Umbilical metastases form a clinical challenge, especially when they represent the first sign of malignant disease and the primary tumor is unknown. Our study aims to generate insight into the origin ...and timing of umbilical metastasis, as well as patient survival, using population‐based data. A nationwide review of pathology records of patients diagnosed with an umbilical metastasis between 1979 and 2015 was performed. Data was collected from the Nationwide Network and Registry of Histopathology and Cytopathology (PALGA) and the Netherlands Cancer Registry. Kaplan‐Meier analyses and log‐rank testing were used to estimate overall survival and a Cox proportional hazard model was used to determine multivariable hazard ratios. A total of 806 patients with an umbilical metastasis were included. There were 210 male (26.1%) and 596 female (73.9%) patients. Distribution of umbilical metastases was different between male and female patients due to the high incidence of umbilical metastases originating from the ovaries in females. They most frequently originated from the ovaries in female patients (38.8%) and from the colon in male patients (43.8%). In 18% of cases no primary tumor could be identified. Prognosis after diagnosis of an umbilical metastasis was dismal with a median survival of 7.9 months (95% confidence interval 6.7‐9.1). The origin of the primary tumor was an independent prognostic factor for overall survival. In conclusion, umbilical metastases relatively rare, mainly originating from intraabdominal primary tumors. Survival is dependent on the origin of the primary tumor and poor overall survival rates warrant early recognition.
What's new?
Umbilical metastases are a rare consequence of malignant disease that pose unique clinical challenges. Very little is known about these metastases, especially regarding incidence and survival. This population‐based analysis of more than 800 patients in the Netherlands shows that the distribution in umbilical metastases differs between males and females. In females, metastases most commonly originated from the ovaries, while in males, the colon was most common. Umbilical metastases, however, were linked to a variety of primary tumors and were frequently diagnosed synchronously with the primary tumor. While prognosis was poor overall, survival was influenced by primary tumor origin.
A significant proportion of ovarian malignancies consists of metastatic tumors, with a wide variety in site of origin. Differentiating between a primary and metastatic malignancy of the ovaries can ...be difficult and misdiagnosis might have considerable impact on both treatment and prognosis. To further examine the origin of malignancies metastatic to the ovary, we performed a large-scale, nationwide search for ovarian metastases in the Dutch Pathology Registry (PALGA). All pathology reports concerning malignancies metastatic to the ovary and associated primary tumors in the Netherlands between 2000 and 2010 were collected. Age, year of diagnosis, tumor type, location of the primary tumor, and side of the ovarian tumor were extracted from the database. We identified 2312 patients fulfilling our selection criteria. The most common primary malignancy sites were colon (33.2 %), endometrium (17.1 %), breast (14.3 %), appendix (7.3 %), and stomach (4.5 %). The metastases were most frequently bilateral (46.3 %) followed by unilateral metastases in the right (26.7 %) and left ovary (19.8 %), while side was unknown in 7.2 % of cases. Of colorectal carcinomas, only 40.2 % metastasized bilaterally, compared to 63.9 % of breast, 62.9 % of gastric, and 58.9 % of appendix carcinomas. Left-sided colorectal carcinomas most often metastasized to the left ovary (
p
< 0.0001). We found colon carcinomas to be most frequently responsible for metastases to the ovaries, followed by endometrial and breast carcinomas. Metastases from breast, stomach, and appendix carcinomas were mostly bilateral, whereas metastases from colorectal carcinomas were mostly unilateral. The mechanisms underlying preferred sites for metastasis or side remain unclear.
Checkpoint inhibitors targeting PD-(L)1 induce objective responses in 20% of patients with metastatic urothelial cancer (UC). CD8
T cell infiltration has been proposed as a putative biomarker for ...response to checkpoint inhibitors. Nevertheless, data on spatial and temporal heterogeneity of tumor-infiltrating lymphocytes in advanced UC are lacking. The major aims of this study were to explore spatial heterogeneity for lymphocyte infiltration and to investigate how the immune landscape changes during the disease course. We performed multiplex immunohistochemistry to assess the density of intratumoral and stromal CD3
, CD8
, FoxP3
and CD20
immune cells in longitudinally collected samples of 49 UC patients. Within these samples, spatial heterogeneity for lymphocyte infiltration was observed. Regions the size of a 0.6 tissue microarray core (0.28 mm
) provided a representative sample in 60.6 to 71.6% of cases, depending on the cell type of interest. Regions of 3.30 mm
, the median tumor surface area in our biopsies, were representative in 58.8 to 73.8% of cases. Immune cell densities did not significantly differ between untreated primary tumors and metachronous distant metastases. Interestingly, CD3
, CD8
and FoxP3
T cell densities decreased during chemotherapy in two small cohorts of patients treated with neoadjuvant or palliative platinum-based chemotherapy. In conclusion, spatial heterogeneity in advanced UC challenges the use of immune cell infiltration in biopsies as biomarker for response prediction. Our data also suggests a decrease in tumor-infiltrating T cells during platinum-based chemotherapy.
Homologous recombination repair deficiency (HRD) is observed in 10% of patients with castrate-resistant prostate cancer (PCa). Preliminary data suggest that HRD-PCa might be more responsive to immune ...checkpoint inhibitors (ICIs). In this study, we compare the tumor immune landscape and peripheral T cell receptor (TCR) repertoire of patients with and without HRD-PCa to gain further insight into the immunogenicity of HRD-PCa. Immunohistochemistry was performed on tumor tissue of 81 patients, including 15 patients with HRD-PCa. Peripheral TCR sequencing was performed in a partially overlapping cohort of 48 patients, including 16 patients with HRD-PCa. HRD patients more frequently had intratumoral CD3
+
, CD3
+
CD8
−
FoxP3
−
or Foxp3
+
TILs above median compared to patients without DNA damage repair alterations (DDRwt; CD3
+
and Foxp3
+
: 77% vs 35%, p = .013; CD3
+
CD8
−
FoxP3
−
: 80% vs 44%, p = .031). No significant difference in CD8
+
TILs or PD-L1 expression was observed. In peripheral blood, HRD patients displayed a more diverse TCR repertoire compared to DDRwt patients (p = .014). Additionally, HRD patients shared TCR clusters with low generation probability, suggesting patient-overlapping T cell responses. A pooled analysis of clinical data from 227 patients with molecularly characterized PCa suggested increased efficacy of ICIs in HRD-PCa. In conclusion, patients with HRD-PCa display increased TIL density and an altered peripheral TCR repertoire. Further research into the efficacy of ICIs and the presence of shared neoantigens in HRD-PCa is warranted.
Objective To evaluate whether the hysteroscopic morcellator (HM) can be used as an alternative for uterine septum removal. Design Case report. Setting Outpatient clinic of a university-affiliated ...teaching hospital (Catharina Hospital, Eindhoven, the Netherlands). Patient(s) A 34-year-old Asian woman with recurrent miscarriages and a large uterine septum and bicornuate uterus. Intervention(s) Septum removal using the HM. Main Outcome Measure(s) Successful removal of a uterine septum. Result(s) Considering obstetric complications, septum removal was carried out. Currently, septum transection using the resectoscope is the gold standard. Instead of transection we achieved nearly complete removal of a septum, using the HM. Conclusion(s) The HM is a safe, effective, and easily manageable alternative for uterine septum removal compared with classic resectoscopy.
Abstract Background Individuals with germline pathogenic variants (gPVs) in BRCA1 or BRCA2 (BRCA1/2) are at a high risk of breast- and ovarian carcinomas (BOCs) with BRCA1/2-deficiency and homologous ...recombination deficiency (HRD) that can be detected by analysis of genome-wide genomic instability features such as large-scale state transitions, telomeric allelic imbalances and genomic loss-of-heterozygosity. Malignancies with HRD are more sensitive to platinum-based therapies and PARP inhibitors. Here, we aim to investigate the fraction of non-BOC malignancies that have BRCA1/2-deficiency and genomic instability features. Methods The full tumor history of a large historical clinic-based consecutive cohort of 2,965 individuals with gPVs in BRCA1/2 was retrieved via the Dutch nationwide pathology databank (Palga). In total, 169 non-BOC malignancies were collected and analyzed with targeted next-generation sequencing and shallow whole-genome sequencing to determine somatic second hit alterations and genomic instabilities indicative of HRD, respectively. Results BRCA1/2-deficiency was detected in 27% (21/79) and 23% (21/90) of 20 different types of non-BOC malignancies of individuals with gPVs in BRCA1 and BRCA2, respectively. These malignancies had a higher genomic instability score than BRCA1- or BRCA2-proficient malignancies (P < .001 and P < .001, respectively). Conclusions BRCA1/2-deficiency and genomic instability features were found in 27% and 23% of a broad spectrum of non-BOC malignancies in individuals with gPVs in BRCA1 and BRCA2, respectively. Evaluation of the effectivity of PARP-inhibitors in these individuals should be focused on tumors with confirmed absence of a wild type allele.
We report a patient with vulvar lichen sclerosus, Langerhans cell histiocytosis (LCH), and later vulvar cancer. In LCH, high amounts of non functional Langerhans cells are present in the affected ...tissue, making it possible that LCH may have contributed to vulvar cancer development in this patient.
Patients with mucinous ovarian carcinoma (MOC) generally have a favorable prognosis, although in advanced stage, prognosis is significantly worse compared to patients with serous ovarian carcinomas ...(SOCs). This might be due to the difficulties in distinguishing MOC from metastatic tumors. In the current study, we investigate prognosis of MOC compared to other types of ovarian cancer and to synchronous metastases to the ovary (sMO).
Age, laterality, International Federation of Gynecology and Obstetrics stage, tumor grade, treatment, and survival were extracted from the Eindhoven Cancer registry for all patients diagnosed with ovarian carcinomas or sMO between 1990 and 2012. Five-year survival analysis and Cox proportional hazards analysis were conducted.
A total of 3556 patients with primary ovarian carcinoma (of which 474 mucinous) and 289 with sMO were identified. In advanced stage, 5-year survival of patients with MOC was comparable to survival of patients with sMO (11% vs 11%, P = 0.32) and decreased compared to patients with SOC (26%, P < 0.01). For MOC, there was no clinically significant effect on 5-year survival of either debulking (12% vs 8%, P < 0.01) or chemotherapy (12% vs 10%, P = 0.02).
Patients with advanced stage MOC have a worse prognosis than advanced stage SOC. Survival is almost identical to that of patients with sMO. Effects of chemotherapy and debulking are limited in patients with MOC, which may be explained by suboptimal treatment due to the admixture of metastases in advanced stage MOC. Methods to differentiate between primary MOC and metastatic disease are needed to provide optimal treatment and insight in prognosis.
Incomplete resection of prostate cancer (PCa) occurs in 15%-50% of PCa patients. Disease recurrence negatively impacts oncological outcome. The use of radio-, fluorescent-, or photosensitizer-labeled ...ligands to target the prostate-specific membrane antigen (PSMA) has become a well-established method for the detection and treatment of PCa.
Here, we developed and characterized multimodal
InIn-DOTA(GA)-IRDye700DX-PSMA ligands, varying in their molecular composition, for use in intraoperative radiodetection, fluorescence imaging and targeted photodynamic therapy of PCa lesions. PSMA-specificity of these ligands was determined in xenograft tumor models and on fresh human PCa biopsies.
Ligand structure optimization showed that addition of the photosensitizer (IRDye700DX) and additional negative charges significantly increased ligand uptake in PSMA-expressing tumors. Moreover, an
incubation study on human tumor biopsies confirmed the PSMA-specificity of these ligands on human samples, bridging the gap to the clinical situation.
We developed a novel PSMA-targeting ligand, optimized for multimodal image-guided PCa surgery combined with targeted photodynamic therapy.
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