Small Metastases Research Articles

Treatment and survival of patients with small cell lung cancer and brain metastasis.

To elucidate treatment patterns and their outcomes in patients with small cell lung cancer (SCLC) and brain metastasis (BM). In this retrospective study, patients with SCLC and BM were stratified by treatment modality into three groups: those treated with systemic therapy only, those treated with stereotactic radiosurgery (SRS) and systemic therapy, and those treated with whole-brain radiotherapy (WBRT) and systemic therapy. The primary outcomes were overall survival (OS) and time to central nervous system progression (TTCP). The analysis included 149 patients. After BM diagnosis, 48 patients (32.2%) received systemic therapy alone, 33 received SRS with systemic therapy, and 68 received WBRT with systemic therapy. The median OS and TTCP were 7.2 months and 8.7 months, respectively. Patients receiving WBRT with systemic therapy exhibited better intracranial control, but not better OS, than did the other patients. Key prognostic factors affecting OS were age, BM lesion count, chemotherapy, and immunotherapy. Notably, the Eastern Cooperative Oncology Group performance status and BM lesion count significantly influenced intracranial control in patients treated with SRS and systemic therapy. Although WBRT combined with systemic therapy offer better intracranial control in patients with SCLC and BM, this approach is not superior to the other approaches in terms of OS benefits. Emerging systemic therapies, such as immunotherapy, may be used as alternative or adjunctive treatments for specific patient populations. Further studies are warranted to refine treatment selection.

Study of thulium-167 cyclotron production: a potential medically-relevant radionuclide.

Introduction: Targeted Radionuclide Therapy is used for the treatment of tumors in nuclear medicine, while sparing healthy tissues. Its application to cancer treatment is expanding. In particular, Auger-electron emitters potentially exhibit high efficacy in treating either small metastases or single tumor cells due to their short range in tissue. The aim of this paper is to study the feasibility of a large-scale production of thulium-167, an Auger-electron emitter radionuclide, in view of eventual systematic preclinical studies. Methods: Proton-irradiated enriched erbium-167 and erbium-168 oxides were used to measure the production cross sections of thulium-165, thulium-166, thulium-167, and thulium-168 utilizing an 18-MeV medical cyclotron equipped with a Beam Transport Line (BTL) at the Bern medical cyclotron laboratory. The comparison between the experimental and the TENDL 2021 theoretical cross-section results were in good agreement. Additional experiments were performed to assess the production yields of thulium radioisotopes in the BTL. Thulium-167 production yield was also measured irradiating five different target materials (167 Er 2 O 3, 168 Er 2 O 3, nat Tm 2 O 3, nat Yb 2 O 3, 171 Yb 2 O 3) with proton beams up to 63MeV at the Injector II cyclotron of Paul Scherrer Institute. Results and Discussion: Our experiments showed that an 8-h irradiation of enriched ytterbium-171 oxide produced about 420 MBq of thulium-167 with a radionuclidic purity of 99.95% after 5 days of cooling time with a proton beam of about 53MeV. Larger activities of thulium-167 can be achieved using enriched erbium-168 oxide with a 23-MeV proton beam, obtaining about 1 GBq after 8-h irradiation with a radionuclidic purity of 99.5% 5 days post end of bombardment.

A Rare Case of Osteosarcoma Metastasis to the Small Bowel Causing Intussusception in a Pediatric Patient: A Case Report and Review of Literature

Osteosarcoma, a type of bone cancer, predominantly metastasizes to the lung and bone. However, rare instances of metastasis to the small bowel have been documented. Cases involving metastasis to atypical sites such as the small bowel are associated with poor prognosis, as the majority also present with concurrent lung metastasis. Intussusception, a condition in which a segment of the intestine folds into another, has been reported in a limited number of cases involving small bowel metastasis, with only four documented cases in pediatric patients, including the current case. While intussusception is primarily idiopathic in pediatric patients, those with oncological diseases represent a unique subgroup. Medical professionals should maintain a high level of suspicion for the presence of metastasis as a leading point in such cases and conduct timely, thorough evaluations to confirm or rule out this possibility.

ITPR1-AS1 promotes small cell lung cancer metastasis by facilitating P21HRAS splicing and stabilizing DDX3X to activate the cRaf-MEK-ERK cascade

The mechanisms underlying the involvement of long non-coding RNAs (lncRNAs) in the metastasis of small cell lung cancer (SCLC) remain largely unknown. Here, we identified that the lncRNA ITPR1-AS1 was upregulated in SCLC and lymph node metastasis tissues and positively correlated with SCLC malignant features. The overexpression of ITPR1-AS1 in SCLC was an independent risk factor for the overall survival of patients with SCLC. Our data confirmed that ITPR1-AS1 induces SCLC cell metastasis both in vitro and in vivo. Mechanistically, ITPR1-AS1 acts as a scaffold to enhance the interaction between SRC-associated in mitosis 68 kDa and heterogeneous nuclear ribonucleoprotein A1, which facilitates the alternative splicing of the H-Ras proto-oncogene (HRAS) pre-mRNA (P21HRAS). Moreover, we observed that ITPR1-AS1 could associate in a complex with and maintain the stability of DEAD-box polypeptide 3 (DDX3X), which inhibited the latter’s ubiquitination and degradation. Our data provide evidence that ITPR1-AS1 activates the cRaf-MEK-ERK cascade by upregulating P21HRAS production and stabilizing DDX3X, to promote SCLC metastasis.

SAT259 A Rare Case Of Bisphosphonate Refractory Hypercalcemia; Cancer Masquerading As Hidradenitis Suppurativa

Abstract Disclosure: L.A. Robles: None. T. Ayub: None. I. Haque: None. C.E. Guillen Lopez, MD: None. S. Guntupalli: None. Introduction: Hypercalcemia of malignancy (HCM) associated with squamous cell carcinoma (SCC) of cutaneous origin is rare, with an estimated prevalence of 4.6%. We present a case of paraneoplastic hypercalcemia from PTHrP production by SCC arising in the setting of long-standing hidradenitis suppurativa (HS). Clinical Case: A 48-year-old male with a 20-year history of severe HS presents with concerns of disease deterioration and HS flare of buttocks, as well as, constipation, weakness, anorexia, and weight loss. Patient had recently discontinued treatment with Adalimumab for three weeks due to Covid-19 infection. Physical examination was significant for extensive hidradenitis to bilateral buttocks with granulation tissue at the base, surrounding induration, and scarring. Laboratory significant for corrected calcium 14.6 mg/dL (8.6-10.2 mg/dL), albumin 3.2, PTH 5 pg/mL(15-65 pg/mL), phosphorus 1.7mg/dL, ionized calcium 1.93 mm/L (1.15-1.30 mm/L), Vitamin D 25 mg/mL, 1,25 Vitamin D 14 pg/mL. Imaging with CT pelvis with innumerable peripherally enhancing centrally hypoattenuating lesions involving bilateral gluteus. Initially, calcium responded temporarily to IV hydration, calcitonin, and Pamidronate. Further work-up revealed PTHrP 24 pg/mL (11-20 pg/mL) and surgical pathology of bilateral buttocks with fragments of moderately to poorly differentiated SCC with perineural invasion of small caliber nerves and metastasis to lymph nodes. Patient remained significantly hypercalcemic during hospital course and received four doses of Pamidronate and eight doses of calcitonin. Diagnosis of bisphosphonate refractory hypercalcemia was established. Denosumab was given after patient became lethargic, and improvement of hypercalcemia followed. Oncology and Radiation therapy stated further treatment was not feasible given the lack of curative options and poor performance status, patient and family opted to pursue comfort care. Conclusion: Hypercalcemia presents in up to 30% of patients with malignancies and tends to predict a poor prognosis. Many mechanisms lead to HCM, with PTHrP production being the most common. Despite the prevalence of HCM, the risk of malignant transformation of HS to SCC is rare, with limited cases reported to date. Additionally, limited literature demonstrates mortality rates greater than 40% and involvement of buttocks, especially in men, exhibits the most malignant potential. Therefore, if a diagnosis of SCC in HS is made, an aggressive approach to management is advised to prevent significant morbidity and mortality. Bisphosphonates are the first-line therapy of HCM, but recent guidelines recommend treating severe HCM with a combination of calcitonin with either bisphosphonate or denosumab as the initial management. Furthermore, in those with bisphosphonate refractory HCM, treatment with denosumab would be the next step, as presented in our case. Presentation: Saturday, June 17, 2023

Intussusception caused by small bowel metastasis from hepatocellular carcinoma.

Intussusception caused by small bowel metastasis from hepatocellular carcinoma.

S3073 Small Bowel Metastasis of Melanoma Presenting as Overt Gastrointestinal Bleeding

S3073 Small Bowel Metastasis of Melanoma Presenting as Overt Gastrointestinal Bleeding

Small Bowel Metastases From Malignant Phyllodes Breast Tumor Detected by 18 F-FDG PET/CT.

The most common sites of distant metastases are lung, bone, pleura, and mediastinum in malignant phyllodes breast tumors. However, small bowel metastasis from malignant phyllodes breast tumors is rare. We reported that using CT and FDG PET/CT imaging we identified a case with small bowel metastasis from breast cancer. PET/CT scan showed that high 18 F-FDG uptake occurred in the duodenum and jejunum. Histopathology and immunohistochemistry analyses further confirmed that malignant phyllodes tumors are derived from the breast.

Lymph node metastases detection in Whole Slide Images using prototypical patterns and transformer-guided multiple instance learning

Abstract Background: The examination of lymph nodes (LNs) regarding metastases is vital for the staging of cancer patients, which is necessary for diagnosis and adequate treatment selection. Advancements in digital pathology, utilizing Whole-Slide Images (WSIs) and convolutional neural networks (CNNs), pose new opportunities to automate this procedure, thus reducing pathologists’ workload while simultaneously increasing the accuracy in metastases detection. Objective: To address the task of LN-metastases detection, the use of weakly supervised transformers are applied for the analysis of WSIs. Methods & Materials: As WSIs are too large to be processed as a whole, they are divided into non-overlapping patches, which are converted to feature vectors using a CNN network, pre-trained on HE-stained colon cancer resections. A subset of these patches serves as input for a transformer to predict if a LN contains a metastasis. Hence, selecting a representative subset is an important part of the pipeline. Hereby, a prototype based clustering is employed and different sampling strategies are tested. Finally, the chosen feature vectors are fed into a transformer-based multiple instance learning (MIL) architecture, classifying the LNs into healthy/negative (that is, containing no metastases), or metastatic/positive (that is, containing metastases). The proposed model is trained only on the Camelyon16 training data (LNs from breast cancer patients), and evaluated on the Camelyon16 test set. Results: The trained model achieves accuracies of up to 92.3% on the test data (from breast LNs). While the model struggles with smaller metastases, high specificities of up to 96.9% can be accomplished. Additionally, the model is evaluated on LNs from a different primary tumor (colon), where accuracies between 62.3% and 95.9% could be obtained. Conclusion: The investigated transformer-model performs very good on LN data from the public LN breast data, but the domain transfer to LNs from the colon needs more research.

585 Surgical Excision of Isolated Gastrointestinal Metastasis from Malignant Melanoma – a 10-Year Survey

Abstract Aim Patients with malignant melanoma (MM) can develop isolated metastasis years after treatment of the primary. The spleen and small bowel are the recognised intra-abdominal sites of isolated metastasis. Excision of these metastases is recommended as several international case series have shown good prognoses after excision. Method This is a 10-year retrospective study of patients with MM diagnoses who underwent excision of isolated metastasis at our Trust. Splenectomy and small bowel resection unrelated to MM and patients with disseminated metastasis were excluded. The surgical management, postoperative outcome and overall survival of the patients were assessed. Results In these 10 years, 2160 patients diagnosed with MM were treated in our Trust. Of these, 4 patients developed isolated splenic metastasis, and one had an additional small bowel metastasis. The primary MM location was the trunk in 2 patients, the posterior auricular region, and the left forearm in the other 2 patients. The patients developed metastasis an average of 47 months after treatment of their primary MM (range 11 - 96 months). The first patient underwent laparoscopic excision; the subsequent 2 patients underwent robotic-assisted excision. The patient with 2 isolated metastases underwent an open procedure. All four patients had no postoperative complications. The mean length of stay was 6 days with a zero-readmission rate. The mean survival time was 28 months (range: 3-60 months). Conclusions Isolated metastasis from MM is very uncommon. Surgical excision should be offered to all suitable patients. The feasibility of minimally invasive surgical excision should be considered in each patient.

Noninvasive Verification of a Very Small Intraocular Prostate Carcinoma Metastasis by 68Ga-PSMA-11 PET/CT.

A male patient underwent 68Ga-PSMA-11 PET/CT for the evaluation of a suspected intraocular metastasis in the right eye. Although the choroidal thickening was very small (4 × 2 mm), and ophthalmoscopy as well as MRI were inconclusive, PET/CT imaging showed distinct PSMA expression in the suspected lesion, confirming prostate cancer metastasis. The ability of dedicated PSMA ligand PET/CT imaging to detect small metastases, even with 68Ga-labeled ligands, has been demonstrated. Therefore, the use of further invasive diagnostic procedures could be avoided. Thus, the possibility of detecting intraocular metastases of prostate cancer should be considered in routine PET/CT imaging.

Laparoscopic resection of a metastatic myxoid liposarcoma in the mesentery of the small intestine: a case report

BackgroundMyxoid liposarcoma (MLS), with its risk factors, tends to spread to the lungs and extraperitoneally, with intraperitoneal metastases occurring rarely. We present an unusual case of a myxoid liposarcoma that metastasized to the abdominal organs.Case presentationA 60-year-old female patient was referred to our hospital for the evaluation of a right upper limb tumor that had been growing for 7 years. The patient refused surgery, and during follow-up, tumor hemorrhage resulted in hemorrhagic shock. The patient’s right upper limb was immediately amputated. MLS was diagnosed histopathologically. Subsequently, the patient underwent adjuvant chemotherapy. Computed tomography (CT) revealed a right buttock mass, a pelvic mass, and left cardiophrenic angle lymph nodes 3 years after the initial surgery. Contrast-enhanced abdominal CT revealed a relatively low-density, lobulated pelvic tumor. Contrast-enhanced pelvic magnetic resonance imaging (MRI) revealed a low-intensity, lobulated mass on T1-weighted images and a high-intensity mass on T2-weighted images. The pelvic mass showed no significant fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET)-CT. On clinical examination, gynecological malignancies were ruled out as the origin of the pelvic lesions. After resection of the right buttock mass, pelvic mass, and left cardiophrenic angle lymph nodes, the patient underwent laparoscopic surgery for a preoperative diagnosis of small intestinal mesenteric metastasis of MLS. A tumor was found in the mesentery of the small intestine and removed with a margin of 5 cm on both the proximal and distal sides. The specimen measured 10 × 8 × 5 cm and contained a multifocal mass. The tumor was found in the mesentery of the small intestine, with no mucosal or submucosal invasion. The patient was diagnosed with MLS with small mesenteric intestinal metastases. On postoperative day 8, the patient was discharged after an uneventful postoperative course. Twelve months after the surgery, there was no evidence of local or distant recurrence.ConclusionsSmall intestinal mesenteric metastases of MLSs are rare. Moreover, there are few reports on laparoscopic resection. In this case, the laparoscopic approach was useful in detecting the tumor location and determining the range of resection.

Additional Value of PET and CT Image-Based Features in the Detection of Occult Lymph Node Metastases in Lung Cancer: A Systematic Review of the Literature.

Lung cancer represents the second most common malignancy worldwide and lymph node (LN) involvement serves as a crucial prognostic factor for tailoring treatment approaches. Invasive methods, such as mediastinoscopy and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), are employed for preoperative LN staging. Among the preoperative non-invasive diagnostic methods, computed tomography (CT) and, recently, positron emission tomography (PET)/CT with fluorine-18-fludeoxyglucose ([18F]FDG) are routinely recommended by several guidelines; however, they can both miss pathologically proven LN metastases, with an incidence up to 26% for patients staged with [18F]FDG PET/CT. These undetected metastases, known as occult LN metastases (OLMs), are usually cases of micro-metastasis or small LN metastasis (shortest radius below 10 mm). Hence, it is crucial to find novel approaches to increase their discovery rate. Radiomics is an emerging field that seeks to uncover and quantify the concealed information present in biomedical images by utilising machine or deep learning approaches. The extracted features can be integrated into predictive models, as numerous reports have emphasised their usefulness in the staging of lung cancer. However, there is a paucity of studies examining the detection of OLMs using quantitative features derived from images. Hence, the objective of this review was to investigate the potential application of PET- and/or CT-derived quantitative radiomic features for the identification of OLMs.

Size-related heterogeneity of colorectal liver metastases (CRLM) in patients with advanced RAS wild-type metastatic colorectal cancer (mCRC) treated in the PanaMa trial: Implication for treatment decisions.

3553 Background: In patients with mCRC, the liver represents the primary site of metastasis. In patients with primarily unresectable metastatic disease, primary tumor location and molecular subtypes mainly determine the therapeutic approach. In addition, image-based characterization of hepatic metastatic pattern may provide additional information concerning prognosis and treatment efficacy. Therefore, CRLM were characterized according to size-based heterogeneity in the PanaMa trial (maintenance therapy with 5-fluoruracil/leucovorin (FU/FA) plus panitumumab (Pmab) vs. FU/FA alone following induction therapy with six cycles of FU/FA, oxaliplatin and Pmab). Methods: Assessments were performed in patients with at least two lesions, considering target and non-target lesions, within a central radiological review of the trial. Variance in size expressed as ratio between the smallest and largest lesion measured (≤/ > threefold difference in size) was evaluated for its prognostic and predictive impact on progression-free (PFS) and overall (OS) survival of maintenance therapy. Time-to-event endpoints were expressed by Kaplan-Meier method and compared by log-rank tests. Cox regressions were used to indicate Hazard ratios (HR) with 95% CIs. Results: Imaging data of 211/248 (85.1%) patients receiving maintenance therapy were evaluable for central radiological review (FU/FA+ Pmab, n = 106; FU/FA, n = 105). Of those, 165/211 patients (78.2%) had at least two CRLM. Size of CRLM ranged between 5–180mm, with the smallest metastasis in the individual assessments measuring a median of 12mm and the largest a median of 53mm. Large heterogeneity with more than a threefold difference in size between the smallest and largest CRLM was observed in 49.7% of patients, particularly pronounced in patients with polymetastatic disease ( > 5 lesions). Homogeneous metastasis in terms of lesion size (≤ threefold difference) was associated with favorable OS (HR 0.63; 95% CI, 0.42–0.95; P = 0.027) - irrespective of study arm- compared to heterogeneous lesion disease. Maintenance therapy with FU/FA+ Pmab compared with FU/FA alone seemed favourably active in both patients with heterogeneous metastases (HR 0.53; 95% CI; 0.34–0.85; P = 0.008) as well as to a numerically lesser extent in patients with homogeneous metastases (HR 0.68; 95% CI, 0.43–1.10; P= 0.116). Conclusions: Imaging-based characterization of CRLM focusing on size-related heterogeneity was associated with favorable prognosis potentially indicating more aggressive underlying tumor dynamics in case of heterogeneous lesion size. In addition, the efficacy of Pmab during maintenance was evident in both patient groups (homogeneous and heterogeneous disease lesions) with a numerically greater effect in patients with heterogeneous lesions. Clinical trial information: NCT01991873 .

Diagnostic methods for peritoneal molecular residual disease in gastric cancer

Peritoneal metastasis of gastric cancer serving as the most frequent form of metastasis, is one of the leading causes of death. A portion of surgically treated patients often suffer from small peritoneal residual metastasis, which will lead to recurrence and metastasis of gastric cancer patients after surgery. Given these, the prevention and treatment of peritoneal metastasis of gastric cancer deserves more attention. Molecular residual disease (MRD) refers to the molecular abnormalities of tumor origin that cannot be found by traditional imaging or other laboratory methods after treatment, but can be found by liquid biopsy, representing the possibility of tumor persistence or clinical progress. In recent years, the detection of MRD based on ctDNA has gradually become a research hotspot in the prevention and treatment of peritoneal metastasis. Our team established a new method for MRD molecular diagnosis of gastric cancer, and reviewed the research achievements in this field.

161Tb-DOTATOC Production Using a Fully Automated Disposable Cassette System: A First Step Toward the Introduction of 161Tb into the Clinic.

161Tb is an interesting radionuclide for application in the treatment of neuroendocrine neoplasms' small metastases and single cancer cells because of its conversion and Auger-electron emission. Tb has coordination chemistry similar to that of Lu; therefore, like 177Lu, it can stably radiolabel DOTATOC, one of the leading peptides used for the treatment of neuroendocrine neoplasms. However, 161Tb is a recently developed radionuclide that has not yet been specified for clinical use. Therefore, the aim of the current work was to characterize and specify 161Tb and to develop a protocol for the synthesis and quality control of 161Tb-DOTATOC with a fully automated process conforming to good-manufacturing-practice guidelines, in view of its clinical use. Methods: 161Tb, produced by neutron irradiation of 160Gd in high-flux reactors followed by radiochemical separation from its target material, was characterized regarding its radionuclidic purity, chemical purity, endotoxin level, and radiochemical purity (RCP) in analogy to what is described in the European Pharmacopoeia for no-carrier-added 177Lu. In addition, 161Tb was introduced into a fully automated cassette-module synthesis to produce 161Tb-DOTATOC, as used for 177Lu-DOTATOC. The quality and stability of the produced radiopharmaceutical in terms of identity, RCP, and ethanol and endotoxin content were assessed by means of high-performance liquid chromatography, gas chromatography, and an endotoxin test, respectively. Results: 161Tb produced under the described conditions showed, as the no-carrier-added 177Lu, a pH of 1-2, radionuclidic purity and RCP of more than 99.9%, and an endotoxin level below the permitted range (175 IU/mL), indicating its appropriate quality for clinical use. In addition, an efficient and robust procedure for the automated production and quality control of 161Tb-DOTATOC with clinically applicable specifications and activity levels, that is, 1.0-7.4 GBq in 20 mL, was developed. The radiopharmaceutical's quality control was also developed using chromatographic methods, which confirmed the product's stability (RCP ≥ 95%) over 24 h. Conclusion: The current study demonstrated that 161Tb has appropriate features for clinical use. The developed synthesis protocol guarantees high yields and safe preparation of injectable 161Tb-DOTATOC. The investigated approach could be translated to other DOTA-derivatized peptides; thus, 161Tb could be successfully applied in clinical practice for radionuclide therapy.

Hepatic myofibroblasts exert immunosuppressive effects independent of the immune checkpoint regulator PD-L1 in liver metastasis of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) represents the 4th most common cause of cancer-related deaths in Western countries. Most patients are diagnosed at advanced stages, often already with metastases. The main site of metastasis is the liver and hepatic myofibroblasts (HMF) play a pivotal role in metastatic outgrowth. Immune checkpoint inhibitors (ICI) targeting programmed death ligand 1 (PD-L1) or programmed cell death protein 1 (PD-1) improved treatment of several cancers but not of PDAC. Therefore, this study aimed to better understand the impact of HMF on PD-L1 expression and immune evasion of PDAC cells during liver metastasis. Formalin-fixed and paraffin embedded biopsy samples or diagnostic resection specimens from liver metastases of 15 PDAC patients were used for immunohistochemical analyses. Serial sections were stained with antibodies directed against Pan-Cytokeratin, αSMA, CD8, and PD-L1. To investigate whether the PD-1/PD-L1 axis and HMF contribute to immune escape of PDAC liver metastases, a stroma enriched 3D spheroid coculture model was established in vitro, using two different PDAC cell lines, HMF, and CD8+ T cells. Here, functional and flow cytometry analyses were conducted. Immunohistochemical analysis of liver tissue sections of PDAC patients revealed that HMF represent an abundant stroma population in liver metastases, with clear differences in the spatial distribution in small (1500 µm) and large (> 1500 μm) metastases. In the latter, PD-L1 expression was mainly located at the invasion front or evenly distributed, while small metastases either lacked PD-L1 expression or showed mostly weak expression in the center. Double stainings revealed that PD-L1 is predominantly expressed by stromal cells, especially HMF. Small liver metastases with no or low PD-L1 expression comprised more CD8+ T cells in the tumor center, while large metastases exhibiting stronger PD-L1 expression comprised less CD8+ T cells being mostly located at the invasion front. HMF-enriched spheroid cocultures with different ratios of PDAC cells and HMF well mimicking conditions of hepatic metastases in situ. Here, HMF impaired the release of effector molecules by CD8+ T cells and the induction of PDAC cell death, an effect that was dependent on the amount of HMF but also of PDAC cells. ICI treatment led to elevated secretion of distinct CD8+ T cell effector molecules but did not increase PDAC cell death under either spheroid condition. Our findings indicate a spatial reorganization of HMF, CD8+ T cells, and PD-L1 expression during progression of PDAC liver metastases. Furthermore, HMF potently impair the effector phenotype of CD8+ T cells but the PD-L1/PD-1 axis apparently plays a minor role in this scenario suggesting that immune evasion of PDAC liver metastases relies on other immunosuppressive mechanisms.

Clinical efficacy of PD-1 inhibitor combined with radiotherapy in a multi-drug resistant patient with liver metastasis from gastric cancer.

A 54-year-old male was diagnosed with extensive liver metastasis and small nodule metastasis in the lungs from gastric adenocarcinoma [Her-2 (-)]. The patient achieved significant partial response (PR) after chemotherapy combined with anti-angiogenesis therapy but developed progressive disease (PD) after 5 months. Then, the chemotherapeutic and anti-angiogenic drugs were replaced. Meanwhile, the delivery route of some chemotherapeutic drugs was changed, and some chemotherapeutic drugs were given via transcatheter arterial chemoembolization (TACE) to achieve PR, and PD developed after 3 months of remission maintenance. During chemotherapy combined with anti-angiogenesis, the application of programmed cell death-1 (PD-1) inhibitor achieved PR again and maintained for 5 months before disease progression. The progression of the lesions in the left lobe of the liver and the hepatic hilar lymph nodes was significant. Hence, chemotherapy was terminated and gamma stereotactic body radiation therapy (SBRT) was performed on left lobe lesions and hilar lymph nodes. The lesions both inside and outside the radiation field regressed significantly, reaching PR and abscopal effects. The immune-related adverse events (irAEs) occurred, including erythema and black and luster hair. The abscopal effects of lesion reduction in the radiation field and the enhancement of the immune function stimulated by radiation are a highlight of the combination of radiation and immunotherapy. In the end, the patient died of gastrointestinal failure, with overall survival of 18 months.

Active Surveillance of Differentiated Thyroid Cancer Metastatic Cervical Lymph Nodes: A Retrospective Single-Center Cohort Study.

Background: The most frequent site of recurrence of differentiated thyroid cancer (DTC) is cervical lymph nodes (LNs), which often necessitates repeated surgical interventions and morbidity in a generally indolent disease. Data on active surveillance (AS) of small cervical nodal metastasis are still scarce, particularly in real-world clinical settings. In this study, we evaluated the DTC outcomes of AS of metastatic cervical LNs and explored factors associated with disease progression. Methods: We conducted a retrospective cohort study, including DTC patients with biopsy-proven metastatic cervical LNs, who were followed on AS in a tertiary care, university-based institution in Brazil. The inclusion criteria were cervical metastasis ≤2.0 cm and an AS duration of at least 6 months. We excluded lesions with aggressive histology, those in close proximity to or invading local structures. The primary outcome was disease progression (enlargement ≥3 mm in any diameter or a new cervical metastasis). Results: Data from 40 patients were analyzed. Most were female (77.5%) and had papillary thyroid cancer (97.5%). The mean age was 47.0 (± standard deviation 15.8) years. The 8th edition of the tumor, node, metastasis stage (TNM8) staging for DTC was as follows: 29 in stage I (74.4%), 8 in stage II (20.5%), and 2 in stage IV (5.0%). The median maximum LN diameter was 0.9 (interquartile range [IQR], 0.8-1.3) cm, and the median AS follow-up duration was 27.5 (IQR, 16.5-47.3) months. Disease progression occurred in 14 (35%) patients: 7 (17.5%) due to enlargement ≥3 mm, and 7 (17.5%) had new cervical metastasis. The cervical progression-free survival was 51.0 (confidence interval, 47.0-55.0) months. No demographic, oncological, or biochemical factors were associated with disease progression. Of the 14 patients with disease progression, 8 were referred for surgery. No permanent surgical complications were reported. Of the six patients who remained on AS despite disease progression, five showed no further progression during subsequent follow-up (range 6-40 months). Conclusions: We observed that most small metastatic cervical LNs remained stable and were safely managed with AS. Nevertheless, these observations are limited by the retrospective design, small sample size, and short follow-up. Further prospective and long-term studies are warranted.

Modified Dynamic Conformal Arcs With Forward Planning for Radiosurgery of Small Brain Metastasis: Each Double Arc and Different To-and-Fro Leaf Margins to Optimize Dose Gradient Inside and Outside the Gross Tumor Boundary.

Dynamic conformal arcs (DCA) are a widely used technique for stereotactic radiosurgery (SRS) of brain metastases (BM) using a micro-multileaf collimator (mMLC), while the planning design and method considerably vary among institutions. In the usual forward planning of DCA, the steepness of the dose gradient outside and inside the gross tumor volume (GTV) boundary is simply defined by the leaf margin (LM) setting to the target volume edge. The dose fall-off outside the small GTV tends to be excessively precipitous, especially with an MLC of 2.5-mm leaf width, which is predisposed to the insufficient coverage of microscopic brain invasion and other inherent inaccuracies. Meanwhile, insufficient dose increase inside the GTV boundary, i.e., less inhomogeneous GTV dose, likely leads to inferior and less sustainable tumor response. The more inhomogeneous GTV dose is prone to the steeper dose gradient outside the GTV and vice versa. Herein, we describe an alternative simply modified DCA (mDCA) planning that was uniquely devised to optimize the dose gradient outside and inside the GTV boundary for further enhancing and consolidating local control of small BM. For a succinct exemplification, a 10-mm spherical target was assumed as a GTV for DCA planning using a 2.5-mm mMLC. The benchmark plan was generated by adding a 0-mm LM to the GTV edge byassigning a single fraction of 30 Gy to the isocenter, in which the GTV coverage by 24 Gy with 80% isodose surface (IDS) was 96%, i.e., D96%, while the coverage of GTV + isotropic 2 mm volume by 18 Gy with 60% IDS was 70%, with the D98% being 12 Gy with 40% IDS, viz., too steep dose fall-off outside the GTV boundary. Alternatively, the increase of LM with or without decreasing the isocenter dose enablesthe increase of the GTV + 2 mm coverage by 18 Gy while resulting in an inadequate GTV dose with either a less inhomogeneous dose or an excessive marginal dose. Meanwhile, in the newly devised mDCA planning, everysingle arc was converted to a double to-and-fro arcwith different LM settings under the same spatial arrangement, which enabled GTV + 2 mm volume coverage with 18 Gy while preserving the GTV marginal dose and inhomogeneity similar to those for the benchmark plan. Additionally, the different collimator angle (CA) setting for the to-and-fro arcs led to further trimming of the dose conformity. The limitations of general forward planning with only adjusting the LM for everysingle arc were demonstrated, which can be a contributing factor for local tumor progressionof small BM. Alternatively, the mDCA with each double to-and-fro arc and different LM and CA settings enables optimization of the dose gradient both outside and inside the GTV boundary according to the planners' intent, e.g., moderate dose spillage margin outside the GTV and steep dose increase inside the GTV boundary.