Metastatic Soft Tissue Research Articles

Randomised phase II trial of stereotactic body radiotherapy in combination with checkpoint inhibitors in metastatic castration-resistant prostate cancer (CheckPRO): a study protocol

IntroductionImmunotherapy with checkpoint inhibitors (CPIs) has revolutionised cancer treatment but has no convincing effect in metastatic castration-resistant prostate cancer (mCRPC). It has been suggested that a combination of CPI and...

Rare Occurrence of Prostate Cancer Metastasizing to the Orbit: A Case Report

Prostate cancer is second most common cancer with frequent metastasis occurring to bone. We report a unique case of soft tissue and bony orbital metastasis from carcinoma prostate. The patient presented with orbital metastasis after defaulting to the advised treatment. He responded well to radiation therapy and the lesion regressed completely. Our patient was diagnosed to have an oligo-metastatic carcinoma of the prostate. He was non-compliant with treatment and presented to us with proptosis, which was later diagnosed to be an orbital metastasis from prostate cancer. It responded well to the external beam chemotherapy. Orbital metastasis is a rare but known complication of carcinoma prostate. One must consider the diagnosis of orbital metastasis from carcinoma prostate in an elderly male presenting with proptosis.

DART: diagnostic-CT-enabled planning: a randomized trial in palliative radiation therapy (study protocol)

Palliative radiotherapy (PRT) is an effective treatment for managing symptoms of advanced cancer. At least half of all radiation treatments are delivered with palliative intent, aimed at relieving symptoms, such as pain or shortness of breath. Symptomatic patients must receive PRT quickly, therefore expeditious treatment planning is essential. Standard radiation planning requires a dedicated CT scan acquired at the cancer centre, called a 'CT simulation', which facilitates treatment planning (i.e. tumor delineation, placement of radiation beams and dose calculation). However, the CT simulation process creates a bottleneck and often leads to delays in starting treatment. Other researchers have indicated that CT simulation can be replaced by the use of standard diagnostic CT scans for target delineation and planning, which are normally acquired through the radiology department as part of standard patient workup. The goals of this feasibility study are to assess the efficacy, acceptability and scalability of diagnostic-CT-enabled planning, compared to conventional CT simulation planning, for patients receiving PRT to bone, soft tissue and lung disease. This is a randomized, phase II study, with 33 PRT patients to be randomized in a 1:2 ratio between conventional CT simulation (Arm 1), and the diagnostic CT enabled planning workflow (Arm 2). Patients will be stratified by treatment target volume (bone and soft tissue metastasis vs. primary or metastatic intrathoracic disease targets). The primary endpoint is the amount of time the patient spends at the cancer centre. Secondary endpoints include efficacy (rate of plan deliverability and rate of plan acceptability on blinded dose distribution review), stakeholder acceptability (based on patient and clinician perception of acceptability questionnaires) and scalability. This study will investigate the efficacy, acceptability and scalability of a "sim-free" PRT pathway compared to conventional CT simulation. The workflow may provide opportunity for resource optimization by using pre-existing diagnostic imaging and requires minimal investment due to its similarity to current PRT models. It also offers potential benefit to patients by eliminating an imaging procedure, reducing the amount of time spent at the cancer centre, and expediting time to treatment. Clinicaltrials.gov identifier: NCT05233904. Date of registration: February 10, 2022; current version: 1.4 on April 29, 2022.

Follicular Carcinoma of Thyroid Presented with Soft Tissue Metastasis: An Uncommon Fine Needle Aspiration Diagnosis

A-60-year-old elderly female presented with long standing swelling over the right shoulder. Thyroid was enlarged on examination and along with the routine work-up of patient, serum thyroid function test; Ultrasonography and Chest X-ray were performed. FNAC was performed from both the swellings i.e., thyroid gland and shoulder, and a provisional diagnosis of metastatic follicular carcinoma of thyroid was made A combination of proper history, along with serological markers, and fine needle aspiration cytology findings are necessary to make a provisional diagnosis of thyroid neoplasms. Also, a long term follow up is necessary to knock down the impact of metastases in previously diagnosed follicular thyroid carcinomas.

Stereotactic body radiotherapy in oligoprogressive metastatic castration-resistant prostate cancer during abiraterone or enzalutamide.

This monocentric, single-arm, retrospective study investigated the role of stereotactic body radiotherapy in patients with metastatic castration resistant prostate cancer who experienced oligoprogression during androgen receptor targeted agents. We retrospectively enrolled metastatic castration resistant prostate cancer patients treated with androgen receptor targeted agents between December 2016 and January 2022. All patients experienced an oligoprogression (defined as the appearance and/or the progression of ⩽5 bone or nodal or soft tissue metastases) during treatment with androgen receptor targeted agents and received stereotactic body radiotherapy upon oligoprogressive sites, preserving the androgen receptor targeted agents. Further stereotactic body radiotherapy upon new metastatic sites was permitted. Patients showing visceral metastases or receiving palliative radiotherapy were excluded. Progressive disease at >5 metastatic sites or the appearance of visceral metastases led to a change of the systemic treatment. Primary endpoints were 36-month survival rate and 36-month rate of patients receiving treatment with androgen receptor targeted agents. Secondary endpoints were local disease control, biochemical response and safety. We analyzed data from 30 patients. The 36-month survival rate was 90% (27 patients); 36-month rate of patients who were still on treatment with androgen receptor targeted agents was 50%. 20 of 30 patients had performed imaging control after a single course of stereotactic body radiotherapy: overall response rate was 50%, while clinical benefit was 93%. No ⩾G2 adverse events related to stereotactic body radiotherapy were recorded. Stereotactic body radiotherapy in oligoprogressive metastatic sites during androgen receptor targeted agent treatment resulted in a feasible and effective treatment to delay the start of next-line systemic treatment and prolong overall survival in metastatic castration resistant prostate cancer. Longer follow-up and further prospective studies are necessary to confirm our preliminary results.

Eligibility for 177Lu-PSMA Therapy Depends on the Choice of Companion Diagnostic Tracer: A Comparison of 68Ga-PSMA-11 and 99mTc-MIP-1404 in Metastatic Castration-Resistant Prostate Cancer.

177Lu-prostate-specific membrane antigen-617 (177Lu-PSMA-617) is an effective therapy for metastatic castration-resistant prostate cancer (mCRPC), with evidence of improved survival over standard care. The VISION trial inclusion criteria required a metastatic lesion-to-liver ratio of greater than 1 on 68Ga-PSMA-11 PET scans. We aimed to determine whether an equivalent ratio is suitable for a SPECT tracer, 99mTc-MIP-1404, and to compare lesion and lesion-to-normal-organ ratios between the 2 radiotracers. Methods: Two cohorts of patients with mCRPC matched for age, prostate-specific antigen level, and total Gleason score, with either 99mTc-MIP-1404 SPECT/CT (n = 25) or 68Ga-PSMA-11 PET/CT (n = 25) scans, were included for analysis. Up to 3 lesions in each site (prostate/prostate bed, lymph nodes, bone and soft-tissue metastases) as well as normal liver, parotid gland, spleen, and mediastinal blood-pool SUVmax were measured. Results: 99mTc-MIP-1404 SPECT lesion SUVmax was not significantly different from 68Ga-PSMA-11 PET (median, 18.2 vs. 17.3; P = 0.93). However, 99mTc-MIP-1404 liver SUVmax was higher (median, 8.5 vs. 5.8; P = 0.002) and lesion-to-liver ratios were lower (median, 2.7 vs. 3.5; P = 0.009). There was no significant difference in parotid gland or splenic SUVmax or lesion-to-parotid gland ratios between the 2 tracers although there was a small difference in lesion-to-spleen ratios (P = 0.034). Conclusion: There are differences in biodistribution and, in particular, liver activity, between 68Ga-PSMA-11 and 99mTc-MIP-1404. Therefore, if 99mTc-MIP-1404 is used to assess eligibility for 177Lu-PSMA-617 therapy, a lower adjusted lesion-to-liver ratio should be used.

Prognostic Importance of Nodal Microenvironment beyond Extracapsular Extension in Breast Cancer Outcomes

<h3>Purpose/Objective(s)</h3> Lymph node (LN) involvement and extracapsular extension (ECE) play important roles in breast cancer risk stratification, management, and outcome. Involvement of other axillary tissues (AXT) excised during surgery is often omitted in pathology reports and its prognostic significance is yet to be elucidated. <h3>Materials/Methods</h3> Medical records of 1,919 breast cancer patients with pathologic lymph nodes treated at our institution from 2000-2019 was retrospectively reviewed. Extensive details of LN involvement are reported by pathologists at our institution and were divided into 4 groups: LN+ only, LN+ECE, LN+AXT without ECE, and LN+ECE+AXT. AXT was defined as the involvement of lymphatic vessels, blood vessels, soft tissue metastasis, matted unspecified masses and combination of any of those forms. The primary endpoint was the impact of AXT on locoregional failure (LRF) defined as recurrence in either breast/chest wall/axilla/supraclavicular fossa, on axillary failure (AF) defined as recurrence in the axilla only and on distant failure (DF) defined as metastasis. Subgroup analysis explored the differences between types of AXT and Cox Hazard models were used. <h3>Results</h3> Among 1,919 patients analyzed, 995 had LN+ only involvement, 534 had LN+ECE, 81 had LN+AXT without ECE, and 309 had LN+ECE+AXT. The overall median follow-up was 6.5 years. The 10 years cumulative incidence of LRF was 5.9%, 6.4%, 11.8% and 10.9% in LN only, LN+ECE, LN+AXT without ECE and LN+ECE+AXT groups, respectively. The 10 years cumulative incidence of AF was 0.92%, 0.83%, 4.1% and 4.4% in LN+ only, LN+ECE, LN+AXT without ECE and LN+ECE+AXT groups, respectively. The 10 years cumulative incidence of DF was 15.7%, 23%, 23.5% and 42.1% in LN+ only, LN+ECE, LN+AXT without ECE and LN+ECE+AXT groups, respectively. On multivariable analysis controlling for number of malignant LN, ECE, tumor biology, grade and size, type of axillary surgery and radiation dose delivered to the draining lymphatics, the presence of other AXT was significantly associated with LRF (HR:2.3, P<0.01), AF (HR:4.7, P<0.01) and DF (HR: 1.4, P=0.02). ECE and number of malignant LN were not associated with LRF and AF, but rather associated with DF (HR:1.4, P=0.009 and HR:1.03, P=0.002, respectively). Delivery of 50 Gy or more to draining lymphatics was associated with better axillary control (HR:0.3, P=0.01) compared to 45 Gy. No significant difference between 45 Gy and 50 Gy to the lymphatics was observed for LRF and DF. Subgroup analysis did not show a difference between the described forms of AXT on LRF and DF. <h3>Conclusion</h3> Pathologic evaluation of the axilla's microenvironment beyond tumor deposits in lymph nodes and ECE is important to ensure adequate local control in the axilla. Given the higher risk of recurrence posed by tumor infiltration into surrounding axillary tissues, delivery of at least 50Gy to lymphatics should be considered. Our findings demonstrate the need for pathology reports to include assessment of the axilla's microenvironment.

Unveiling the tumor immune microenvironment of organ-specific melanoma metastatic sites

BackgroundThe liver is a known site of resistance to immunotherapy and the presence of liver metastases is associated with shorter progression-free and overall survival (OS) in melanoma, while lung metastases...

Durvalumab plus tremelimumab in advanced or metastatic soft tissue and bone sarcomas: a single-centre phase 2 trial

Few standard treatment options are available for patients with metastatic sarcomas. We did this trial to evaluate the efficacy, safety, and changes in the tumour microenvironment for durvalumab, an anti-PD-L1 drug, and tremelimumab, an anti-CTLA-4 drug, across multiple sarcoma subtypes. In this single-centre phase 2 trial, done at The University of Texas MD Anderson Cancer Center (Houston, TX USA), patients aged 18 years or older with advanced or metastatic sarcoma with an Eastern Cooperative Oncology Group performance status of 0 or 1 who had received at least one previous line of systemic therapy were enrolled in disease subtype-specific groups (liposarcoma, leiomyosarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma, synovial sarcoma, osteosarcoma, alveolar soft-part sarcoma, chordoma, and other sarcomas). Patients received 1500 mg intravenous durvalumab and 75 mg intravenous tremelimumab for four cycles, followed by durvalumab alone every 4 weeks for up to 12 months. The primary endpoint was progression-free survival at 12 weeks in the intention-to-treat population (all patients who received at least one dose of treatment). Safety was also analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02815995, and is completed. Between Aug 17, 2016, and April 9, 2018, 62 patients were enrolled, of whom 57 (92%) received treatment and were included in the intention-to-treat population. With a median follow-up of 37·2 months (IQR 1·8-10·1), progression-free survival at 12 weeks was 49% (95% CI 36-61). 21 grade 3-4 treatment-related adverse events were reported, the most common of which were increased lipase (four [7%] of 57 patients), colitis (three [5%] patients), and pneumonitis (three [5%] patients). Nine (16%) patients had a treatment related serious adverse event. One patient had grade 5 pneumonitis and colitis. The combination of durvalumab and tremelimumab is an active treatment regimen for advanced or metastatic sarcoma and merits evaluation in specific subsets in future trials. AstraZeneca.

Dynamic plasticity of prostate cancer intermediate cells during androgen receptor-targeted therapy.

Treatment-emergent small cell neuroendocrine prostate cancer (t-SCNC) is associated with an epithelial lineage switch from an androgen receptor (AR)-positive to neuroendocrine (NE)-marker-positive status. Understanding the potential for reversibility of this aggressive disease state has been hampered by the paucity of models suitable for studying rate-limiting, transitional, or intermediate tumor cell subpopulations. We define a dual reporter model that measures acute transcriptional changes in response to castration or AR targeting agents. We identify steady-state transcriptional heterogeneity in AR and NE biomarkers, including intermediate subpopulations that are coordinately high for prostate-specific antigen (PSA) and neuron-specific enoclase (NSE) promoter activity. In the presence of castration or AR inhibitors, intermediate cells were necessary and sufficient for therapy-induced conversion of human PC cells to an NSE-high transcriptional status. Using hormone add-back studies, treatment-induced PSA-NSE transcriptional plasticity was reversible in PTEN-deficient PC cells but not in the presence of secondary genetic driver genes, including MYCN.

Abstract 2417: Elucidating the role of SMARCB1 in bladder cancer progression and metastasis

Abstract Bladder cancer (BLCA) is the second most common urological malignancy in the US and is usually not curable at an advanced stage. The transcriptomic profiling data of bladder cancer revealed that 64% of BLCA patients have frequent dysregulation of the components of the SWI/SNF, a chromatin remodeling complex. Alterations in chromatin remodeling genes have been previously implicated in human oncogenesis. SMARCB1/INI1 is one of the critical core components of the SWI/SNF complex. In this study, we demonstrate that primary BLCA patients harboring SMARCB1 loss strongly associate with worse survival. Specifically, the biallelic inactivation of the SMARCB1 (SMARCB1 knockout (KO)) in BLCA cell lines resulted in the emergence of aggressive tumor growth leading to soft tissue metastasis to lungs, liver, kidney, and intestine in vivo. Mechanistic studies revealed that IL-6- STAT3 axis is upregulated in SMARCB1 KO BLCA cells. Our data suggest that the STAT3 specific inhibitor, inhibits invasive potential of SMARCB1 KO cells suggesting potential therapeutic efficacy for STAT3 inhibitor to treat subsets of BLCA harboring SMARCB1 loss. In addition, we identified a unique transcriptional signature activated upon SMARCB1 loss, which is predictive of poor patient outcome in BLCA, and hence may be clinically valuable. Bladder cancer (BLCA) is the second most common urological malignancy in the US and is usually not curable at an advanced stage. The transcriptomic profiling data of bladder cancer revealed that 64% of BLCA patients have frequent dysregulation of the components of the SWI/SNF, a chromatin remodeling complex. Alterations in chromatin remodeling genes have been previously implicated in human oncogenesis. SMARCB1/INI1 is one of the critical core components of the SWI/SNF complex. In this study, we demonstrate that primary BLCA patients harboring SMARCB1 loss strongly associate with worse survival. Specifically, the biallelic inactivation of the SMARCB1 (SMARCB1 knockout (KO)) in BLCA cell lines resulted in the emergence of aggressive tumor growth leading to soft tissue metastasis to lungs, liver, kidney, and intestine in vivo. Mechanistic studies revealed that IL-6- STAT3 axis is upregulated in SMARCB1 KO BLCA cells. Our data suggest that the STAT3 specific inhibitor, inhibits invasive potential of SMARCB1 KO cells suggesting potential therapeutic efficacy for STAT3 inhibitor to treat subsets of BLCA harboring SMARCB1 loss. In addition, we identified a unique transcriptional signature activated upon SMARCB1 loss, which is predictive of poor patient outcome in BLCA, and hence may be clinically valuable. Citation Format: Chandra Sekhar Amara, Karthik Reddy Reddy, Yuntao Yang, Badrajee Waduge Danthasinghe, Allison Bellman, Andrea B. Apollo, David J. Shih, Leomar Ballester, Pavlos Msaouel, Wenjin J. Zheng, Matthew J. Ellis, Seth P. Lerner, Arun Sreekumar, Shyam M. Kavuri, Nagireddy Putluri. Elucidating the role of SMARCB1 in bladder cancer progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2417.

Abstract 653: Molecular pathology of metastatic prostatic adenocarcinoma treated with bipolar androgen therapy (BAT) reveals a correlation between MYC mRNA and protein

Abstract Molecular analysis of tissue samples from metastatic cancer lesions can improve our understanding of drug response and resistance. Since prostate cancer cells initially require androgen signaling through the androgen receptor (AR) for proliferation, the treatment of metastatic prostate cancer involves surgical or chemical castration. While most patients respond initially, nearly all develop acquired resistance to combined androgen blockade using both first and second line agents. This resistance is often related to overexpression of AR, which is frequently driven by AR gene amplification. In some patients, this increased AR appears to render tumor cells sensitive to high dose androgens in a manner that paradoxically inhibits their growth. Bipolar Androgen Therapy (BAT) was introduced several years ago at our institution in which patients with castration resistant prostate cancer (CRPC) are treated intermittently with high dose testosterone. Prior clinical trials have shown that BAT can produce biochemical and objective responses, and may re-sensitize prostate cancer to subsequent second generation AR inhibitors. To define the mechanism(s) by which BAT results in tumor regression, we performed a clinical trial (NCT03554317) for patients with CRPC that included biopsies of soft tissue metastases before BAT and after 3 cycles of BAT (C4D1). Up to four tissue cores were taken per biopsy with two cores for formalin fixation and paraffin embedding (FFPE) and the others snap frozen. Histologically viable tumor cells were present for both the pretreatment and C4D1 time points for 24 of the 42 enrolled patients. The FFPE samples were stained for H&amp;E and by IHC for AR, MYC and Ki67. MYC and Ki67 IHC stained slides were subjected to quantitative image analysis using HALO software (Indica Labs). Adequate frozen tumor tissue was available for laser capture microdissection and adequate amounts of RNA were obtained from 15 patients with paired pretreatment and C4D1 biopsies. RNAseq libraries were prepared using the NuGEN Ovation RNA-Seq System V2 and barcoded libraries were sequenced to an average depth of &amp;gt; 100 million reads per sample on an Illumina NovaSeq. Gene expression values were obtained with RSEM using Star aligner with GRCh38 (human). When comparing the C4D1 samples to the pretreatment samples, there were marked decreases in tumor MYC protein levels in approximately half of the treated patients, which was associated with decreased Ki67, decreased tumor volume, and prolonged progression-free survival on BAT. Using an image analysis computed H-SCORE for MYC, there was a strong correlation between MYC protein levels and MYC mRNA using RNAseq (r=0.81, p = 2.3 x 10-7). This indicates that MYC protein levels correlate with MYC mRNA and that reductions of MYC protein by BAT are likely related to reductions of MYC mRNA in clinical metastatic tissue samples. Citation Format: Carolina Gomes Alexandre, Tracy Jones, Jessica L. Hicks, John T. Isaacs, Anuj Gupta, Alyza Skaist, Laura Sena, Jennifer Meyers, Emmanuel Antonarakis, Mark Markowski, Samuel Denmeade, Srinivasan Yegnasubramanian, Angelo Michael De Marzo. Molecular pathology of metastatic prostatic adenocarcinoma treated with bipolar androgen therapy (BAT) reveals a correlation between MYC mRNA and protein [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 653.

LITESPARK-022: A phase 3 study of pembrolizumab + belzutifan as adjuvant treatment of clear cell renal cell carcinoma (ccRCC).

TPS4602 Background: Patients with locally advanced renal cell carcinoma (RCC) may experience recurrence after surgery. In the phase 3 KEYNOTE-564 (NCT03142334) trial, adjuvant pembrolizumab demonstrated significant improvement in disease-free survival (DFS) in ccRCC, leading to FDA approval of pembrolizumab (November 17, 2021) for adjuvant treatment of patients with RCC at intermediate-high or high risk for recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions. Despite benefit of pembrolizumab, there is an unmet need for more effective adjuvant treatment for patients at risk for recurrence after definitive surgery. The HIF-2α inhibitor belzutifan (MK-6482) has shown activity and good tolerability in patients with advanced ccRCC and von Hippel-Lindau (VHL) disease–associated RCC. Combining belzutifan with pembrolizumab may be a therapeutic option as adjuvant treatment of ccRCC. This global, multicenter, double-blind, randomized, phase 3 study LITESPARK-022 (NCT05239728) is designed to compare the efficacy and safety of belzutifan + pembrolizumab with that of placebo + pembrolizumab as adjuvant treatment of ccRCC after nephrectomy. Methods: Approximately 1600 patients with histologically or cytologically confirmed RCC (intermediate-high [pT2, grade 4 or sarcomatoid, N0, M0 or pT3, any grade, N0, M0], high [pT4, any grade, N0, M0 or pT, any stage/grade, N+, M0] or M1 NED [patients who present with the primary kidney tumor and solid, isolated, soft tissue metastases that can be resected at the time of nephrectomy or ≤2 years from nephrectomy) with a clear cell component and had not previously received systemic therapy will be enrolled. Patients must have undergone nephrectomy and/or metastasectomy ≤12 weeks before randomization and be tumor free, confirmed by CT/MRI. Stratification factors are tumor grade (1 or 2 vs 3 or 4) and risk type (intermediate-high vs high vs M1 NED). Patients will be randomly assigned 1:1 to receive belzutifan 120 mg orally once daily + pembrolizumab 400 mg IV every 6 weeks (Q6W) or oral placebo + pembrolizumab 400 mg IV Q6W. Pembrolizumab treatment will be administered for up to 9 doses (̃1 year); belzutifan and placebo may be continued for a maximum of 54 weeks. Disease recurrence will be evaluated radiologically Q12W from randomization through year 2, Q16W in years 3-5, and Q24W in years 6 and beyond. Adverse events (AEs) will be monitored by NCI CTCAE v5.0 through 30 days (90 days for serious AEs) after cessation of study drug. The primary end point is DFS, as assessed by investigator, defined as time from randomization to first documented event of local recurrence, occurrence of distant kidney cancer metastasis, or death from any cause, whichever occurs first. The key secondary end point is overall survival. Other secondary end points are safety, disease recurrence–specific survival and patient-reported outcomes. Clinical trial information: NCT05239728.

Synchronous lung and multiple soft tissue metastases developed from osteosarcoma of tibia: a rare case report and genetic profile analysis

BackgroundOsteosarcoma is the most common primary malignant bone tumor with a highly metastatic propensity in children and young adolescents. The majority of metastases develope in the lung, while metastases to the extrapulmonary locations have rarely been discussed, especially in skeletal muscle.Case presentationWe reported a young patient with pathologically diagnosed osteosarcoma of the right tibia who was initially treated with standard chemotherapy and complete surgical resection. However, pulmonary metastases and multiple soft tissue masses in skeletal muscle developed four years after the index surgical resection. Subsequently, a targeted next-generation sequencing assay based on an 806 oncogenes and tumor suppressor genes panel was performed to analyze genetic alterations in this patient with rare metastatic pattern. The genetic analysis revealed canonical somatic mutations of RB1 and germline variants of ALK (c.862 T > C), BLM (c.1021C > T), PTCH1 (c.152_154del), MSH2 (c.14C > A), RAD51C (c.635G > A). Using silico prediction programs, the germline variants of the MSH2 and RAD51C were predicted as “Possibly Damaging” by Polymorphism Phenotyping v2 (PolyPhen-2) and “Tolerated” by Sorting Intolerant from Tolerant (SIFT); BLM was classified as “Tolerated”, while the germline variant of ALK was predicted to be pathogenic by both PolyPhen-2 and SIFT.ConclusionsOsteosarcoma with extrapulmonary metastases is rare, especially located in the skeletal muscle, which predicts a worse clinical outcome compared with lung-only metastases. The several novel variants of ALK, BLM, PTCH1 in this patient might expand the mutational spectrums of the osteosarcoma. All the results may contribute to a better understanding of the clinical course and genetic characteristics of osteosarcoma patients with metastasis.

CDKN2A-positive melanoma patient treated with combination immunotherapy – A case report

Germline aberrations in the CDKN2A gene are observed in 20%–40% of families susceptible to melanoma. Positive CDKN2A status is associated with early age of onset of melanoma, multiple primary melanomas, and pancreatic cancer. We report here a melanoma patient with a germline mutation c.68G>A p.(Gly23Asp) in CDKN2A who had a history of multiple cutaneous melanomas and a family history consistent with familial atypical multiple mole melanoma (FAMMM) syndrome. He developed oligometastatic disease with BRAF-positive melanoma metastases in soft tissue and gallbladder and was treated with surgical resection followed by combination therapy of PD-1 and CTLA-4 immune checkpoint inhibitor, which resulted in good remission. Molecular analysis of all primary melanomas and both metastatic sites revealed the same BRAF c.1799T>A p.(Val600Glu) V600E mutations.

Lung cancer metastasis to oral soft tissues; Systematic review of 122 cases.

Lung cancer metastasis to oral region is very rare. Studies have been published analysing the cases of metastatic tumours to the oral cavity by many researchers. But very few research work has been conducted till date to analyse only the oral soft tissue metastasis from Lung cancer as the primary source. The goal of this study was to examine published cases of oral soft tissue metastasis from lung cancer as the only primary source from 1st August 1977 to 31st December 2021. An electronic search of the published English literature was performed in PubMed/ Medline, Scopus, Google Scholar, and Research gate databases, using keywords like 'Lung cancer', OR/ AND 'Lung carcinoma' OR/ AND 'Oral cavity', OR/AND 'Metastasis', OR/AND 'Primary', OR/AND 'Source', OR/AND 'Initial', OR/AND 'Tongue', OR/AND 'Palate', OR/ AND 'Tonsil', OR/AND 'Lip', OR/AND 'Buccal mucosa', OR/AND 'Floor of mouth', OR/AND 'Salivary glands', OR/ AND 'Parotid', OR/ AND 'Submandibular', OR/ AND 'Sublingual' OR/ AND 'Mandible', OR/AND 'Maxilla. We also searched all related journals manually. Reference list of all articles was also checked. Our research revealed total 122 patients. The most prevalent diagnosed metastatic lung cancer was adenocarcinoma. Gingiva, tongue and tonsils were the most common site of metastasis. 54% patients died of metastasis with a survival time of 1 week to 2.5 years. Oral soft tissue metastasis from lung cancer has a bad prognosis. More cases need to be published in order to raise awareness of these lesions and gain a better understanding of their characteristics. Key words:Lung cancer, metastasis, oral, primary, soft tissues.

Stereotactic radiotherapy for soft tissue and bone sarcomas: real-world evidence.

Introduction:Selected patients with locally advanced or metastatic soft tissue and bone sarcomas (STBS) may benefit from intensive local treatment, such as stereotactic radiotherapy (SRT). This study aimed to summarize the utilization and outcomes of SRT in STBS and to identify predictive factors for progression and survival.Materials and methods:Consecutive patients with advanced STBS who underwent STBS in a sarcoma tertiary center were identified. We collected tumor- and treatment-related factors. Endpoints comprised time to local progression (TTLP), local progression-free survival (LPFS), time to progression, progression-free survival, and overall survival (OS). The Cox proportional-hazards model was used to identify prognostic factors.Results:We identified 141 patients who underwent 233 SRTs. Median follow-up was 21 months. Local and distant progression occurred after 19 and 163 SRTs, respectively. SRT for lung metastases was predictive for better TTLP and LPFS (hazard ratio, HR = 0.12, p = 0.007 and HR = 0.42, p = 0.002, respectively). Bone sarcoma (HR for TTLP = 3.18, p = 0.043; HR for LPFS = 1.99, p = 0.028) and lower administered dose (HR for TTLP = 0.98, p = 0.007; HR for LPFS = 0.99, p = 0.012) were predictive for worse TTLP and LPFS. SRT for oligometastases (HR = 0.46, p = 0.021) and lung metastases (HR = 0.55, p = 0.046) was predictive for better OS, whereas diagnosis of bone sarcoma (HR = 2.05, p = 0.029) was predictive for worse OS.Conclusion:SRT provides excellent local control in STBS patients without significant toxicity. Patients with oligometastatic disease, lung metastases, and soft tissue sarcomas benefit the most from SRT. The dose escalation moderately enhances local control; however, it does not translate into better survival.

Prognostic Value of Interim 18F-DOPA and 18F-FDG PET/CT Findings in Stage 3-4 Pediatric Neuroblastoma.

This retrospective study aimed to determine the prognostic value of imaging parameters derived from midtherapy 18F-fluorodihydroxyphenylalanine (18F-DOPA) and 18F-FDG PET in pediatric patients with stage 3-4 neuroblastoma. We enrolled 32 stage 3-4 pediatric neuroblastoma patients who underwent 18F-DOPA and 18F-FDG PET/CT scans before and after 3 chemotherapy cycles. We measured metabolic and volumetric parameters and applied a metabolic burden scoring system to evaluate the primary tumor extent and soft tissue metastases and that of bone/bone marrow involvement. The associations between these parameters and clinical outcomes were investigated. Over a median follow-up period of 47 months (range, 3-137 months), 16 patients experienced disease progression, and 13 died. After adjustment for clinical factors, multivariate Cox proportional hazard models showed that interim tumor FDG/FDOPA SUVmax (hazard ratio [HR], 5.94; 95% confidence interval [CI], 1.10-34.98) and interim FDOPA whole-body metabolic burden scores (WBMB) (HR, 7.30; 95% CI, 1.50-35.50) were significant prognostic factors for overall survival (OS). Only interim FDOPA WBMB scores (HR, 7.05; 95% CI, 1.02-48.7) were predictive of progression-free survival. Based on median cutoff values, prognosis (OS and progression-free survival) was significantly associated with an interim FDOPA WBMB score ≥21.92 (all P < 0.05) and interim tumor FDG/FDOPA (SUVmax) score ≥0.57 with poor OS (P < 0.05). Our results indicate that midtreatment FDG and FDOPA PET/CT could serve as prognostic markers in stage 3-4 neuroblastoma patients.

Soft-tissue metastasis from carcinoma: Clinical characteristics of 11 cases with surgical treatment

Soft-tissue metastasis from carcinoma: Clinical characteristics of 11 cases with surgical treatment

Modular Design of High-Brightness pH-Activatable Near-Infrared BODIPY Probes for Noninvasive Fluorescence Detection of Deep-Seated Early Breast Cancer Bone Metastasis: Remarkable Axial Substituent Effect on Performance.

We herein report a series of high-brightness pH-activatable near-infrared (NIR) BODIPY probes for high-contrast intravital imaging of deep-seated early breast cancer bone metastasis by harnessing the axial substituent effect. These probes exhibit tunable pKa, higher brightness, and antiquenching capabilities in aqueous solution, which can be simultaneously adjusted by axial steric substituents. The optimized probe BODO-3 bearing axial dimethyl substituents exhibited a higher pKa value of 5.6 and a brighter NIR fluorescence under tumor acidic pH, showing 10.3-fold and 6.5-fold enhanced brightness (εΦ) at pH 5.5 and 6.5, respectively. Due to the higher brightness, BODO-3 with a brilliant NIR emission at 700 nm allows for deep optical penetrations of 5 and 8 mm at pH 6.5 and 4.5, respectively. Meanwhile, covalent functionalization with glucose (BODO-3-Glu) could further enhance breast cancer and its soft tissue metastasis imaging in vivo. Notably, covalent functionalization with bisphosphonate (BODO-3-PO3H2) allowed the successful targeting and visualization of deep-seated bone metastases of breast cancer with a high tumor to normal contrast of 8/1, outperforming X-rays in early detection. This strategy may provide insights for designing high-brightness activatable NIR probes for detecting deep-seated tumors and metastases.