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Adoptive transfer of allogeneic natural killer (NK) cells is an attractive therapy approach against ovarian carcinoma. Here, we evaluated the potency of highly active NK cells derived from human CD34+ haematopoietic stem and progenitor cells (HSPC) to infiltrate and mediate killing of human ovarian cancer spheroids using an in vivo-like model system and mouse xenograft model. These CD56+Perforin+ HSPC-NK cells were generated under stroma-free conditions in the presence of StemRegenin-1, IL-15, and IL-12, and exerted efficient cytolytic activity and IFNγ production toward ovarian cancer monolayer cultures. Live-imaging confocal microscopy demonstrated that these HSPC-NK cells actively migrate, infiltrate, and mediate tumor cell killing in a three-dimensional multicellular ovarian cancer spheroid. Infiltration of up to 30% of total HSPC-NK cells within 8 h resulted in robust tumor spheroid destruction. Furthermore, intraperitoneal HSPC-NK cell infusions in NOD/SCID-IL2Rγnull (NSG) mice bearing ovarian carcinoma significantly reduced tumor progression. These findings demonstrate that highly functional HSPC-NK cells efficiently destruct ovarian carcinoma spheroids in vitro and kill intraperitoneal ovarian tumors in vivo, providing great promise for effective immunotherapy through intraperitoneal HSPC-NK cell adoptive transfer in ovarian carcinoma patients.

An unassigned and prominent resonance in the region from delta 2.0-2.1 ppm has frequently been found in the in vivo MR spectra of cancer patients. We demonstrated the presence of this resonance with in vivo MRS in the cyst fluid of a patient with an ovarian tumor. (1)H-NMRS on the aspirated cyst fluid of this patient confirmed the observation. A complex of resonances was observed between 2.0 and 2.1 ppm. It was also present in 11 additional ovarian cyst fluid samples randomly chosen from our biobank. The resonance complex was significantly more prominent in samples from mucinous tumors than in samples from other histological subtypes. A macromolecule (10 kDa) was found responsible for this complex of resonances. A correlation spectroscopy (COSY) experiment revealed cross peaks of two different types of bound sialic acid suggesting that N-glycans from glycoproteins and/or glycolipids cause this resonance complex. In the literature, plasma alpha-1 acid glycoprotein (AGP), known for its high content of N-linked glycans, has been suggested to contribute to the delta 2.0-2.1 spectral region. The AGP cyst fluid concentration did not correlate significantly with the peak height of the delta 2.0-2.1 resonance complex in our study. AGP may be partly responsible for the resonance complex but other N-acetylated glycoproteins and/or glycolipids also contribute. After deproteinization of the cyst fluid, N-acetyl-L-aspartic acid (NAA) was found to contribute significantly to the signal in this spectral region in three of the 12 samples. GC-MS independently confirmed the presence of NAA in high concentration in the three samples, which all derived from benign serous tumors. We conclude that both NAA and N-acetyl groups from glycoproteins and/or glycolipids may contribute to the delta 2.0-2.1 ppm resonance complex in ovarian cyst fluid. This spectral region seems to contain resonances from biomarkers that provide relevant clinical information on the type of ovarian tumor.

Sister Mary Joseph nodule is one of the less well-known signs of intra-abdominal metastatic disease. The primary tumor site is nearly always detected because of specific morphologic and immunohistochemical features of the umbilical tumor. We describe a case of a 74-year-old woman with a Sister Mary Joseph nodule, which appeared most likely to be metastatic from a primary serous papillary ovarian carcinoma based on the histologic examination and the immunohistochemical analysis. Despite an extensive workup, no primary tumor could be detected and therefore we ultimately diagnosed the tumor as an extraovarian carcinoma with primary site at the umbilicus. After a literature search we concluded that a primary adenocarcinoma of the umbilicus is extremely rare and to our knowledge has never been described with both morphologic and immunohistochemical features of a serous ovarian carcinoma.

The alpha(v)beta(3) integrin is expressed on proliferating endothelial cells such as those present in growing tumors, as well as on tumor cells of various origin. Tumor-induced angiogenesis can be blocked in vivo by antagonizing the alpha(v)beta(3) integrin with small peptides containing the Arg-Gly-Asp (RGD) amino acid sequence. This tripeptidic sequence, naturally present in extracellular matrix proteins, is the primary binding site of the alpha(v)beta(3) integrin. Because of selective expression of alpha(v)beta(3) integrin in tumors, radiolabeled RGD peptides are attractive candidates for alpha(v)beta(3) integrin targeting in tumors. We studied the in vivo behavior of the radiolabeled dimeric RGD peptide E-[c(RGDfK)](2) in the NIH:OVCAR-3 s.c. ovarian carcinoma xenograft model in BALB/c nude mice. Conjugation of the 1,4,7,10-tetraazadodecane-N,N',N",N"'-tetraacetic acid (DOTA) and hydrazinonicotinamide (HYNIC) chelators enabled efficient radiolabeling with (111)In/(90)Y and (99m)Tc, respectively. The radiolabeled peptide was rapidly excreted renally. Uptake in nontarget organs such as liver and spleen was considerable. Tumor uptake peaked at 7.5% injected dose (ID)/g ((111)In-DOTA-E-[c(RGDfK)](2)) or 6.0%ID/g ((99m)Tc-HYNIC-E-[c(RGDfK)](2)) at 2 and 1 h postinjection, respectively. Integrin alpha(v)beta(3) receptor binding specificity was demonstrated by reduced tumor uptake after injection of the scrambled control peptide (111)In-DOTA-E-[c(RDKfD)](2) (0.28%ID/g at 2 h p.i.) and after coinjection of excess nonradioactive (115)In-DOTA-E-[c(RGDfK)](2) (0.22%ID/g at 2 h p.i.). A single injection of (90)Y-DOTA-E-[c(RGDfK)](2) at the maximum-tolerated dose (37 MBq) in mice with small s.c. tumors caused a significant growth delay as compared with mice treated with 37 MBq (90)Y-labeled scrambled peptide or untreated mice (median survival of 54 versus 33.5 versus 19 days, respectively). In conclusion, the radiolabeled RGD peptides (111)In-DOTA-E-[c(RGDfK)](2) and (99m)Tc-HYNIC-E-[c(RGDfK)](2) demonstrated high and specific tumor uptake in a human tumor xenograft. Injection of (90)Y-DOTA-E-[c(RGDfK)](2) induced a significant delay in tumor growth. Potentially, these peptides can be used for peptide receptor radionuclide imaging as well as therapy.