We discuss alternative strategies to develop the chemotherapeutic agent based on targeting ErbB family ligands rather than their receptors. A phase I study of CRM197 for advanced ovarian cancer has already begun, which is the first approved trial of ErbB-ligand-targeted therapy. We also discuss clinical adaptations based on combination of CRM197 with other conventional chemotherapeutic agents.

A new drug dosage form comprising activated carbon particles adsorbing mitomycin C (MMC-CH) is designed to slowly release its components, and has affinity for the tumor surface and lymph nodes and a tendency to stay long in the local portion. The therapeutic index of MMC-CH in experimental carcinomatous peritonitis is 3.1 times as high as that of MMC-solution. In clinical experiments 81 patients with carci-nomatous effusions were administered with MMC-CH (2.0-2.4 mg/kg in terms of MMC) in bolus in-tracavitarily. Fifty-one patients responded well to the MMC-CH therapy. Nineteen patients were alive for more than 6 months. The responders showed marked improvement in subjective symptoms, and 26 patients became dischargeable from hospital. Bone marrow suppression and peritoneal irritation were main adverse effects, but the symptoms were temporary and not so serious in spite of a high dose of MMC. Cancer 59:245-251, 1987. OR CARCINOMATOUS peritonitis or pleuritis, many F kinds of anticancerous agents in solution form have been administered intracavitarily. These methods are not always successful to control the local lesion, because therapeutic agents injected intracavitarily in solution form are easily absorbed through the large serosal surface into blood plasma and it is difficult to keep a high concentration of the agents for a long time in the ~ a v i t y. ~ To surmount this difficulty we have decided to utilize the functional slow-releasing ability of adsorbents, and devised a new dosage form, called MMC-CH,6 comprising fine activated carbon particles adsorbing mitomycin C (MMC). Experiments with animals have shown that MMC-CH slowly releases its components, and has affinity for the tumor surface and lymphatics, and a tendency to stay long in the cavity. Rat experiments indicate that MMC-CH has higher therapeutic effects on experimental carcinomatous peritonitis than MMC-solution.

Primary sarcoma of the fallopian tube is a very rare neoplasm. We report the case of a 69-year-old woman affected with leiomyosarcoma of the left fallopian tube. Her chief complaint was lower abdominal pain. The preoperative diagnosis was a left adnexal malignant tumor based on pelvic examination, abdominal computed tomography, and magnetic resonance imaging. Following a laparotomy, she was ultimately diagnosed with a FIGO IIc fallopian tube leiomyosarcoma. She was treated with total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic lymph node dissection, partial omentectomy, and low anterior resection for rectal invasion. The patient subsequently received adjuvant chemotherapy with pirarubicin and ifosfamide. Thirty months after the first therapy, a computed tomography scan revealed metastasis of the liver, lung, and supraclavicular lymph node. The patient died of the disease 39 months after the initial treatment.

BackgroundBK-UM (CRM197) is a mutant form of diphtheria toxin and a specific inhibitor of heparin-binding epidermal growth factor-like growth factor (HB-EGF). We assessed the safety, pharmacokinetics, recommended dose, and efficacy of BK-UM in patients with recurrent ovarian cancer (OC) or peritoneal cancer (PC), and measured HB-EGF levels in serum and abdominal fluid after BK-UM administration.MethodsEleven patients with advanced or recurrent OC or PC were enrolled and treated with BK-UM via the intraperitoneal route. The dose was escalated (1.0, 2.0, 3.3, and 5.0 mg/m2) using a 3 + 3 design.ResultsEight of 11 patients completed treatment. No dose-limiting toxicity (DLT) was experienced at dose levels 1 (1.0 mg/m2) and 2 (2.0 mg/m2). Grade 3 transient hypotension as an adverse event (defined as a DLT in the present study) was observed in two of four patients at dose level 3 (3.3 mg/m2). Treatment with BK-UM was associated with decreases in HB-EGF levels in serum and abdominal fluid in seven of 11 patients and five of eight patients, respectively. Clinical outcomes included a partial response in one patient, stable disease in five patients, and progressive disease in five patients.ConclusionsBK-UM was well tolerated at doses of 1.0 and 2.0 mg/m2, with evidence for clinical efficacy in patients with recurrent OC or PC. A dose of 2.0 mg/m2 BK-UM is recommended for subsequent clinical trials.Trial registrationThis trial was prospectively performed as an investigator-initiated clinical trial. The trial numbers are UMIN000001002 and UMIN000001001, with registration dates of 1/30/2008 and 2/4/2008, respectively. UMIN000001001 was registered as a trial for the continuous administration of BK-UM after UMIN000001002.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3071-5) contains supplementary material, which is available to authorized users.

ObjectivesAge-related changes in the expression of hormonal receptors have not been well examined in the fallopian tube (FT). We herein report the effect of menopause on the hormone receptors in ampullae of the FTs (AFTs), in comparison with cortical inclusion cysts (CICs) of the ovary.MethodsA total of 84 AFTs and 16 fimbriae of FTs, which were obtained from 26 premenopausal and 58 postmenopausal women; and 27 postmenopausal CICs were immunohistochemically studied for the expression of p53, Ki-67, estrogen receptor-alpha (ER-α), and progesterone receptor A (PRA). Apoptotic cells were identified using a TUNEL assay.ResultsPostmenopausal AFTs showed a significantly lower labeling index (LI) for Ki-67 (P<0.001), apoptosis (P=0.03), and PRA (P<0.001) than premenopausal AFTs. No significant correlation with immunohistochemical markers was found in premenopausal AFTs, but the LI for PRA was positively correlated with that for Ki-67 (P=0.004) and inversely with that for p53 (P=0.023) in postmenopausal AFTs. The expression of immunohistochemical markers was closely correlated between ampullae and fimbriae of the FT. The p53 signature (p53S) was detected in five postmenopausal AFTs (mean age: 70.2 years) and was not detected in any CICs. The immunohistochemical profile of p53S was low expression of Ki-67, apoptosis, and PRA, and high expression of ER-α. The expression of PRA in CICs was significantly higher than that in AFTs (P=0.001).ConclusionThe expression of PRA was significantly lower in postmenopausal AFTs than in premenopausal AFTs, whereas the expression of PRA was well preserved in postmenopausal CICs.

Granulocyte colony-stimulating factor (G-CSF) is commonly used in clinical practice to accelerate neutropenia recovery after chemotherapy. G-CSF is a myeloid growth factor produced by monocytes, macrophages, fibroblasts and endothelial cells. Generally, aortitis and arteritis are not a known side effect of G-CSF and is thought to be extremely rare. Here, we present a case of a 77-year-old woman who underwent adjuvant chemotherapy (combined paclitaxel and carboplatin) for ovarian cancer, and then developed acute arteritis after receiving G-CSF. She developed grade 4 neutropenia on day 7 of the third chemotherapy cycle and received six G-CSF administrations. Two days after G-CSF administration, she came down with a high-grade fever that persisted for 2 weeks. Laboratory tests revealed a white blood cell count of 8700 UI, neutrophilic sequestration of 61.5%, and C-reactive protein of 8.43 mg/dl at the highest point of her fever. Considering that we were initially treating neutropenia, we diagnosed a bacterial infection, and she was treated with a course of antibiotics. However, her blood and urinalysis cultures were negative, and antibiotics were ineffective; thus, we performed a computed tomography scan to search for the cause of her persistent fever. The computed tomography scan showed remarkable thickness of the bilateral common carotid artery and the left subclavian artery consistent with arteritis. With cessation of the antibiotics course, she was followed closely without therapy, and her condition resolved in a few days. We conclude that G-CSF induced arteritis due to our exclusion of other probable etiologies.

Dienogest is a novel progestin with potent oral progestational activity that inhibits the clinical symptoms of endometriosis. We herein evaluated the effect of dienogest on ovarian endometriotic cysts via immunohistochemistry. Ovarian endometriotic cyst specimens were collected from 12 patients treated with dienogest and 20 patients not treated with hormones (controls). The expression of estrogen receptor (ER)-α, progesterone receptor A (PRA), and Ki-67 was studied by immunohistochemistry. As compared with the controls, the cell proliferation index was significantly reduced in both epithelial and stromal cells of the endometriotic cysts following the use of dienogest (P = 0.022 and P = 0.004, respectively). However, there was no significant difference between endometriotic cysts with and without the use of dienogest in the expressions of ER-α and PRA in the epithelial and stromal cells. Irrespective of the use of dienogest, the expression levels of ER-α and PRA in the epithelial cells were low (median: 32% and 8%, respectively). Conversely, the expression levels of ER-α and PRA in the stromal cells were well preserved (median: 68% and 92%, respectively). In the controls, there was no significant difference between endometriotic cysts in the expression levels of Ki-67, ER-α and PRA in epithelial and stromal cells during the proliferative and secretory phases. The finding of a reduction in the cell proliferation index by the use of dienogest with no change in the expressions of hormonal receptors may not support the direct progestational effect of dienogest on ovarian endometriotic cysts.

This case suggests that PCPS can lead to favorable clinical outcomes in patients with large uterine leiomyomata and severe PTE.