Characteristics and outcome of synchronous bilateral Wilms tumour in the SIOP WT 2001 Study: Report from the SIOP Renal Tumour Study Group (SIOP-RTSG).

BACKGROUND: Among patients with nephroblastoma, those with bilateral disease are a unique population where maximising tumour control must be balanced with preserving renal parenchyma. METHODS: The SIOP 2001 protocol recommended surgery after neoadjuvant cycle(s) of Dactinomycin and Vincristine (AV) with response-adapted intensification, if needed. Adjuvant treatment was given based on the lesion with the worst histology. RESULTS: Three hundred and twenty seven patients with stage V disease were evaluable: 174 had bilateral Wilms tumour (BWT), 101 unilateral WT and contralateral nephroblastomatosis (NB) and 52 bilateral nephroblastomatosis. In these three groups, the estimated 5y-EFS was 76.1%, 84.6%, and 74.9%, respectively. AV chemotherapy alone was the successful chemotherapy for 58.7% of all the patients and 65.6% of the non-metastatic patients. Among the 174 patients with BWT, 149 (88.2%) had at least one nephron-sparing surgery. Twenty of 61 bilateral stage I patients were treated with four-week AV postoperatively achieving 94.4% 5y-EFS. At last follow-up, 87% of patients had normal renal function. CONCLUSIONS: This study demonstrates that AV without anthracyclines is sufficient to achieve NSS and good survival in the majority of patients. For patients with bilateral stage I WT and intermediate risk histology, only four weeks adjuvant AV seems to be sufficient. CLINICAL TRIAL REGISTRATION: NCT00047138.

Upfront resection versus no resection of the primary tumor in patients with synchronous metastatic colorectal cancer: the randomized phase III CAIRO4 study conducted by the Dutch Colorectal Cancer Group and the Danish Colorectal Cancer Group.

BACKGROUND: Upfront primary tumor resection (PTR) has been associated with longer overall survival (OS) in patients with synchronous unresectable metastatic colorectal cancer (mCRC) in retrospective analyses. The aim of the CAIRO4 study was to investigate whether the addition of upfront PTR to systemic therapy resulted in a survival benefit in patients with synchronous mCRC without severe symptoms of their primary tumor. PATIENTS AND METHODS: This randomized phase III trial was conducted in 45 hospitals in The Netherlands and Denmark. Eligibility criteria included previously untreated mCRC, unresectable metastases, and no severe symptoms of the primary tumor. Patients were randomized (1 : 1) to upfront PTR followed by systemic therapy or systemic therapy without upfront PTR. Systemic therapy consisted of first-line fluoropyrimidine-based chemotherapy with bevacizumab in both arms. Primary endpoint was OS in the intention-to-treat population. The study was registered at ClinicalTrials.gov, NCT01606098. RESULTS: Between August 2012 and February 2021, 206 patients were randomized. In the intention-to-treat analysis, 204 patients were included (n = 103 without upfront PTR, n = 101 with upfront PTR) of whom 116 were men (57%) with median age of 65 years (interquartile range 59-71 years). Median follow-up was 69.4 months. Median OS in the arm without upfront PTR was 18.3 months (95% confidence interval 16.0-22.2 months) compared with 20.1 months (95% confidence interval 17.0-25.1 months) in the upfront PTR arm (P = 0.32). The number of grade 3-4 events was 71 (72%) in the arm without upfront PTR and 61 (65%) in the upfront PTR arm (P = 0.33). Three deaths (3%) possibly related to treatment were reported in the arm without upfront PTR and four (4%) in the upfront PTR arm. CONCLUSIONS: Addition of upfront PTR to palliative systemic therapy in patients with synchronous mCRC without severe symptoms of the primary tumor does not result in a survival benefit. This practice should no longer be considered standard of care.

Complete response to chemoimmunotherapy with bevacizumab in synchronous multiple primary cancers: pulmonary adenocarcinoma and sarcomatoid carcinoma.

A small percentage of patients have multiple synchronous primary cancers at presentation. In the last five years, many regimens associated with immunotherapy and chemotherapy were approved for first-line metastatic non-small-cell lung cancer (NSCLC) and other solid tumors, but the study of immunotherapy when multiple cancers are present in one patient remains incomplete. Next-generation sequencing biomarkers and immunotherapy markers including PD-L1 can be effectively utilized in the diagnosis and treatment plan for multiple synchronous primary cancers. Immune biomarkers and PD-L1 expression warrant individualized treatments in synchronous primary adenocarcinoma and pulmonary sarcomatoid carcinoma. We describe the case of a patient with pulmonary sarcomatoid carcinoma and lung adenocarcinoma, metastatic to brain de novo. The patient achieved a complete response after only three cycles of carboplatin, paclitaxel, bevacizumab, and atezolizumab and remains free of any evidence of disease after 18 mo of maintenance therapy.

Successful first-line treatment of simultaneous multiple primary malignancies of lung adenocarcinoma and renal clear cell carcinoma: A case report.

Background: Multiple Primary Malignancies (MPMs) refer to the occurrence of two or more primary malignancies in the same organ or multiple organs and tissues of the same patient simultaneously or sequentially, with an incidence rate ranging from 2-17%. According to the difference in the time of occurrence of each primary tumor, MPMs can be classified as simultaneous malignancies and heterochronic malignancies. The former refers to the occurrence of two or more malignancies one after another within 6 months, while the latter refers to the occurrence of two malignancies at an interval of more than 6 months. Currently, there is a lack of effective treatment options for MPMs both nationally and internationally. Case presentation: The patient was a 65-year-old male smoker with a definite diagnosis of advanced lung adenocarcinoma with kirsten rat sarcoma viral oncogene (KRAS) mutation, concomitant with primary renal clear cell carcinoma (RCCC), who had a progression-free survival (PFS) for 7 months after first-line treatment with albumin-bound paclitaxel and cisplatin in combination with sintilimab. Conclusion: In this paper, we report a case of advanced lung adenocarcinoma combined with RCCC as a concurrent double primary malignancy, which achieved a satisfactory outcome after first-line chemotherapy combined with immunotherapy, with the aim of exploring effective treatment modalities for this type of MPMs, in order to improve the survival and prognosis of the patient.

Synchronous multiple primary tumors in patients with malignant lymphoma: a retrospective study.

BACKGROUND: Synchronous multiple primary malignant tumors (sMPMTs) are sometimes diagnosed in patients with malignant lymphoma. We herein investigated the prognostic impact of sMPMT in lymphoma patients and the optimal treatment strategy. METHODS: Seventy-five patients with sMPMTs (5.8%) among 1285 patients with lymphoma newly diagnosed between August 2004 and April 2020 were enrolled. RESULTS: In patients with indolent lymphoma, those with sMPMTs had a worse prognosis than those without sMPMTs (5-year overall survival [OS]: 73.4% and 87.8%, respectively; P = 0.047). Among those with high and low tumor burden, the cumulative rate of death due to solid tumors was significantly higher in patients with sMPMTs than those without sMPMTs (high tumor burden: 26.7% vs. 1.6%, P < 0.001; low tumor burden: 12.7% vs. 1.0%, P = 0.003). The presence of sMPMTs did not have a significant impact on outcomes in patients with diffuse large B-cell lymphoma (DLBCL) (5-year OS: 65.4% and 66.9%, respectively; P = 0.74; 5-year progression-free survival [PFS]: 65.5% and 59.9%, respectively; P = 0.65). However, the cumulative rate of death from solid tumor in patients with sMPMTs was significantly higher than in patients without sMPMTs (5-year cumulative rate: 7.4% and 2.1%, respectively; P = 0.004). The treatment sequence did not have a significant effect on outcomes or the relative dose intensity of chemotherapy. CONCLUSIONS: In patients with indolent lymphoma, those with sMPMTs had a significantly worse prognosis than those without sMPMTs, mainly because of high mortality due to solid tumors. The presence of sMPMTs was not a significant prognostic factor in patients with DLBCL. It is important to assess the status and need for early treatment of each type of malignancy in patients with sMPMTs.

Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease.

BACKGROUND: Patients with von Hippel-Lindau (VHL) disease have a high incidence of renal cell carcinoma owing to VHL gene inactivation and constitutive activation of the transcription factor hypoxia-inducible factor 2α (HIF-2α). METHODS: In this phase 2, open-label, single-group trial, we investigated the efficacy and safety of the HIF-2α inhibitor belzutifan (MK-6482, previously called PT2977), administered orally at a dose of 120 mg daily, in patients with renal cell carcinoma associated with VHL disease. The primary end point was objective response (complete or partial response) as measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1, by an independent central radiology review committee. We also assessed responses to belzutifan in patients with non-renal cell carcinoma neoplasms and the safety of belzutifan. RESULTS: After a median follow-up of 21.8 months (range, 20.2 to 30.1), the percentage of patients with renal cell carcinoma who had an objective response was 49% (95% confidence interval, 36 to 62). Responses were also observed in patients with pancreatic lesions (47 of 61 patients [77%]) and central nervous system hemangioblastomas (15 of 50 patients [30%]). Among the 16 eyes that could be evaluated in 12 patients with retinal hemangioblastomas at baseline, all (100%) were graded as showing improvement. The most common adverse events were anemia (in 90% of the patients) and fatigue (in 66%). Seven patients discontinued treatment: four patients voluntarily discontinued, one discontinued owing to a treatment-related adverse event (grade 1 dizziness), one discontinued because of disease progression as assessed by the investigator, and one patient died (of acute toxic effects of fentanyl). CONCLUSIONS: Belzutifan was associated with predominantly grade 1 and 2 adverse events and showed activity in patients with renal cell carcinomas and non-renal cell carcinoma neoplasms associated with VHL disease. (Funded by Merck Sharp and Dohme and others; MK-6482-004 ClinicalTrials.gov number, NCT03401788.).

Ovarian Serous Carcinoma With a Novel HSP90AB1 Mutation in a Patient With Synchronous Primary Fallopian Tube Serous Carcinoma.

BACKGROUND/AIM: Ovarian carcinoma is the fifth leading cause of cancer-related deaths in women in the United States. Serous papillary carcinoma is the most common histological type of ovarian carcinoma that often goes undetected until it has spread within the pelvis and abdomen leading to poor prognosis. Translation of next-generation sequencing (NGS) technology into personalized medicine and identification of new potential targets for therapeutic applications may be helpful. CASE REPORT: We report a case of a 59-year-old female who initially presented in the emergency department with increasing abdominal girth, and bloating. Computed tomography showed ascites and omental and pelvic masses. Fine needle biopsy of the omental mass showed high-grade papillary adenocarcinoma consistent with high-grade ovarian serous carcinoma. She was treated with chemotherapy followed by debulking surgery. Primary ovarian serous carcinoma and synchronous primary fallopian tube serous carcinoma with multiple leiomyomas were identified in the surgical specimen. Pleural biopsy was also positive for carcinoma. NGS and programmed death-ligand 1 (PD-L1) expression testing were performed in the ovarian serous carcinoma. The results showed mutations of breast cancer type 1 (BRCA1) and type 2 (BRCA2), tumor protein p53 (TP53) (c.524G>A at pR175H), and heat shock protein 90 alpha family class B member 1 (HSP90AB1) (p.R456C), as well as low RNA expression score of PD-L1. CONCLUSION: Identification of these mutations and PD-L1 abnormality at the diagnosis of ovarian carcinoma may shed light for clinicians to provide targeted therapy with poly (ADP-ribose) polymerase (PARP) inhibitors and immune checkpoint inhibitors for ovarian serous carcinoma. This is the first documented case of ovarian serous carcinoma to have found a HSP90AB1 (p.R456C) mutation.

Transition to Targeted Therapies Improved the Prognosis and Increased the Utilization of Medical Treatments among Patients with Synchronous Metastatic Renal Cell Cancer.

Since the introduction of targeted therapies (TTs) for metastatic renal cell cancer (mRCC) in 2005, a limited amount of epidemiological data on efficacy of modern drug therapies for synchronous mRCC has been published. We present a comprehensive nationwide cohort including all cases of primarily metastasized renal cell cancer among adults diagnosed between 2005 and 2010, based on data from the Finnish Cancer Registry and patient records from treating hospitals. Applied treatment protocols and survival outcomes were analyzed. A total of 977 patients were included in the analysis; 499 patients were diagnosed between 2005 and 2007 and 478 patients were diagnosed between 2008 and 2010. The median overall survival (OS) was 8.80 months (95% confidence interval (CI): 7.60-10.02). The median OS of the patients diagnosed at the latter era was significantly better (11.1; 95% CI: 8.8-13.4 vs. 7.0; 95% CI: 5.7-8.3 months, p ≤ 0.001). A total number of 524 (53.8%) patients received drug therapy. Altogether, TTs including tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors (mTORi), and vascular endothelial growth factor inhibitor covered 331 (63.2%) of first-line treatments, whereas interferon and its combinations with chemotherapy were used for 186 (35.5%) patients. The median OS rates for TT and interferon as first-line therapy groups were 19.9 (16.9-22.8) and 14.9 (12.3-17.4) months, respectively. The OS for patients who did not receive drug therapy after cytoreductive nephrectomy was dismal. We found that the OS estimate of mRCC patients in Finland has improved since the introduction of tyrosine kinase inhibitors. However, the prognosis remains poor for frail, elderly patients with an impaired performance status.

De novo isolated myeloid sarcoma: comparative analysis of survival in 19 consecutive cases.

Institutional database search (1999-2020) for acute myeloid leukaemia (AML) identified 109 cases of myeloid sarcoma (MS), of which 19 were isolated and presented de novo. The latter displayed longer survival (median 78 months), compared to MS with synchronous intramedullary AML (n = 32; median 16 months) and de novo AML without MS (n = 729; median 22 months; P = 0·13). However, the difference in survival was no longer apparent after accounting for bone marrow cytogenetic risk status (P = 0·67). Treatment-induced MS tumour resolution was not affected by the presence of intramedullary disease (P = 0·61). The current study clarifies the prognosis of de novo isolated MS, in the context of AML.

Case Report: A Rare Case of Metachronous Multiple Primary Lung Cancers in a Patient With Successful Management by Switching From Anti-PD-1 Therapy to Anti-PD-L1 Therapy.

Without global standard diagnostic criteria, distinguishing multiple primary lung cancers (MPLCs) from intrapulmonary metastasis or histologic transformation has been a big challenge in clinical practice. Here, we described a rare case of metachronous adenocarcinoma and small cell lung cancer (SCLC) in a patient who developed drug resistance to pembrolizumab. Both DNA-sequencing and RNA-sequencing were performed on primary adenocarcinoma and resistant lesions. Through the comparison of primary adenocarcinoma and novel lesion mutation profiles, along with bioinformatic estimation of immune proportion by using RNA sequence data, we revealed the origin and tumor microenvironment of the two lesions. No shared mutations were detected between lung adenocarcinoma (LUAD) and SCLC from the same patient, suggesting these two lesions might be from separate primary lung cancers. Compared to LUAD, SCLC showed a relatively cold microenvironment, including negative PD-L1. The patient obtained durable clinical benefits upon treatment with atezolizumab, without experiencing immune-related adverse events. Disease progression should be monitored with prompt re-biopsy and molecular profiling to spot a potential histologic change and to shed light on therapeutic alternatives. The use of atezolizumab, either alone or in combination with other agents, may be a potential therapeutic strategy for patients with both LUAD and SCLC.

Clonal evidence for the development of neuroblastoma with extensive copy-neutral loss of heterozygosity arising in a mature teratoma.

Mature teratomas are usually benign tumors that rarely undergo malignant transformation. We report an advanced neuroblastoma arising in a mature teratoma of the ovary. Whole-exome sequencing identified extensive copy-neutral loss of heterozygosity (LOH) in both neuroblastoma and teratoma elements, suggesting that the neuroblastoma evolved from the teratoma. In addition, several truncating germline heterozygous variants in tumor suppressor genes, including RBL2 and FBXW12, became homozygous as a result of LOH. Collectively, we speculate that extensive LOH in teratoma cells may force heterozygous germline variants to become homozygous, which, in turn, may contribute to the development of neuroblastoma with the acquisition of additional chromosomal changes.

Multiomics analysis reveals a distinct response mechanism in multiple primary lung adenocarcinoma after neoadjuvant immunotherapy.

Multiple primary lung cancer (MPLC) remains a tough challenge to diagnose and treat. Although neoadjuvant immunotherapy has shown promising results in early stage non-small cell lung cancer, whether such modality can benefit all primary lesions remains unclear. Herein, we performed integrated multiomics analysis in one patient with early stage MPLC with remarkable tumor shrinkage in a solid nodule and no response in two subsolid nodules after treatment with three cycles of neoadjuvant pembrolizumab. Genomic heterogeneity was observed among responding nodules with high levels of infiltrating CD8+ and CD68+ immune cells. Substantially downregulated human leukocyte antigen (HLA)-related genes and impaired T lymphocyte function were observed in non-responding nodules. A larger proportion of infiltrating tissue resident memory T cells (Trm) along with high T cell receptor repertoire clonality in responding nodules were validated as predictive and prognostic biomarkers in multiple cancer types using external public datasets. These results suggested that neoadjuvant programmed death 1 (PD-1)/programmed death ligand 1 inhibitors alone may not be an optimal therapeutic strategy for MPLC due to disparities in genomic alterations and immune microenvironment among different lesions. Additionally, we postulate that increased infiltration of Trm may be a unique marker of early immune responses to PD-1 blockade.

Synchronous Primary Lung Adenocarcinoma and Hepatocellular Carcinoma Successfully Treated with a Combination of Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel.

Chemotherapy for multiple primary malignancies is challenging. We herein report a case of synchronous primary lung adenocarcinoma and hepatocellular carcinoma (HCC). A 72-year-old man was admitted for the evaluation of an abnormal shadow on his lung. Computed tomography revealed a lung nodule in the right upper lobe and multiple liver masses. He was diagnosed with synchronous primary lung adenocarcinoma and HCC. Atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) chemotherapy was efficacious for both tumors. ABCP chemotherapy may be a potential treatment option for synchronous primary lung adenocarcinoma and HCC.

Case Report: Clinical Responses to Tislelizumab as a First-Line Therapy for Primary Hepatocellular Carcinoma With B-Cell Indolent Lymphoma.

Background: As an emerging therapy with a promising efficacy, immunotherapy has been widely used in the treatment of solid tumors and hematologic malignancies. This clinical study compares the efficacy of tislelizumab, a domestic immune checkpoint inhibitor (ICI), to that of sorafenib when used as a first-line therapeutic option in hepatocellular carcinoma (HCC), and the concurrence of HCC and non-Hodgkin's lymphoma (NHL) is rare, especially in the treatment of ICIs. Case presentation: A 61-year-old patient presenting with primary HCC and indolent B-cell lymphoma had a partial clinical response to tislelizumab for his primary HCC. Besides, we described a phenomenon of pseudo-progression and delayed diagnosis of his lymphoma during a long course of treatment. Conclusion: Tislelizumab, an immunotherapeutic option with a favorable efficacy and toxicity, can be used to manage double primary tumors. However, studies should aim to elucidate the probable mechanisms of this therapy. Pseudo-progression and separation remission make the treatment of double primary tumors even more challenging, which calls for additional caution in patients undergoing immunotherapy to avoid misdiagnosis and, therefore, begin early appropriate interventions.

Neoadjuvant ipilimumab plus nivolumab in synchronous clinical stage III melanoma.

BACKGROUND: Patients with synchronous clinical stage III melanoma can present with primary melanoma lesions, locally recurrent melanoma or in-transit metastases. Neoadjuvant ipilimumab plus nivolumab induces high pathologic response rates and an impressive relapse-free survival in patients with nodal macroscopic stage III melanoma. Whether primary site melanoma and in-transit metastases respond similarly to lymph node metastases with neoadjuvant immunotherapy is largely unknown. Such data would clarify whether surgical excision of these melanoma lesions should be performed before neoadjuvant therapy or whether it could be deferred and performed in conjunction with lymphadenectomy following neoadjuvant immunotherapy. PATIENTS: Patients with synchronous clinical stage III melanoma were identified from the OpACIN, OpACIN-neo and PRADO neoadjuvant trials, where all patients were treated with ipilimumab plus nivolumab. An additional case treated outside those clinical trials was included. RESULTS: Seven patients were identified; six patients had a concordant response in primary site melanoma lesions or in-transit metastasis and the lymph node metastases. One patient had concordant progression in both the primary and nodal tumour lesions and developed stage IV disease during neoadjuvant treatment, and thus, no resection was performed. CONCLUSION: Pathologic response following neoadjuvant ipilimumab plus nivolumab in primary site melanoma lesions or in-transit metastasis is concordant with a response in the lymph node metastases, indicating that there may be no need to perform upfront surgery to these melanoma lesions prior to neoadjuvant treatment.

Granulosa cell ovarian cancer with synchronous multiple bone metastases: case report of extreme rarity.

BACKGROUND: Adult granulosa cell tumor (AGCT) of the ovary generally has a good prognosis. Recurrences tend to be late and confined to the abdominopelvis. Bone metastases are extremely rare. We report an extremely rare case of AGCT with synchronous multiple bone metastases and discuss diagnostic procedures and management. CASE DESCRIPTION: A 35-year-old woman presented with abdominal bloating. On the day of surgery, acting on the complaint of right shoulder pain, an X-ray revealed a permeative lesion involving the neck of humerus, suggestive of a metastatic pathologic fracture. The patient underwent a full staging debulking surgery. Further imaging demonstrated multiple bone metastases. Histology confirmed an AGCT of the ovary. Diagnosis was established by a core bone biopsy from the left femur showing cells consistent with those seen with granulosa cell tumor. The patient received adjuvant chemotherapy with concurrent zoledronic acid as targeted therapy for her bone metastases. Endocrine systemic maintenance treatment was given. The patient rapidly deteriorated and died from her disease at 20 months from the initial diagnosis. CONCLUSION: Unpredictable biological behavior and clinical manifestations raise a high degree of suspicion for accurate AGCT diagnosis. Management of bone metastases often warrants input from the multidisciplinary team, and treatment may involve chemotherapy, palliative radiotherapy, or orthopaedic interventions.

Malignant mesothelioma without asbestos exposure diagnosed during EGFR-TKI treatment of lung adenocarcinoma: A case report.

Synchronous malignant mesothelioma (MM) and lung carcinoma are extremely rare in patients without a history of asbestos exposure and poses tremendous difficulties in clinical management. We report a patient without asbestos exposure diagnosed with MM during EGFR-TKI treatment of lung adenocarcinoma (LUAD), who responded to first-line chemotherapy with pemetrexed plus carboplatin and failed to subsequent systemic therapy. Clinicians should be careful about the possibility of MM comorbidity in LUAD patients whose lesions respond differently to EGFR-TKI, even in those without a history of asbestos exposure.

Survival outcome and prognostic factors for colorectal cancer with synchronous bone metastasis: a population-based study.

Prognostic factors of synchronous bone metastatic colorectal cancer (CRC) are still undetermined. We aimed to investigate survival outcome and prognostic factors of patients with synchronous bone metastatic CRC. Information of patients with synchronous bone metastatic CRC were obtained from the Surveillance, Epidemiology, and End Results (SEER) and West China Hospital (WCH) databases. Cases from SEER database composed construction cohort, while cases from WCH database were used as validation cohort. A novel nomogram was constructed to predict individual survival probability based on Cox regression model. The performance of the nomogram was internally and externally validated using calibration curves and concordance index (C-index). Three hundred and eighty-one patients from SEER database were eligible. The median disease specific OS was 9.0 months (95% confidence interval [CI]: 7.3-10.7 months). Multivariate Cox analysis identified seven independent prognostic factors including histological type, differentiation grade, T stage of primary tumor, CEA level, systemic chemotherapy, combined with liver metastasis and combined with lung metastasis. A novel nomogram was established based on these variables. In the internal validation, the C-index (0.72, 95% CI 0.69-0.75) and calibration curve indicated well performance of this nomogram at predicting survival outcome in bone metastatic CRC. In the external validation, the C-index was 0.57 (95% CI 0.46-0.68). The prognosis of synchronous bone metastatic CRC is very poor. Histological type, differentiation grade, T stage of primary tumor, CEA level, systemic chemotherapy, combined with liver metastasis and combined with lung metastasis are independent prognostic factors. Further study is warranted to confirm the practicality of the prognostic nomogram.