Generalized sarcoidlike granulomas with systemic angiitis, crescentic glomerulonephritis, and pulmonary hemorrhage. Report of an autopsy case

A 19-year-old woman showed rapidly progressive renal and respiratory failure and died after a short clinical course. The autopsy revealed that death was due to crescentic glomerulonephritis and pulmonary hemorrhage. The intrathoracic lymph nodes, lungs, kidneys, and other organs contained numerous epithelioid granulomas, some of which had foci of central coagulative necrosis. The aorta, its major branches, and small- to medium-sized vessels of various organs also had multiple areas of granulomatous angiitis. This is, to our knowledge, the first report of such autopsy findings. A discussion of the etiopathogenesis of the disease is presented.     

An autopsy case of thymic carcinoma producing various tumor markers and the examination of 222 autopsy cases of thymic malignant tumor in Japan

The autopsy of a 76-year-old Japanese female patient, which revealed thymic carcinoma with various tumor markers such as NSE, CYFRA, and CA-125, is presented. The patient died from hepatic failure because the liver was overtaken by the tumors. At autopsy, the thymic carcinoma was found to have metastased only in the liver. From microscopical analyses and electron microscopical findings, we diagnosed poorly differenciated squamous cell carcinoma of thymic origin. In the histochemical analyses, the tumor cells were positively stained in CA 125, CA 19-9, EMA, NSE, AE 1, AE 3, CEA, S-100, glimerius and Bcl-2. These date suggest that the tumor cells produced various tumor markers. In 222 autopsy cases of thymic malignant tumor observed in Japan over a period of 4 years, the dominant pathohistological image was squamous cell carcinoma. It is interesting that the greatest number of combined malignant tumors with thymic malignancies were thyroid papillary carcinomas.     

Weekly paclitaxel administration and intraabdominal CBDCA injection possibly beneficial treatment for recurrent breast cancer associated with metastatic ovarian cancer and peritoneal dissemination after operation--a case report

A 46-year-old woman who had received mastectomy for breast cancer 6 years earlier complained of abdominal distension. Computed tomography and ultrasonography revealed massive ascites and ovarian swelling of both sides. She was diagnosed as having primary ovarian cancer and peritoneal dissemination, and underwent a total hysterectomy as well as ovarectomy on both sides. After surgery, she received a sequential chemotherapy, ie, intraabdominal injection of carboplatin (CBDCA 300 mg/m2) and div administration of paclitaxel (PTX 180 mg/m2) as a standard regimen for advanced ovarian cancer. However, detailed histological examinations showed that the ovarian cancer had metastasized from her breast cancer. It is well-known that breast cancer easily metastasizes to the bone, liver, pleura and lymph node, but rarely to the ovarium or peritoneum when chemotherapy is conducted. Therefore, no standard therapy has been established for breast cancer metastasizing to the ovarium. Our patient received 4 cycles of weekly administration of PTX (PTX 80 mg/m2, 3 consecutive weeks, 1-week break), followed by oral administration of doxifluridine+anastrozole on an outpatient basis. No evidence of recurrence of breast cancer has been noted 1 year after surgery. This result suggests that weekly administration of PTX and intraabdominal injection of CBDCA might be beneficial in the treatment of recurrent breast cancer associated with metastatic ovarian cancer and peritoneal dissemination after operation.     

Influence of response to prior docetaxel on sensitivity to cabazitaxel in prostate cancer patients with PTEN alterations

The purpose of this study was to investigate factors predicting the sensitivity to cabazitaxel therapy in metastatic castration‐resistant prostate cancer (mCRPC) patients with phosphatase and tensin homolog deleted from chromosome 10 (PTEN) alterations. This single‐institution, retrospective study included 12 mCRPC patients with PTEN alterations who had received cabazitaxel therapy. Five patients (41%) responded to cabazitaxel therapy with a prostate‐specific antigen (PSA) level decline of ≥30% from baseline, and all of them had responded to prior docetaxel therapy with a PSA decline of ≥30%. None of the patients with a poor response to prior docetaxel therapy responded well to cabazitaxel therapy. Of the seven patients who did not respond to cabazitaxel and whose PSA declined from baseline was <30%, five (71%) were also refractory to prior docetaxel therapy. The PSA responses to docetaxel and cabazitaxel were significantly correlated (p = 0.027). Kaplan–Meier analysis revealed that progression‐free survival (PFS) for cabazitaxel was significantly shorter for prior docetaxel nonresponders (3.3 versus 9.1 months, p = 0.028). Multivariate analysis revealed that a poor response to prior docetaxel (PSA decline < 30%) (hazard ratio [HR] = 6.382, 95% confidence interval [CI] 1.172–34.750, p = 0.032) and baseline PSA of ≥20 ng/ml (HR = 33.584, 95% CI 2.332–483.671, p = 0.010) were independent prognostic factors for PFS with cabazitaxel therapy. These results demonstrate cross‐resistance between docetaxel and cabazitaxel. The response to prior docetaxel therapy can influence the sensitivity to cabazitaxel therapy in mCRPC patients with PTEN alterations.     

Analyses of very early hemopoietic regeneration after bone marrow transplantation: comparison of intravenous and intrabone marrow routes

In bone marrow transplantation (BMT), bone marrow cells (BMCs) have traditionally been injected intravenously. However, remarkable advantages of BMT via the intra-bone-marrow (IBM) route (IBM-BMT) over the intravenous route (IV-BMT) have been recently documented by several laboratories. To clarify the mechanisms underlying these advantages, we analyzed the kinetics of hemopoietic regeneration after IBM-BMT or IV-BMT in normal strains of mice. At the site of the direct injection of BMCs, significantly higher numbers of donor-derived cells in total and of c-kit(+) cells were observed at 2 through 6 days after IBM-BMT. In parallel, significantly higher numbers of colony-forming units in spleen were obtained from the site of BMC injection. During this early period, higher accumulations of both hemopoietic cells and stromal cells were observed at the site of BMC injection by the IBM-BMT route. The production of chemotactic factors, which can promote the migration of a BM stromal cell line, was observed in BMCs obtained from irradiated mice as early as 4 hours after irradiation, and the production lasted for at least 4 days. In contrast, sera collected from the irradiated mice showed no chemotactic activity, indicating that donor BM stromal cells that entered systemic circulation cannot home effectively into recipient bone cavity. These results strongly suggest that the concomitant regeneration of microenvironmental and hemopoietic compartments in the marrow (direct interaction between them at the site of injection) contributes to the advantages of IBM-BMT over IV-BMT. Disclosure of potential conflicts of interest is found at the end of this article.     

Prostaglandin F2 alpha metabolite levels in plasma, amniotic fluid, and urine during pregnancy and labor.

Levels of 13, 14-dihydro 15-keto-prostaglandin F2alpha (dhk PGF2alpha) in the plasma of 30 patients as well as in the amniotic fluid of 17 patients, and 5alpha,7alpha-dihydroxy 11-keto tetranor-prostane 1,16-dioic acid (the main urinary metabolite of PGF2alpha [PGF2alpha MUM]) levels in the urine of 30 patients were measured by radioimmunoassay during pregnancy, labor, and the puerperium. During pregnancy, no increase in dhk PGF2alpha (ng/ml) in plasma was detected as the time of delivery approached. The levels of dhk PGF2alpha during the second stage (0.64 +/- 0.15) and also at delivery (0.88 +/- 0.27) were significantly elevated over those in the first stage (0.38 +/- 0.29) (P less than 0.025 and P less than 0.005, respectively). Its level 2 hours after delivery was reduced to predelivery levels. Its levels in umbilical arterial and venous blood were 0.71 +/- 0.26 and 0.67 +/- 0.26, respectively. A significant elevation (P less than 0.01) of dhk PGF2alpha from 0.89 +/- 0.21 before labor to 6.16 +/- 2.40 at delivery was found in amniotic fluid. The hourly excretion of PGF2alpha MUM (microgram/hour) increased significantly from pregnancy levels to 1.06 +/- 0.45 in the first stage (P less than 0.01), to 7.67 +/- 4.31 (P less than 0.005) for the first 2 hours after delivery, and 2.37 +/- 1.08 from 2 to 12 hours after delivery (P less than 0.01). The excretion of PGF2alpha MUM decreased to pregnancy levels 12 hours post partum. These data indicate that during labor the production of PGF2alpha is remarkably increased.     

An endogenous growth factor extracted from the human ovary

A growth factor which stimulates DNA synthesis in resting mouse Balb/c 3T3 cells (3T3 cells) has been extracted from human follicular ovaries and partially purified. The dialyzed cytosol stimulated 3H-DNA synthesis in 3T3 cells dose-relatedly. When the extract was subjected to salting-out procedures with ammonium sulfate, there was found a 60% saturation cut containing growth promoting activity. Ion exchange on a cation exchanger of the active 60% cut produced an active fraction in the 1M NaCl elute. Gel filtration of ovarian cytosol yielded an active fraction that eluted between chymotrypsin (25,000 MW) and cytochrome C (12,400 MW). The data presented here indicate the presence of an endogenous growth factor in human ovary. The factor appears to be a basic protein, heat-labile and soluble in 40% or less ammonium sulfate, with a molecular weight of between 12,400-25,000. With respect to the biochemical characteristics, this growth factor is quite similar to the porcine ovarian growth factor previously reported.     

On-treatment C-reactive protein control could predict response to subsequent anti-PD-1 treatment in metastatic renal cell carcinoma

Objective

The aim of this study was to evaluate the clinical significance of the on-treatment C-reactive protein (CRP) status during systemic treatment as the predictive marker for the response of subsequent nivolumab monotherapy in patients with refractory metastatic renal cell carcinoma (mRCC).

Patients and methods

A total of 73 mRCC patients treated with nivolumab were retrospectively reviewed. We evaluated the serum CRP levels before and after molecular-targeted treatments. Patients whose CRP did not exceed baseline value were defined as the CRP-control group and the others were defined as the CRP-progression group. The clinical impact of CRP-control on the efficacy of nivolumab was assessed.

Results

Twenty-four patients (33%) were categorized into the CRP-control group. The CRP-control group patients (median PFS not reached) had significantly longer PFS than the CRP-progression group (median PFS 11.9 months, 95% confidence interval, CI 4.1–19.8, p?=?0.038). The CRP-control group had a tendency of longer OS from nivolumab initiation than the CRP-progression group (p?=?0.071). By multivariate analysis, the on-treatment CRP-control was the independent predictive factor for PFS (hazard ratio HR 0.37, 95% CI 0.14–0.99, p?=?0.047).

Conclusion

The on-treatment CRP-control could be the predictive factor for the efficacy of nivolumab in refractory mRCC patients.