Multiple Organ Metastases Research Articles

Significance of Lateral Pelvic Lymph Node Dissection in Resectable Stage IV Low Rectal Cancer: Experience from a Single Center in Japan.

To investigate the significance of lateral pelvic lymph node dissection (LPLND) in resectable stage IV low rectal cancers, reviewing the treatment outcomes from a single cancer center dedicated to LPLND. Consecutive 56 patients with stage IV low rectal cancers who underwent primary tumor resection (PTR) between 2007 and 2022 were identified. Sixteen patients with non-curative PTR were excluded, and 40 with curative PTR were analyzed. The dominant metastatic organ was the liver in 30 (75.0%) patients, followed by the lung in 9 (22.5%). Seven (17.5%) patients had multiple organ metastasis. Five of 40 patients had cT1bN0 or cT2N0 disease, 8 did not receive LPLND for other reasons, and accordingly, 27 (67.5%) finally received LPLND. A total of 15 patients (37.5% of all 40 cases and 55.5% of 27 LPLND cases) had LPLN metastasis. Six (15.0%) patients had bilateral metastasis, and 6 (15.0%) had LD3 metastasis. Eight (20.0%) patients developed local recurrence (LR), and the 5Y-LR rate was 22.3%. Twelve (30.0%) patients underwent preceding chemotherapy before PTR, 26 (65.0%) received chemotherapy after PTR, and 23 (57.5%) achieved complete resection. Twelve (52.2%) of 23 patients developed distant recurrence after complete resection. 5Y-overall survival for all patients was 42.4%. A high rate of LPLN metastasis implies the significance of management for LPLN metastasis; meanwhile, an unsatisfactory complete resection rate and overall survival implies that LPLN metastasis in this cohort should be dealt with as a systemic disease.

Re-evaluation of the role of endoscopic submucosal dissection in the treatment of early gastric cancer based on additional gastrectomy results.

Endoscopic submucosal dissection (ESD) plays a pivotal role in treating early gastric cancer (EGC). Some patients require additional gastrectomy because of non-curative ESD. This study aimed to analyze the clinical factors associated with non-curative ESD and to re-evaluate the role of ESD according to its indication criteria. Altogether, 134 patients who had undergone additional gastrectomy with lymphadenectomy for non-curative ESD based on the pathological results of ESD specimens were included. Their data including pre-ESD diagnosis, reasons for requesting additional gastrectomy, and surgical outcomes were analyzed retrospectively. Of the 134 patients with EGC in the final pathology of ESD specimens, 56 underwent staging ESD for a diagnostic approach, of whom 28 were diagnosed with atypical glands and 28 with high-grade dysplasia (HGD) prior to ESD. The remaining 78 patients of the 134 were identified to have EGC and received ESD for therapy. Based on the pathological results of ESD specimens, additional gastrectomy was commissioned with non-curative ESD because of one or more causes such as deep submucosal invasion, lymphatic invasion, positive vertical margin, undifferentiated histology, positive lateral margin, and venous invasion. Regarding surgical specimens, 13 patients had lymph node metastasis (LNM) and 9 had local residual tumor; one of them had both LNM and a local residual tumor. In patients with atypical glands, 4 had LNM and 3 had a local residual tumor; one of them had both LNM and a local residual tumor, and then died of multiple organ metastasis. In patients with HGD, 4 had LNM and 1 had a local residual tumor. Additionally, 4 patients who were absolutely indicated for ESD had LNM, of whom 2 had atypical glands, and the other 2 had HGD. Similarly, in 6 patients with a local residual tumor absolutely indicated for ESD, 2 had atypical glands and 1 had HGD. Positive vertical margin, lymphatic invasion, and deep submucosal invasion were identified as independent risk factors for LNM. ESD may play diagnostic and therapeutic roles in determining the optimal treatment of EGC when the diagnosis is equivocal or insufficient in endoscopic assessments for gastric cancer screening.

6634 Dual-Mediated PTH And Osteolytic Hypercalcemia In Metastatic Endometrial Carcinoma

Abstract Disclosure: C.K. Persaud: None. D.J. Beckman: None. Background: Hypercalcemia of malignancy occurs in 20-30% of advanced stage cancer patients. Etiologies include parathyroid hormone-related peptides (PTHrP)-mediated, osteolytic metastases-mediated, overproduction of 1,25-dihydroxycholecalciferol, and rarely parathyroid hormone (PTH)-mediated. PTH-mediated hypercalcemia of malignancy is rare and occurs through ectopic PTH production or primary hyperparathyroidism. We report a rare case of both PTH-mediated and osteolytic-mediated hypercalcemia in the setting of malignancy. Clinical Case: A 57-year-old female with history of endometrial cancer and multiple solid organ metastasis, presented with two weeks of progressive poor oral intake, nausea, emesis, and right flank pain. On hospital admission, she had a serum calcium of >20.1 mg/dL (8.6-10.2), PTH of 203 pg/mL (15.0-65.0), and creatinine of 1.7 mg/dL (0.7-1.2, baseline 1.3). Non-contrasted CT chest/abdomen/pelvis noted increased size of known right adrenal metastasis, new left adrenal metastasis, periaortic lymphadenopathy, and scattered nodules in the subcutaneous tissues of the abdomen and chest, however bone metastasis were not noted. Patient’s hypercalcemia was treated with zoledronic acid, calcitonin, cinacalcet, and eventually denosumab due to difficulty controlling hypercalcemia. Additional labs obtained during evaluation included ionized calcium >2.5 nmol/L (1.12-1.32), PTHrP <2.0 pmol/L (<2.0), 1,25-dihydroxycholecalciferol <10 pg/mL (21-65). Patient’s right adrenal metastasis biopsy one month prior to admission was subsequently stained for PTH and was negative. Technetium-99m sestamibi scan was obtained for localization of parathyroid adenoma or carcinoma. The scan did not localize, however did show numerous new lytic lesions in the skull, spine, sternum, rib cage, and right humerus. Patient’s hospital course was complicated by progressively worsening renal function, anemia, and thrombocytopenia. Patient was discharged to a long-term acute rehab facility off hypercalcemia treatment with a corrected calcium of 10.0 mg/dL. Conclusion: PTH-mediated hypercalcemia is a rare cause of hypercalcemia of malignancy. PTH levels are typically low or low-normal in osteolytic mediated hypercalcemia. Generally, if PTH is elevated in hypercalcemia, an alternate etiology is not evaluated. This case highlights a rare dual-mediated hypercalcemia of malignancy. The patient’s PTH level elevation was discordant with her high degree of hypercalcemia and prolonged treatment course. She was subsequently found to have widespread bone metastases contributing to hypercalcemia. While multiple etiologies of hypercalcemia can be rare, it is important to evaluate for all contributing causes, especially with additional clinical conditions, such as malignancy. Presentation: 6/3/2024

The Chick Chorioallantoic Membrane as a Xenograft Model for the Quantitative Analysis of Uveal Melanoma Metastasis in Multiple Organs.

Uveal melanoma (UM) is the most common intraocular tumor in adults, and nearly 50% of patients develop metastatic disease with a high mortality rate. Therefore, the development of relevant preclinical in vivo models that accurately recapitulate the metastatic cascade is crucial. We exploited the chick embryo chorioallantoic membrane (CAM) xenograft model to quantify both experimental and spontaneous metastasis by qPCR analysis. Our study found that the transplanted UM cells spread predominantly and early in the liver, reflecting the primary site of metastasis in patients. Visible signs of pigmented metastasis were observed in the eyes, liver, and distal CAM. Lung metastases occurred rarely and brain metastases progressed more slowly. However, UM cell types of different origins and genetic profiles caused an individual spectrum of organ metastases. Metastasis to multiple organs, including the liver, was often associated with risk factors such as high proliferation rate, hyperpigmentation, and epithelioid cell type. The severity of liver metastasis was related to the hepatic metastatic origin and chromosome 8 abnormalities rather than monosomy 3 and BAP1 deficiency. The presented CAM xenograft model may prove useful to study the metastatic potential of patients or to test individualized therapeutic options for metastasis in different organs.

A phase 1 study of LB4330, a peptide fused to CLDN18.2 antibody targeting the tumor antigen associated (TAA) CD8+T cells in patients with advanced solid tumors.

e15074 Background: PD-1/PD-L1-targeted immunotherapies have become critical in the treatment for many tumors. However, there has been limited progress in low immunogenic cancers such as pancreatic ductal adenocarcinoma (PDAC) or CRC. LB4330 is a novel, bi-functional molecule targeting Claudin18.2 and IL-10 with high affinity anti-CLDN18.2 (14pM). It may activate TAA CD8+ T cells in the tumor microenvironment (TME) and has potential alone or in combination with immunotherapeutic agents, including PD-1/PD-L1 mAbs, for the treatment of advanced solid tumors. A FIH, phase 1 study to evaluate the safety, tolerability, pharmacokinetics and immunogenicity of LB4330 in patients with advanced solid tumors (MEETCD8-001) is ongoing in China. Methods: Eligible patients were ≥ 18 years old with ECOG PS 0-1. Dose cohorts ranged from 0.001 mg/kg to1 mg/kg IV QW: 0.001mg/kg-0.05mg/kg in an accelerated titration design, and 0.2mg/kg-1 mg/kg using traditional 3+3 design. The primary objective is safety, including dose-limiting toxicities (DLTs). The secondary/exploratory objectives include efficacy, pharmacokinetics (PK), and immunogenicity. Results: As of January 5, 2024, 30 patients with advanced solid tumors who have failed standard treatments or who did not have standard treatments available or applicable at this stage were recruited, including 17 PDAC, 6 GC, 3 CRC and 4 other solid tumor patients. All patients enrolled had multiple organ metastases. Treatment emergent AEs (TEAEs) occurred in 90.3% of patients. The most common Treatment related AEs (TRAE) were thrombocytopenia, anemia, fever, rash/itching, and fatigue. 7 patients (23.3%) had grade 3 TRAE which were infusion reaction, skin itching, rash, fever, abdominal distension, anemia, and thrombocytopenia. 1 patient (3.2%) had grade 4 AE, thrombocytopenia. On-treatment scan for efficacy was available for 20 patients, and 7 had stable disease. Target lesion shrinkage was observed in 2 pts, including one PDAC patient whose sum of target lesion reduced by 32.9% from baseline. PK was generally dose proportional, with t½ ~2 days. The immune activating Th1 cytokine IL-18 was elevated in 77.8% of patients treated with LB4330. Updated data will be presented. Conclusions: LB4330 has manageable safety and shows preliminary efficacy at tolerable doses. Dose and efficacy expansion study is ongoing in more PDACs and other solid tumors. In the meantime, Phase I study of LB4330 in combination with PD1/TIM-3 bispecific antibody LB1410 has been initiated in different tumor types as well. Clinical trial information: NCT05707676 .

Pulmonary Metastasectomy; Analyse and Clinical Overview of 20 Patients

It has been revealed that metastasectomy surgery performed on patients whose primary tumor is under control and who have only lung metastases can show better survival after complete surgical resection compared to cases with multiple organ metastases. In our study, we retrospectively shared our experience with metastasectomies and their impact on survival. In our clinic, 20 patients (12 men, 8 women; average age 49 years) who were operated on due to metastasis detected in the lung between 2010 and 2020 were retrospectively examined. Patients were determined according to age, gender, primary tumor pathology, disease-free time, radiologically and surgically. It was evaluated according to the number of metastatic lesions detected, the type of operation and the follow-up period. Respiratory function tests were performed on all patients. Patients with isolated pulmonary lesions whose primary tumors were under control underwent resection if their cardiopulmonary status was suitable for resection. Three of the twenty patients underwent video-assisted thoracoscopic surgery (VATS), and the other 17 patients underwent open thoracotomy, for a total of 28 metastasectomy operations. While the number of nodules detected before the operation was 39, a total of 51 nodules were excised during the operation. No major complications were observed. While 9 of our patients died due to widespread metastases within the 5-year postoperative period, 11 patients are being followed up disease-free without pulmonary metastases. It is known that metastasectomy positively affects survival in cases with isolated pulmonary metastases whose primary tumor is under control. The possibility of missing radiological findings when evaluating the number of nodules still makes the importance of open surgical treatment and digital palpation current in metastasectomy.

Abstract B038: CD4Th1 cytokine interferon gamma regulates genome profiles and inhibits tumorigenesis of disseminated cancer cells in breast cancer

Abstract Detection and persistence of disseminated cancer cells (DCCs) in the bone marrow (BM) of breast cancer (BC) patients has been identified as a primary source for late recurrence and distant metastasis in multiple organs and the central nervous system. Selective targeting and eradication of DCCs in BM can be of a significant advantage to prevent future recurrence and enhance disease-free survival in BC patients. Unfortunately, no such targeted therapy presently exists. Instead, intense chemotherapy in the adjuvant or neoadjuvant setting are given with the ultimate goal to prevent DCC-driven metastasis in these patients. Clinical studies have confirmed that DCCs have not been effectively eradicated by conventional chemotherapies. DCCs express unique gene signatures that differ from circulating tumor cells (CTC) in BC, but only limited knowledge is available for the genome profiles of DCCs compared to primary and metastatic lesions in BC patients. Here we investigated the detailed gene expression profiles of DCCs compared to primary and metastatic lesions from a murine spontaneous metastasis model and BC patients. Using a two-step immunomagnetic enrichment assay, we were able to successfully isolate highly enriched EpCAM+ DCCs from both the BM aspirates of HER2+ early BC patients and BALB-HER2/neu transgenic (BALB-neuT) spontaneous metastasis mice. RNA sequencing revealed that DCCs from HER2+ BC patients and BALB-neuT mice displayed remarkably similar genomic expression profiles, but both had substantially different profiles when comparing to primary and metastatic lesions. We identified highly enriched signatures in DCCs associated with cancer stemness, epithelial to mesenchymal transition (EMT), cell cycle, cell adhesion, progesterone signaling and cholesterol biosynthesis. Notably, these DCCs showed loss of MHC class I, MHC class II, and CD1d expression leading to a defect in antigen presentation machinery and their subsequent escape from CD4 T, CD8 T, B and NKT-cell mediated clearance. Interestingly, we observed for the first time that anti-tumor CD4Th1 cells, through interferon gamma (IFN-γ) production, upregulated CD1d, MHC class I and II expressions in DCCs leading to high infiltration of CD4Th1, NKT and B cells into the BM to selectively target and eliminate DCC burden. IFN-γ remarkably downregulated stemness, EMT, self-renewing potential and their genome signatures and induced apoptosis and irreversible senescence in DCCs of HER2+ BC patients. Notably, these IFN-γ treated patient DCCs lost their ability to grow into tumors in an immunodeficient NSG mouse model. Collectively, these results provide a detailed genome profile of DCCs from HER2+ BC patients and a novel role for anti-tumor CD4Th1 response in inhibiting DCC-driven tumorigenesis and metastasis. Citation Format: Ganesan Ramamoorthi, Marie Catherine Lee, Krithika Kodumudi, Colin Snyder, Namrata Gautam, Saurabh K. Garg, Shari Pilon-Thomas, Brian Czerniecki. CD4Th1 cytokine interferon gamma regulates genome profiles and inhibits tumorigenesis of disseminated cancer cells in breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B038.

Efficacy of immune checkpoint inhibitors in advanced large cell neuroendocrine carcinoma of the lung: A single‑institution experience.

Large cell neuroendocrine carcinoma (LCNEC) is a rare and highly invasive lung cancer subtype with an overall poor prognosis. Due to its low incidence rate and unusual pathological features, the clinical management of LCNEC remains controversial. The present study aimed to assess the effect of immune checkpoint inhibitors (ICIs) on treatment response and survival outcomes in patients with advanced LCNEC. The clinical data from 148 patients with LCNEC treated with ICIs at The First Affiliated Hospital of Zhengzhou University (Zhengzhou, China) between January 2019 and September 2021 were retrospectively analyzed. Kaplan-Meier and multivariable Cox regression analyses were used to evaluate associations between clinicopathological variables and patient outcomes. Patients treated with ICIs demonstrated extended median overall survival (mOS) times [23.5 months; 95% confidence interval (CI), 18.524-28.476] compared with patients who did not receive ICIs (11.2 months; 95% CI, 4.530-18.930) (P<0.001). Univariate analysis revealed that histological subtype (P=0.043), lymph node metastases (P=0.032) and number of metastatic organs (P=0.009) were associated with a poor prognosis. The heterogeneity of pathological components was associated with prognosis, and the mOS time was shorter for mixed LCNEC than that for pure LCNEC (P=0.043). The median progression-free survival (mPFS) (9.78 vs. 9.37 months; P=0.82) and mOS (20.70 vs. 25.79 months; P=0.181) times showed no significant association with regard to different regimens of immuno-based combination therapy (chemotherapy combined with ICIs vs. anti-angiogenic agents combined with ICIs). Poor Eastern Cooperative Oncology Group performance status score (P=0.04), multiple organ metastases (P=0.02) and high cancer antigen 125 levels (P=0.01) were independent risk factors of a poor prognosis. The present findings offer valuable insights into potential prognostic markers and highlight the favorable impact of ICIs on OS in advanced LCNEC. Prospective clinical studies are required to validate the therapeutic value of ICIs in LCNEC.

Clinical and radiological outcomes of n-HA/PA66 cages in anterior spine reconstruction following total en bloc spondylectomy for tumors.

This retrospective monocentric study was conducted to evaluate the clinical and radiological outcomes of the nano-hydroxyapatite/polyamide66 (n-HA/PA66) cage in reconstructing the anterior column of the spine following total en bloc spondylectomy (TES). A cohort of 24 patients, 20 diagnosed with primary malignant tumors and 4 with metastatic malignancies, was selected based on specific inclusion criteria. All were subjected to TES and anterior column reconstruction with the n-HA/PA66 cage from January 2013 to July 2023 at a single institution. Pre-operative embolization was performed on all patients. Documented factors included operation duration, intraoperative blood loss, length of hospital stay, treatment history, and involved level. Mechanical complications and radiological parameters such as the local kyphotic angle (LKA), anterior vertebral height (AVH), posterior vertebral height (PVH), cage subsidence, and bone fusion time were evaluated. Quality of life and neurological function were gauged using tools like the Visual Analog Scale (VAS), Eastern Cooperative Oncology Group (ECOG) performance score, Karnofsky Performance Score (KPS) scale, and American Spinal Injury Association (ASIA) grading. All patients were followed up for 12-127 months, with an average period of 39.71 months. An average operation time of approximately 8.57 h and a blood loss volume of about 1,384 ml were recorded. No instances of tumor recurrence or multiple organ metastases were reported, though recurrence was detected in 2 living patients. Solid fusion was achieved in all patients at a mean time of 6.76 ± 0.69 months. Cage breakage or migration was not observed. Subsidence into the adjacent vertebral bodies was identified in 3 patients but was deemed clinically irrelevant. Significant improvements in VAS, ECOG performance score, KPS scale, and ASIA scores were noted from pre- to post-surgery (P < 0.05). A marked enhancement in the AVH was observed from before surgery to immediately after (P < 0.05). LKA, AVH, and PVH values between postoperative and final follow-up showed no significant variance (P > 0.05). The integration of TES and the n-HA/PA66 cage was found to yield promising clinical and radiological outcomes in anterior column spine reconstruction. The use of this material did not hinder oncological care, including the provision of adjuvant treatments (chemo/radiotherapy), ultimately contributing to the enhanced long-term quality of life for spinal tumor patients.

Uterine giant cell tumor of soft tissue: A case report.

Giant cell tumor of soft tissue (GCT-ST) is a rare primary soft tissue tumor. GCT-ST mainly occurs in the trunk and extremities. There is no standard treatment for GCT-ST. This paper reports a rare case of primary uterine GCT-ST. A 48-year-old female patient underwent a transabdominal subhysterectomy for uterine leiomyoma. Postoperative pathological examination showed GCT-ST with unclear tissue boundary (10.0 × 6.0 × 5.0 cm). A small amount of GCT-ST tissue could be seen on the local edge of the leiomyoma. Residual tumor tissue was found around the uterine cavity. The patient reported persistent lower abdominal distension pain 3 months after the operation. Pelvic and abdominal imaging showed a huge tumor and multiple pelvic and abdominal organ metastasis. No pulmonary metastasis was found. Exploratory surgery revealed widespread metastases in the abdominal and peritoneal cavities, involving both ovaries, right tubal serous membrane, appendix serous membrane, bladder, pelvic peritoneum, and abdominal wall incision. After surgery, the patient had 6 cycles of docetaxel and carboplatin but stopped treatments due to economic reasons. The patient died 3 months later because of multiple organs failure. GCT-ST is generally benign but has unpredictable behavior. A massive recurrence with wide invasion is possible after subtotal resection.

Prognostic and predictive impact of metastatic organ involvement on maintenance therapy in advanced metastatic colorectal cancer: Subgroup analysis of patients treated within the PanaMa trial (AIO KRK 0212).

Despite molecular selection, patients (pts) with RAS wildtype mCRC represent a heterogeneous population including diversity in metastatic spread. We investigated metastatic patterns for their prognostic and predictive impact on maintenance therapy with 5-fluorouracil/folinic acid ± panitumumab. The study population was stratified according to (1) number of involved metastatic sites (single vs multiple organ metastasis), liver-limited disease vs (2) liver metastasis plus one additional site, and (3) vs liver metastasis plus ≥two additional sites. Kaplan-Meier method and Cox regressions were used to correlate efficacy endpoints. Single organ metastasis was observed in 133 pts (53.6%) with 102 pts (41.1%) presenting with liver-limited disease, while multiple organ metastases were reported in 114 pts (46.0). Multiple compared to single organ metastases were associated with less favorable PFS (HR 1.48, 95% CI 1.13-1.93; P = .004) and OS (HR 1.37, 95% CI 0.98-1.93; P = .068) of maintenance therapy. While metastatic spread involving one additional extrahepatic site was not associated with clearly impaired survival compared to liver-limited disease, pts with liver metastasis plus ≥two additional sites demonstrated less favorable PFS (HR 1.92, 95% CI 1.30-2.83; P < .001), and OS (HR 2.38, 95% CI 1.51-3.76; P < .001) of maintenance therapy. Pmab-containing maintenance therapy appeared active in both pts with multiple (HR 0.58; 95% CI, 0.39-0.86; P = .006) as well as to a lesser numerical extent in pts with single organ metastasis (HR 0.83; 95% CI, 0.57-1.21; P = .332; Interaction P = .183). These data may support clinical decisions when EGFR-based maintenance therapy is considered.

A nomogram predicting the outcome of gallbladder cancer patients with different target organ metastases.

Gallbladder cancer (GBC) is a highly aggressive malignancy that is associated with a high mortality rate globally. Unfortunately, distant metastases are often detected at the time of diagnosis. Therefore, we investigated the survival outcomes of gallbladder cancer patients with different metastases targeting organs, analyzed their prognosis, and explored their hidden clinical value. Through data screening, a total of 398 patients with GBC with different target organ metastases were analyzed retrospectively, including patients with solitary bone metastasis, solitary liver metastasis, solitary lung metastasis, and multiple organ metastases. The survival results of different variables were plotted as Kaplan-Meier survival curves. Univariate and multivariate Cox regression models were used to screen study variables and identify independent prognostic factors. Finally, a nomogram was established to systematically evaluate the prognosis of patients with multiple organ metastasis. In the patient cohort, thirteen (3.3%) had solitary bone metastasis, 290 (72.9%) had solitary liver metastasis, 22 (5.5%) had solitary lung metastasis, and 73 (18.3%) had multiple organ metastases (including liver, lung, bone and brain metastases). Multivariate Cox analysis showed that the overall survival (OS) of patients with solitary lung metastasis was significantly better than that of patients with other organ metastasis (p = 0.038), while the difference in tumor cancer-specific survival (CSS) of this factor was not statistically significant (p > 0.05). Surgery and chemotherapy were independent prognostic protective factors for OS and CSS. The OS-related models exhibited a C-index of 0.74 (95% CI: 0.71-0.77), while the CSS-related models showed a slightly lower C-index of 0.73 (0.70-0.76). Both the OS- and CSS-related clinical prediction models had good accuracy. This study shows that different target organ metastases may affect the OS of patients with distant metastatic GBC. Patients receiving palliative surgery, primary site resection, radical surgery, and chemotherapy have significant survival benefits in terms of OS and CSS.

Post-Progression Survival in Patients with Oligometastatic or Polymetastatic Pancreatic Adenocarcinoma

Distant progression following surgical resection of stage I-III pancreatic ducal adenocarcinoma (PDAC) is a major cause of morbidity and mortality. Herein, we investigated the impact of tumor burden at the time of distant progression on survival. We hypothesize that patients with limited number of metastases (≤5) in a single organ will have improved survival post progression. We queried our institutional database for patients with the following inclusion criteria: 1-Stage I-III PDAC who underwent curative resection, and 2-Metachronous single organ (liver or lung) distant failure >3 months from the date of surgery. Patients with serosal and/or multiple organ metastases were excluded. Single organ metastases other than liver or lung were also excluded. Patients were stratified into oligometastatic (≤5 tumors), and polymetastatic (>5 tumors). Primary endpoint was survival post failure, while secondary endpoints were distant failure free survival (DFFS) and overall survival. Reverse KM curve was used to calculate median follow up. KM curves were plotted for DFFS identified from date of surgery until date of distant failure, survival post failure was identified from date of distant failure until death/last follow up, and overall survival was identified from date of surgical resection until death/last follow up. Out of 128 patients who developed metachronous distant progression following surgical resection, we identified 76 patients who met the inclusion criteria with a median follow up of 50 months. Among those, at the time of distant failure, 63% (n = 48) and 37% (n = 28) patients had ≤5 vs >5 metastases respectively. Median number of metastases was one (range 1-5) and eight (range 6-33), while 12 and 11 patients developed local failure in the oligometastatic and polymetastatic cohorts respectively. Among the 48 patients who developed oligometastases, 69% (n = 33) and 31% (n = 15) had liver and lung metastases respectively. On the other hand, 68% (n = 19) and 32% (n = 9) had liver and lung polymetastases respectively. Median DFFS was 11, and 9 months (HR = 1.59, 95 % CI 0.95-2.64, p value = 0.046), survival post distant failure was 17.8 and 5.3 months (HR = 3.03, 95 % CI 1.52-6.01, p value<0.0001), and median survival was 29.8, and 16.7 months (HR = 2.52, 95 % CI 1.31-4.86, p value = 0.0007) among patients with oligometastases and polymetastases respectively. Within the surgically resected stage I-III PDAC who developed single organ liver or lung metachronous disease, oligometastases (one-five lesions) were more prevalent, had more durable DFFS, had improved survival post failure, and a longer median survival compared to patients with polymetastatic recurrence (>five metastases). Trials on treatment of metastatic PDAC should stratify by number of metastases, and the oligometastatic subset may derive survival benefit from ablative radiation therapy.

Prediction of adenocarcinoma and squamous carcinoma based on CT perfusion parameters of brain metastases from lung cancer: a pilot study.

Predicting pathological types in patients with adenocarcinoma and squamous carcinoma using CT perfusion imaging parameters based on brain metastasis lesions from lung cancer. We retrospectively studied adenocarcinoma and squamous carcinoma patients with brain metastases who received treatment and had been pathologically tested in our hospital from 2019 to 2021. CT perfusion images of the brain were used to segment enhancing tumors and peritumoral edema and to extract CT perfusion parameters. The most relevant perfusion parameters were identified to classify the pathological types. Of the 45 patients in the study cohort (mean age 65.64 ± 10.08 years; M:F = 24:21), 16 were found to have squamous cell carcinoma. Twenty patients were with brain metastases only, and 25 patients were found to have multiple organ metastases in addition to brain metastases. After admission, all patients were subjected to the CT perfusion imaging examination. Differences in CT perfusion parameters between adenocarcinoma and squamous carcinoma were analyzed. The receiver operating characteristic (ROC) curves were used to predict the types of pathology of the patients. Among the perfusion parameters, cerebral blood flow (CBF) and mean transit time (MTT) were significantly different between the two lung cancers (adenocarcinoma vs. squamous cell carcinoma: p < 0.001, p = 0.012.). Gender and tumor location were identified as the clinical predictive factors. For the classification of adenocarcinoma and squamous carcinoma, the model combined with CBF and clinical predictive factors showed better performance [area under the curve (AUC): 0.918, 95% confidence interval (CI): 0.797-0.979). The multiple organ metastasis model showed better performance than the brain metastasis alone model in subgroup analyses (AUC: 0.958, 95% CI: 0.794-0.999). CT perfusion parameter analysis of brain metastases in patients with primary lung cancer could be used to classify adenocarcinoma and squamous carcinoma.

The Incidence and Effect of Different Organ Metastasis on the Prognosis of NSCLC.

The aim of this study was to explore the effect of different organ metastasis on the prognosis of non-small cell lung cancer (NSCLC). Patients with distant metastatic NSCLC were selected from Surveillance, Epidemiology, and End Results database during 2016 to 2019. The incidence of different organ metastasis and their association with clinicopathological factors were explored. Overall survival (OS) and lung cancer-specific survival (LCSS) for metastatic NSCLC were calculated, and multivariate Cox regression analysis was performed with a nomogram for OS being constructed based on Cox regression. Total 26,210 patients with distant metastatic NSCLC were included in this study. Around 48.9% of the metastatic NSCLC were multiple-organ metastasis and bone was the most commonly involved organ (44.4%). For patients with single-organ metastasis, the prognosis for lung or distant lymph nodes (LNs) metastasis was better than others (with median OS of 15 and 16 months for lung and distant LNs metastasis, respectively), and liver metastasis resulted in the worst prognosis with median OS of 8 months. A nomogram was constructed to visualize Cox regression model, along with the receiver operating characteristic (ROC) curve demonstrated good discrimination for the predictive model with 1- and 2-year area under the curve of ROC of 0.687 and 0.702, respectively. The prognosis of NSCLC patients with distant metastasis was poor. Liver metastasis results in the worst prognosis among the single-organ metastasis. The nomogram developed based on the Cox regression model has provided a useful tool to estimate the probability of OS of the metastatic NSCLC.

Premetastatic Niche Mimicking Bone-On-A-Chip: A Microfluidic Platform to Study Bone Metastasis in Cancer Patients.

Primary cancer modulates the bone microenvironment to sow the seeds of dormancy and metastasis in tumor cells, leading to multiple organ metastasis and death. In this study, 3D printing and bone-on-a-chip (BOC) are combined to develop a BOC platform that mimics the pre-metastatic niches (PMNs) and facilitates elucidation of the interactions between bone-resident cells and metastatic tumor cells under the influence of primary cancer. Photocrosslinkable gelatin methacrylate (GelMA) is used as a 3D culturing hydrogel to encapsulate cells, and circulate tumor culture medium (CM) adjacent to the hydrogel to verify the critical role of mesenchymal stem cells (MSCs) and osteoclasts (RAW264.7s). Three niches: the dormancy niche, the perivascular niche, and the "vicious cycle" niche, are devised to recapitulate bone metastasis in one chip with high cell viability and excellent nutrient exchange. With respect to tumor dormancy and reactivation, the invadopodia formation of A549 lung cancer cells in communication with MSCs and RAW264.7 via the cortactin pathway is researched. As a proof of concept, the functionality and practicality of the platform are demonstrated by analyzing the invadopodia formation and the influence of various cells, and theestablishment of the dynamic niches paves the way to understanding PMN formation and related drug discovery.

Prognostic impact of metastatic patterns and treatment modalities on overall survival in lung squamous cell carcinoma: A population-based study.

This study aimed to investigate the impact of distinct metastasis patterns on the overall survival (OS) of individuals diagnosed with organ metastatic lung squamous cell carcinoma (LUSC). OS was calculated using the Kaplan-Meier method, and univariate and multivariate Cox regression analyses were conducted to further assess prognostic factors. A total of 36,025 cases meeting the specified criteria were extracted from the Surveillance, Epidemiology, and End Results database. Among these patients, 30.60% (11,023/36,025) were initially diagnosed at stage IV, and 22.03% (7936/36,025) of these individuals exhibited metastasis in at least 1 organ, including the liver, bone, lung, and brain. Among the 4 types of single metastasis, patients with bone metastasis had the lowest mean OS, at 9.438 months (95% CI: 8.684-10.192). Furthermore, among patients with dual-organ metastases, those with both brain and liver metastases had the shortest mean OS, at 5.523 months (95% CI: 3.762-7.285). Multivariate Cox regression analysis revealed that metastatic site is an independent prognostic factor for OS in patients with single and dual-organ metastases. Chemotherapy was beneficial for patients with single and multiple-organ metastases; although surgery was advantageous for those with single and dual-organ metastases, it did not affect the long-term prognosis of patients with triple organ metastases. Radiotherapy only conferred benefits to patients with single-organ metastasis. LUSC patients exhibit a high incidence of metastasis at the time of initial diagnosis, with significant differences in long-term survival among patients with different patterns of metastasis. Among single-organ metastasis cases, lung metastasis is the most frequent and is associated with the longest mean OS. Regarding treatment options, patients with single-organ metastasis can benefit from chemotherapy, surgery, and radiotherapy, and those with metastasis in 2 organs can benefit from chemotherapy and surgery. Patients with metastasis in more than 2 organs, however, can only benefit from chemotherapy. Understanding the variations in metastasis patterns assists in guiding pretreatment assessments and in determining appropriate therapeutic interventions for LUSC.

DP24 A case of digital papillary adenocarcinoma linked to human papillomavirus-42

Abstract A 60-year-old man with known stage-4 non-small cell lung cancer (NSCLC) and previous right-thumb hidradenoma presented with a 5-month history of a growing vascular lesion on his right great toe. Histology revealed a digital papillary adenocarcinoma (DPA) and positive quantitative polymerase chain reaction (qPCR) for human papilloma virus (HPV)-42 (courtesy of Thomas Wiesner’s research team in Austria). Review of previous histology for the lung and thumb lesions showed histological features consistent with DPA. He re-presented after 2 years with metastatic DPA in his right posterior calf. Following wide local excision (WLE), this locally reoccurred, requiring further excision. Aside from chemotherapy for NSCLC, he was not immunosuppressed and had no history of HPV-related disease. Digital papillary adenocarcinoma is a rare and aggressive neoplasm of sweat glands. Despite being a low-grade tumour, the rates of metastases and reoccurrence are high. Distant metastases are common and can present years after initial presentation. Distant metastases without lymph node spread have been reported. The annual incidence in the USA is ~0.08 cases per 1 000 000, typically presenting in men aged 50–70 years as a solitary lesion on the digits. It can invade muscle, tendons and bone. Owing to its rarity, misdiagnosis and treatment delay are common (Kobayashi T, Hiura A, Oishi K et al. Aggressive digital papillary adenocarcinoma with multiple organ metastases: a case report and review of the literature. Am J Dermatopathol 2016; 38:910–14). Studies show a link between HPV-42 and DPA, with qPCR detecting HPV-42 in known DPA cases (HPV-42 negative in hidradenoma). Human papilloma virus-42 was previously unknown to be oncogenic, and HPV vaccines do not target HPV-42 (Leiendecker L, Neumann T, Jung PS et al. Human papillomavirus 42 drives digital papillary adenocarcinoma and elicits a germ cell-like program conserved in HPV-positive cancers. Cancer Discov 2022; 13:70–84). There are no clear management guidelines and no drug therapy for DPA. Case studies have shown chemotherapy to be ineffective. Management is surgical with either amputation or WLE to avoid reoccurrence or metastases (Leiendecker et al.). Clinical suspicion for DPA should be high given its aggressive nature with regular long-term follow-up to detect reoccurrence or metastases early. More research is required on the epidemiology of this rare tumour in the UK and Europe and on treatment strategy beyond surgical resection, targeting the link between HPV-42 and DPA.

The clinicopathological spectrum and treatment outcomes in metastatic colorectal cancer in the KwaZulu-Natal province of South Africa.

In high-income countries (HICs) 17-20% of colorectal cancer (CRC) patients have metastatic CRC (mCRC) at the time of diagnosis, of which 10-25% are or become resectable, and a further 4-11% of patients will develop metachronous metastases. The study aimed to establish the prevalence and pattern of metastatic CRC to document treatment outcomes in KwaZulu-Natal (KZN), and to compare results to international norms. The study population comprised patients with mCRC presenting between 2000 and 2019. Demographics, primary tumour site, spectrum of metastatic disease and resection rate were assessed. MCRC occurred in 33% of the CRC patient population. Eight hundred and thirty-six patients had metastatic disease, comprising Africans (325, 38.8%), Indians (312, 37.3%), Coloureds (37, 4.4%) and Whites (161, 19.2%). Six hundred and fifty-four patients (79%) had synchronous metastases and 182 patients had metachronous metastases (21%). Single organ metastases occurred in 596 patients (71.2%) (M1A) and multiple organ metastasis occurred in 240 patients (28.7%) (M1B). Metastases occurred in the liver (613), lung (240) and peritoneum (85). Fifty-two patients (6.2%) underwent resection of their metastases. The prevalence of stage IV CRC in our setting is at the upper limit of international norms. mCRC occurred in 33%, with similar proportions in all races. Resection rate for metastases is low.

Abiraterone acetate and prednisone in metastatic castration-resistant prostate cancer: a real-world retrospective study in China.

This research work was aimed at evaluating the incidence and risk factors of adverse events (AEs) occurring in patients treated with abiraterone acetate (AA) and prednisone (PDN) outside clinical trials. These associations were assessed regarding the survival outcomes. The study included 191 patients aged ≥18 years of confirmed metastatic castration-resistant prostate cancer (mCRPC) between March 2017 and April 2022. AE incidences were descriptively summarized from the whole cohort. Baseline characteristics, safety (treatment-emergent AEs and severe AEs), and efficacy [progression-free survival (PFS)] were analyzed. Multi-variable Cox proportional hazards models were employed to assess the factors linked with PFS. Overall, the median PFS was 17.16 months (range, 0.5-57.58). Patient baseline prostate-specific antigen (PSA) ≧̸10 ng/ml (p = 0.000), multiple organ metastasis (p = 0.007), hypertension (p = 0.004), and coronary heart disease (p = 0.004) were associated with worse PFS; however, radiotherapy (p = 0.028) was linked to better PFS at univariate analysis in the overall cohort. Baseline multiple organ metastasis, hypertension, and radiotherapy remained statistically significant in multivariable models (p = 0.007, p= 0.005, and p = 0.011, respectively).Incidence of AEs showed increased bilirubin (BIL) (55/191 patients, 28.8%) followed by increased alanine aminotransferase/aspartate aminotransferase (ALT/AST) (48/191 patients, 25.09%). The most common grade 3 AEs were increased ALT (3/191, 1.57%) followed by elevated BIL, hypercholesterolemia, and hypokalemia. Anemia had shorter PFS. There were no unexpected AEs in any patient. AA is effective and tolerated in asymptomatic or slightly symptomatic mCRPC in "real-life" setting. The survival outcomes are influenced by multiple organ metastasis, hypertension, and radiotherapy.