Impact of Cytoreductive Nephrectomy Following Nivolumab Plus Ipilimumab Therapy for Patients With Advanced Renal Cell Carcinoma.

BACKGROUND/AIM: CheckMate 214 study revealed that nivolumab plus ipilimumab combination therapy showed a strong and durable effect compared to sunitinib for patients with advanced renal cell carcinoma (aRCC). Most of the patients underwent previous nephrectomy before systemic treatment. We retrospectively investigated the clinical outcomes of Japanese patients treated with cytoreductive nephrectomy following nivolumab plus ipilimumab for aRCC. PATIENTS AND METHODS: Seventy-nine patients were treated with systemic therapy for aRCC between October 2018 and August 2021 at the Saitama Medical University International Medical Center. Ten of 61 patients treated with nivolumab plus ipilimumab underwent cytoreductive nephrectomy after the combined immunotherapy. RESULTS: The median overall survival and progression-free survival were 24.3 and 15.9 months, respectively. The objective response rate was 50.8%; 9.8% of patients had a complete response, and the median time to objective response was 3.2 (range=1.3-19.7) months. The estimated percentage of patients who sustained an objective response at 30 months was 73.0%. Twenty-three patients (74%) in the complete or partial response (CR/PR) group, 11 patients (52%) in the stable disease (SD) group, and two patients (22%) in the progressive disease (PD) group had immune-related adverse events of grade 3 or higher, respectively. For all 10 patients, cytoreductive nephrectomy following nivolumab plus ipilimumab treatment were completed safely. Three patients achieved a pathological complete response without viable cancer cells. Only two patients had residual lesions on images after deferred cytoreductive nephrectomy; the remaining patients achieved radiological CR. CONCLUSION: Cytoreductive nephrectomy after nivolumab plus ipilimumab treatment could be useful in a limited number of cases, possibly resulting in curative nephrectomy due to the durable therapeutic effect of immunotherapy.

Efficacy of Nivolumab Plus Ipilimumab in a Patient With Renal Cell Carcinoma Concomitant With Cardiac Metastasis: A Case Report.

BACKGROUND/AIM: Patients with metastatic renal cell carcinoma (RCC) with cardiac metastasis have had poor outcomes in the era of molecular targeted therapy. There are few reported outcomes for patients with cardiac metastasis of RCC treated with immune checkpoint inhibitors (ICIs). CASE REPORT: A 32-year-old female presented with metastatic RCC (unclassified type) with contralateral renal and cardiac metastases, as well as renal hilar lymph node metastases (cT4N2M1). An 18F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) computed tomographic (CT) scan was useful in diagnosing cardiac metastasis. Nivolumab plus ipilimumab achieved prominent shrinkage of almost all tumors except for one cardiac tumor. FDG-PET/CT scan also revealed the marked attenuation of FDG uptake in each tumor. In addition, a needle biopsy of the remaining primary renal tumor was pathologically observed to have no viable cancer cells. CONCLUSION: This successful case suggests that ICIs might provide a better outcome even for patients with cardiac metastasis of RCC, and that FDG-PET/CT scan might be useful for therapeutic assessment, as well as diagnosis.

Serum Lactate Dehydrogenase Before Nivolumab Treatment Could Be a Therapeutic Prognostic Biomarker for Patients With Metastatic Clear Cell Renal Cell Carcinoma.

BACKGROUND/AIM: The purpose of this retrospective study was to identify the predictive biomarkers of response to pretreatment for patients with metastatic renal cell carcinoma (mRCC) treated with nivolumab. MATERIALS AND METHODS: The subjects were 54 patients treated with nivolumab for mRCC with a clear cell component (mccRCC) between September 2016 and February 2018. We analyzed the impact of serum biomarkers (lactate dehydrogenase [LDH], neutrophil-to-lymphocyte ratio, and C-reactive protein) on patients treated with nivolumab. We adopted the International Metastatic Renal Cell Carcinoma Database Consortium prognostic model using six clinical factors (0=favorable, 1 or 2=intermediate, 3 to 6=poor risk groups, respectively). RESULTS: The prognostic risk classification (non-poor vs. poor) and serum LDH levels were correlated with the objective response of nivolumab treatment for mccRCC. Elevated serum LDH levels at baseline were an independent biomarker for progression-free survival (PFS) of mccRCC patients receiving nivolumab [HR=2.268 (95%CI=1.014-5.051), p=0.046]. Notably, high LDH levels were associated with a poorer PFS for patients in the favorable-risk group. CONCLUSION: Serum LDH levels at baseline before nivolumab treatment were associated with the objective response and clinical outcome of nivolumab treatment.

In-depth comparison of library pooling strategies for multiplexing bacterial species in NGS.

For bacterial genome sequencing, libraries from different strains are usually multiplexed in a single run. Normalized libraries are most often pooled in equal volumes, as recommended by next-generation sequencing platform manufacturers. This equal-volume strategy is well suited for multiplexing isolates from the same species. However, for runs involving multiple microbial species, an equimolar library pooling is more adapted because of the variation in bacterial genome size. To demonstrate its utility in clinical microbiology, we compared both equal-volume and equimolar strategies using a menu comprising 13 bacterial species involved in healthcare-associated infections. We show that equimolar pooling limits the retesting risk due to insufficient coverage depth, particularly when interspecies genome size difference is more than 2-fold. The use of this alternative strategy for multiplexing pathogenic bacteria should lead to more cost effective whole-genome sequencing applications in clinical microbiology.

Predicting pathogen-specific CD8 T cell immune responses from a modeling approach.

The primary CD8 T cell immune response constitutes a major mechanism to fight an infection by intra-cellular pathogens. We aim at assessing whether pathogen-specific dynamical parameters of the CD8 T cell response can be identified, based on measurements of CD8 T cell counts, using a modeling approach. We generated experimental data consisting in CD8 T cell counts kinetics during the response to three different live intra-cellular pathogens: two viruses (influenza, vaccinia) injected intranasally, and one bacteria (Listeria monocytogenes) injected intravenously. All pathogens harbor the same antigen (NP68), but differ in their interaction with the host. In parallel, we developed a mathematical model describing the evolution of CD8 T cell counts and pathogen amount during an immune response. This model is characterized by 9 parameters and includes relevant feedback controls. The model outputs were compared with the three data series and an exhaustive estimation of the parameter values was performed. By focusing on the ability of the model to fit experimental data and to produce a CD8 T cell population mainly composed of memory cells at the end of the response, critical parameters were identified. We show that a small number of parameters (2-4) define the main features of the CD8 T cell immune response and are characteristic of a given pathogen. Among these parameters, two are related to the effector CD8 T cell mediated control of cell and pathogen death. The parameter associated with memory cell death is shown to play no relevant role during the main phases of the CD8 T cell response, yet it becomes essential when looking at the predictions of the model several months after the infection.

Correlation with larval body size of mRNA levels of growth hormone, growth hormone receptor I and insulin-like growth factor I in larval torafugu Takifugu rubripes.

The full-length of insulin-like growth factor (IGF) complementary (c)DNAs encoded by igf-I and igf-II from torafugu pufferfish Takifugu rubripes were cloned in the present study. The deduced amino acid sequences of the two genes showed c. 80% identity each with those of Igf-I and Igf-II from other teleosts, respectively. Two growth hormone (GH) receptors, ghr1 and ghr2, were also cloned in silico using the T. rubripes Fugu genome database. The transcripts of T. rubripes igf-I were detected in slow muscle, heart, skin, gill, liver and intestine but not in fast muscle, spleen and testis of adult fish, whereas those of igf-II were found in all tissues examined. Subsequently, the accumulated messenger (m)RNA levels of igf-I and igf-II were investigated in an F(2) population derived from a male of an apparent fast-growing T. rubripes strain and a wild female T. rubripes together with those of other growth-related genes encoding Gh, Ghr1 and Ghr2, and with those of prolactin (Prl) and leptin (Lep) previously reported. The accumulated mRNA levels of igf-I, gh and ghr1 were significantly correlated to growth rate at larval stages in the population, but not for those of igf-II, prl, ghr2 and lep. Although it is unclear whether or not this phenotype is directly related to the heredity of the fast-growing strain, the findings suggest that the expression of igf-I, gh and ghr1 is involved in the regulation of growth rate at larval stages in T. rubripes.

A novel heat stress-responsive gene in the marine diatom Chaetoceros compressum encoding two types of transcripts, a trypsin-like protease and its related protein, by alternative RNA splicing.

We investigated the change of mRNA expression patterns in the laboratory-grown diatom Chaetoceros compressum under heat-stress conditions by mRNA arbitrarily primed (RAP) RT-PCR. Cells grown at 20 degrees C were subjected to heat treatment at 30 degrees C for 15 min and subsequently maintained at 20 degrees C for 8 h. Four genes including HI-5 were detected as heat stress-responsive genes by fingerprint analysis of RAP RT-PCR. Cloning for full-length cDNA sequences of HI-5 transcripts and related genomic DNA analysis revealed that two types of mRNA, HI-5a and HI-5b, were transcribed from the single HI-5 gene. While the HI-5a protein contained a catalytic domain characteristic to trypsin-like proteases, the HI-5b protein lacked this domain due to an insertion in the associated mRNA of 112 nucleotides; this insertion sequence contained a stop codon near the central region. Quantitative RT-PCR was performed to investigate the changes in expression levels of the two types of mRNA following heat treatment. The HI-5b transcripts were constitutively expressed in both unstressed and heat-stressed cells. In contrast, the number of HI-5a transcripts markedly increased in cells immediately after heat stress, reaching levels 19-fold higher at 8 h after heat stress than that in unstressed cells. These results suggest that RNA splicing plays a key role in heat stress-dependent expression of the HI-5a and HI-5b transcripts from the single HI-5 gene in the diatom.

Urinary bladder injury during inguinal herniorrhaphy in a renal transplant patient: report of a case.

The urinary bladder was injured in a renal transplant patient during inguinal herniorrhaphy. The bladder was mistakenly identified as an internal inguinal hernia. The protuberant bladder from the thin muscle layers was caused by a previous renal transplantation. The defect in the bladder was sutured by absorbable suture material, and the posterior wall of the inguinal canal was reinforced by artificial mesh. Surgeons performing inguinal herniorrhaphy on the grafted side in a renal transplant patient should thus be warned not to injure the bladder during the operation.

Insulinoma in a patient with non-insulin-dependent diabetes mellitus.

Insulinoma in a patient with pre-existing diabetes is exceedingly rare. Only a small number of well-documented cases have been reported in the world during the last 40 years. We describe a case with non-insulin-dependent diabetes mellitus who after seven years of sulfonylurea treatment experienced recurrent episodes of hypoglycemia. Endogenous hyperinsulinism was found and radiographical examination and transhepatic venous sampling confirmed an insulin secreting pancreatic tumor. After surgical excision of the tumor, patient was relieved from hypoglycemic attacks but required to initiate insulin injection for the treatment of hyperglycemia.

Growth hormone-releasing hormone (GRH)-producing pancreatic tumor with no evidence of multiple endocrine neoplasia type 1.

The characteristic features of a 48-year-old male presenting with isolated acromegaly caused by a GRH-producing pancreatic endocrine tumor bearing no relation to MEN1 was reported. The clinical features, laboratory findings, and sellar enlargement were improved after removal of the pancreatic tumor. The resected pancreatic tumor showed positive GRH immunoreactivity and contained abundant GRH mRNA. This tumor is extremely rare and to date only 10 cases have been reported. In the management of acromegaly, the measurement of GRH is recommended and the search for an ectopic source will prevent unnecessary and potentially ineffective pituitary surgery.

Sarcomatoid renal cell carcinoma with widespread metastases to liver and bones in a kidney transplant recipient.

A case of sarcomatoid renal cell carcinoma with widespread metastases to liver and bones in a cadaver renal transplant recipient is reported in this article. The patient underwent a kidney transplant at the age of 43 and was treated with various immunosuppressive agents after surgery. Twelve months after the transplantation, multiple tumors were found in the liver, and the patient died 8 months later. Pathological examination at autopsy revealed renal cell carcinoma with a sarcomatoid component in the right native kidney and metastases to liver and bones. It is unusual for renal cell carcinoma to undergo sarcomatous transformation and to metastasize to the liver before reaching other organs. We speculate that immunosuppressants may have altered malignant cell proliferation, invasion, and the form of metastasis in this case.

Primary malignant melanoma of the rectum.

We present a case of primary malignant melanoma arising in the rectum of a 71-year-old woman who had presented with intermittent rectal bleeding following bowel movement 2 months previously. Digital and sigmoidoscopic examination of the rectum revealed a 3 x 2 x 1 cm exophytic tumor with a granular surface in the rectum 35 mm from the dentate line. No increased pigmentation was detected. Biopsy revealed degenerated mucosa accompanied by severe infiltration of inflammatory cells, but no malignant cells. The tumor and normal mucosa surrounding the tumor was excised 12 days after the biopsy. Light microscopy revealed the tumor to consist of malignant melanocytes and showed that the tumor was surrounded by normal mucosa. Immunohistochemical staining with antimelanoma antibody and HMB-45 substuntiated the diagnosis. Clinical and laboratory examination excluded the presence of melanoma at sites other than rectum. The patient refused an abdomino-perineal resection of the rectum and combination chemotherapy was performed. She died 18 months after the initial operation due to local recurrences and metastases to pelvic lymph nodes, liver, and lung.

Preoperative intraperitoneal chemotherapy for gastric cancer, with special reference to delayed peritoneal complications.

Preoperative intraperitoneal (IP) chemotherapy was performed in 23 patients with gastric malignancies to inhibit peritoneal recurrence. Cis-diamminedichloroplatinum (CDDP) and mitomycin C (MMC) were administered intraperitoneally 3 days prior to surgery, at which time a very viscid peritoneum and mucinous intraperitoneal fluid were found in 100% and 83% of the patients, respectively. Inflammatory changes were microscopically observed in the subserosal layer of the resected stomachs and in the intraperitoneal fluid, but degenerative changes characteristic of cancer cells could not be seen. The 3-year survival rate of the stage III patients was 55.6%, and peritoneal recurrence was found in three of six patients with recurrence. Extensive adhesions were found in eight patients (34.8%) as a delayed peritoneal complication, and chronic bowel obstruction resulting from the adhesion developed in five patients (21.7%). Thus, we conclude that the administration of this IP chemotherapy demonstrated no definite antitumor effects or survival benefits, but was frequently associated with delayed peritoneal complications.

Effects of parathyroid hormone on pancreatic exocrine secretion.

The role of parathyroid hormone (PTH) and calcium on pancreatic exocrine secretion were observed using sham-operated and parathyroidectomized dogs. First, exocrine secretion of the pancreas stimulated with secretin and cholecystokinin octapeptide (CCK-8) was examined in vivo 3 weeks after parathyroidectomy. Secondly, perfusion experiments of isolated pancreas in the sham-operated and parathyroidectomized dogs were examined. In one experiment, volume of pancreatic juice and bicarbonate output, but not amylase output, was decreased in the parathyroidectomized dogs compared with those in the sham-operated dogs; no participation of calcium in exocrine secretion was revealed. In another experiment, high doses of PTH evoked increases of pancreatic juice and bicarbonate output without changing amylase output; as before, no participation of calcium in the exocrine secretion was observed. We conclude that (a) PTH increases volume of pancreatic juice and bicarbonate output, and (b) pancreatic exocrine secretion is modified by direct effect of PTH, and the pancreatic ductular cells, not the acinar cells, are the target for PTH.

[Treatment of liver metastases from gastric cancer].

Nine patients with liver metastases from gastric cancer were treated in our department since 1986. Hepatectomy was performed in 3 cases and hepatic arterial infusion chemotherapy was performed in 6 cases. In 3 patients in whom hepatectomy was performed, the extent of liver metastases showed 2 H1 and 1 H2. One has survived for 20 months, but the other 2 died after 5 and 7 months, respectively. In 6 patients in whom hepatic arterial infusion chemotherapy was performed, the extent of liver metastases was H3. These patients were treated with 5-FU.EPIR.MMC (3 cases), CDDP.MMC (1 case), MMC only (1 case) and 5-FU.ADM.MMC.CDDP (1 case). This treatment revealed a 50% response rate (CR 1, PR 2). The patient with CR has survived for 6 years and 2 patients with PR died after 8 and 12 months. The patient with CR showed high AFP level (55, 480 ng/ml), and 2 patients with PR showed high AFP level (24, 327 ng/ml) or high CEA level (3,903 ng/ml). The prognosis of hepatectomy for liver metastases from gastric cancer was not so good. Hepatic arterial infusion chemotherapy seemed to be a useful treatment for liver metastases from gastric cancer.

Clinical and immunological studies on patients with Graves' disease preoperatively treated with corticosteroids and iodides.

The purpose of this study was to evaluate the acute effects of corticosteroid and iodide preoperative therapy in patients with Graves' disease in terms of thyroid function and immunological parameters. The above combination was prescribed for 4 patients who had experienced severe side effects from antithyroid drugs (ATD) in order to reduce the possibility of post-thyroidectomy thyroid storm. Corticosteroids were employed daily for four days, and iodides were given daily for two weeks prior to thyroidectomy. The free T3 values decreased rapidly to euthyroid levels following the administration of both drugs, although the free T4 values were still much higher than normal in 3 of the 4 patients at the time of surgery. By comparison, 3 of 8 patients treated with ATD also had thyroid hormone levels above normal. Studies of lymphocyte subsets revealed that the percentage of helper T cells was significantly less in the corticosteroid-iodide treatment group than in the control and ATD groups. It is thus possible that postoperative thyroid storm might be prevented through corticosteroid-iodide therapy by virtue of the reduction of free T3 values to within the normal range by the time of surgery. The acute suppression of helper T cells was another results of this form of therapy observed.

Clinical evaluation of the response to surgical treatment of Graves' disease.

Included in this study are 513 patients with Graves' disease who underwent thyroidectomy between 1970 and 1983. The patients were divided into three groups by dividing the period in which the surgical procedures were done. The weight of the remnant of the thyroid gland and the incidence of surgical complications were collated for the patients in each group studied. Postoperative function of the thyroid gland was evaluated clinically and biochemically and compared with the remnant weight and total weight of the thyroid gland. The remnant weight was greatest in the first period and least in the third period. There were no differences between the frequencies of postoperative complications among the three groups in site of a remarkable decrease of the remnant weight in the third period. Remission of hyperthyroidism, including those with a latent hypothyroid state, was most frequently observed in the group in which the remnant weight was from 4 to less than 8 grams. These results indicate that the remnant weight appears to be one of the most crucial factors influencing the postoperative outcome; it thus seems appropriate to leave only small remnants of the thyroid gland (4 to less than 8 grams) at thyroidectomy. In our hands, surgical treatment is an effective and safe procedure for Graves' disease, although the precise mechanism for the remission induced by this procedure has not been elucidated.

[Therapeutic strategy for adenomatous goiter from the viewpoint of postoperative outcome and epidermal growth factor receptor study].

Adenomatous goiter (AG) is regarded as a benign tumor-like lesion. In the present study, both the postoperative outcome and the localization of epidermal growth factor receptor (EGF-R) were investigated to determine proper therapeutic modalities for AG. In this series, 377 surgical patients were studied. Immunohistochemical observation was carried out according to the ABC procedure. Results were as follows: 1) among the all 377 patients, primary cases were 343 and the remainder, 34 cases (9%), recurrent, 2) majority of the 34 recurrent patients showed multinodular goiter type occupying one whole lobe or both sides. Initial surgical strategy for these cases was only enucleation of the all nodules confirmed macroscopically, 3) coexistence of cancer in AG was observed in 18 cases (5%). Seventeen out of them were latent carcinomas found in the multinodular goiter, and 4) those multinodular patients associated with latent carcinoma revealed presence of EGF-R not only in the malignant lesions but also in the hyperplastic parts. These observations suggest that surgical treatment should be considered for multinodular AG patients. In addition, near-total lobectomy of the diseased side might be recommended as an operative procedure because of the prevention of postoperative recurrence and complications.

[Clinical evaluation of surgical treatment of Graves' disease].

Five hundred and thirteen surgical patients with Graves' disease from 1970 to 1983 were subjected to this study. They were divided into three groups by period in which operation was performed; 1st period from 1970 to 1974, 2nd from 1975 to 1979, and 3rd from 1980 to 1983. Postoperative thyroid function was evaluated. The weight of remnant thyroid was the greatest in the first period and the smallest in the third. There were no differences of frequency of postoperative complications among these periods in spite of remarkable decrease of weight of remnant thyroid tissue in the third period. Remission of thyroid function, was most frequently observed in the group of the remnant thyroid weight from 4 to 8 grams. Recurrence of hyperthyroidism was frequently observed in the group of the greatest weight of remnant thyroid and hypothyroid state was frequently observed in the group of the smallest remnant thyroid. These results indicate that the remnant thyroid weight may be one of the most crucial factors which influence on the postoperative functional state of patients with Graves' disease, and remnant thyroid tissue weighing from 4 to 8 grams may be the most appropriate in subtotal thyroidectomy.