% of such nodules remained stable in size, decreased or even disappeared and that the vast majority of the patients remained clinically stable with no need for treatment 5 years after the diagnosis.

When to Stop TKIs in Patients with Chronic Myeloid Leukemia and How to Follow Them Subsequently.

OPINION STATEMENT: ABL1 tyrosine kinase inhibitors (TKI) have dramatically improved the outcome for CML (chronic myeloid leukemia) patients. When TKI therapy is addressed appropriately, it can lead to an optimal molecular response in the majority of CML patients and a life expectancy that approaches that of the general population. However, lifelong TKI therapy may have consequences, including chronic, mostly low-grade, adverse events that can substantially impact patients' quality of life, adherence to therapy and, consequently, success of treatment. In the last few years, several groups have demonstrated that approximately 50% of chronic phase CML patients (CP-CML) who have achieved a stable deep molecular response (DMR) can stop therapy without suffering molecular relapse. Nowadays, treatment-free remission (TFR) has a significant role in the management of CML and should be considered in selected motivated patients that fulfill well-defined requirements to maximize the probability of successful discontinuation of TKI therapy.

Spontaneous Regression of a Pulmonary Metastasis Secondary to Contralateral Metastasectomy.

Spontaneous regression is defined as the partial or complete resolution of a malignant neoplasm either with treatment that is perceived to be inadequate or in the absence of therapy. This report describes a case of spontaneous regression of a pulmonary metastasis of renal cell carcinoma secondary to metastasectomy in the contralateral lung.

Mathematical simulation of tumour angiogenesis: angiopoietin balance is a key factor in vessel growth and regression.

Excessive tumour growth results in a hypoxic environment around cancer cells, thus inducing tumour angiogenesis, which refers to the generation of new blood vessels from pre-existing vessels. This mechanism is biologically and physically complex, with various mathematical simulation models proposing to reproduce its formation. However, although temporary vessel regression is clinically known, few models succeed in reproducing this phenomenon. Here, we developed a three-dimensional simulation model encompassing both angiogenesis and tumour growth, specifically including angiopoietin. Angiopoietin regulates both adhesion and migration between vascular endothelial cells and wall cells, thus inhibiting the cell-to-cell adhesion required for angiogenesis initiation. Simulation results showed a regression, i.e. transient decrease, in the overall length of new vessels during vascular network formation. Using our model, we also evaluated the efficacy of administering the drug bevacizumab. The results highlighted differences in treatment efficacy: (1) earlier administration showed higher efficacy in inhibiting tumour growth, and (2) efficacy depended on the treatment interval even with the administration of the same dose. After thorough validation in the future, these results will contribute to the design of angiogenesis treatment protocols.

Bevacizumab-associated glomerular microangiopathy that occurred after postoperative chemotherapy for ovarian cancer.

Bevacizumab is a monoclonal antibody against vascular endothelial growth factor (VEGF) that is used to treat patients with various cancers. However, it is known to be associated with adverse events, such as hypertension and proteinuria. The histology of bevacizumab-induced nephropathy is known as thrombotic microangiopathy or minimal change nephrotic syndrome. Recently, however, the terms "bevacizumab-associated glomerular microangiopathy" and "anti-VEGF therapy-induced glomerular microangiopathy" have been proposed. We present a case of a 68-year-old woman who was administered postoperative chemotherapy (carboplatin, paclitaxel, and bevacizumab) for stage IV ovarian cancer. Proteinuria and hypertension appeared after three courses; however, six courses were completed. Then, gemcitabine and carboplatin were administered for recurrence of her cancer. She was diagnosed with nephrotic syndrome after eight courses. Renal biopsy showed accumulation of periodic acid-Schiff (PAS)-positive substances in the capillary walls and para-mesangial areas. Double contouring of basement membranes was also observed. Immunofluorescence microscopy revealed positive staining for IgG, IgA, IgM, C3, C4, and C1q. Immunosuppressive therapy was administered, but was ineffective. Further examination by electron microscopy and immunostaining led to a diagnosis of bevacizumab-associated glomerular microangiopathy.

Reporting regression in primary cutaneous melanoma. Part 1: history, histological criteria and pathogenesis.

Regression is an important histopathological parameter reported for the diagnosis of primary cutaneous melanoma. Histological regression is defined by The College of American Pathologists as the replacement of tumour cells by lymphocytic inflammation, with attenuation of the epidermis, and nonlaminated dermal fibrosis with inflammatory cells, melanophagocytosis and telangiectasia. Histological regression may be reported as absent versus present and, if present, as complete, partial or segmental. The stages of histological regression are early, intermediate and late, depending on the extent of histological inflammation and fibrosis. Regression occurs when the host's immune system attacks primary melanocytic tumour cells via tumour-infiltrating lymphocytes, resulting in fibrosis. The immunological mechanisms driving complete, partial and segmental regression may vary. In this first part of this two-part review, we review the history, histological criteria and pathogenesis of regression in primary cutaneous melanoma, while in Part 2 we will review the effect of histological regression on prognosis, evaluation and management.