Perspective on immune oncology with liquid biopsy, peripheral blood mononuclear cells, and microbiome with non-invasive biomarkers in cancer patients

Antibodies against immune checkpoint inhibitors such as anti-programmed cell death protein 1 (PD-1) and anti-programmed death ligand 1 (PD-L1) play a key role in the treatment of advanced lung cancer. To examine the clinical benefits of these agents, preclinical and clinical studies have been conducted to identify definitive biomarkers associated with cancer status. Analysis of the blood and feces of tumor patients has attracted attention in recent studies attempting to identify non-invasive biomarkers such as cytokines, soluble PD-L1, peripheral blood mononuclear cells, and gut microbiota. These factors are believed to interact with each other to produce synergistic effects and contribute to the formation of the tumor immune microenvironment through the seven steps of the cancer immunity cycle. The immunogram was first introduced as a novel indicator to define the immunity status of cancer patients. In this review, we discuss the progress in the identification of predictive biomarkers as well as future prospects for anti-PD-1/PD-L1 therapy

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Perspective on immune oncology with liquid biopsy, peripheral blood mononuclear cells, and microbiome with non-invasive biomarkers in cancer patients.

Antibodies against immune checkpoint inhibitors such as anti-programmed cell death protein 1 (PD-1) and anti-programmed death ligand 1 (PD-L1) play a key role in the treatment of advanced lung cancer. To examine the clinical benefits of these agents, preclinical and clinical studies have been conducted to identify definitive biomarkers associated with cancer status. Analysis of the blood and feces of tumor patients has attracted attention in recent studies attempting to identify non-invasive biomarkers such as cytokines, soluble PD-L1, peripheral blood mononuclear cells, and gut microbiota. These factors are believed to interact with each other to produce synergistic effects and contribute to the formation of the tumor immune microenvironment through the seven steps of the cancer immunity cycle. The immunogram was first introduced as a novel indicator to define the immunity status of cancer patients. In this review, we discuss the progress in the identification of predictive biomarkers as well as future prospects for anti-PD-1/PD-L1 therapy.

Metformin alters DNA methylation genome-wide via the H19/SAHH axis.

The molecular mechanisms underlying the antineoplastic properties of metformin, a first-line drug for type 2 diabetes, remain elusive. Here we report that metformin induces genome-wide alterations in DNA methylation by modulating the activity of S-adenosylhomocysteine hydrolase (SAHH). Exposing cancer cells to metformin leads to hypermethylation of tumor-promoting pathway genes and concomitant inhibition of cell proliferation. Metformin acts by upregulating microRNA let-7 through AMPK activation, leading to degradation of H19 long noncoding RNA, which normally binds to and inactivates SAHH. H19 knockdown activates SAHH, enabling DNA methyltransferase 3B to methylate a subset of genes. This metformin-induced H19 repression and alteration of gene methylation are recapitulated in endometrial cancer tissue samples obtained from patients treated with antidiabetic doses of metformin. Our findings unveil a novel mechanism of action for the drug metformin with implications for the molecular basis of epigenetic dysregulation in cancer. This novel mechanism of action also may be occurring in normal cells.

Phase II study of medroxyprogesterone acetate plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer.

BACKGROUND: Metformin, widely used in the treatment of type 2 diabetes mellitus, reduces the risk of cancer and relapse after treatment. Fertility-sparing treatment for endometrial cancer (EC) with progestin is associated with a high chance of disease regression, and the high relapse rate continues to be a problem. We assessed the efficacy of metformin in preventing recurrence after medroxyprogesterone acetate (MPA) as fertility-sparing treatment for atypical endometrial hyperplasia (AEH) and EC. PATIENTS AND METHODS: This phase II study enrolled 17 patients with AEH and 19 patients with EC limited to the endometrium (age, 20-40 years). MPA (400 mg/day) and metformin (750-2250 mg/day) were administered for 24-36 weeks to achieve a complete response (CR). Metformin was administered until conception, even after MPA discontinuation. The primary end point was relapse-free survival (RFS) after remission. We analyzed all efficacy end points in the full analysis set. RESULTS: The body mass index was ≥25 kg/m(2) in 27 patients (mean, 31 kg/m(2); range, 19-51 kg/m(2)), and the homeostasis model assessment for insulin resistance index was ≥2.5 in 24 patients (mean, 4.7; range, 0.7-21). Two patients showed progression at 12 weeks [6%; 95% confidence interval (CI) 2-18]. At 36 weeks, 29 (81%; 95% CI 65-90) patients achieved CR, and 5 (14%; 95% CI 6-29) patients achieved partial response. During a median follow-up of 38 months (range, 9-66 months) after remission, relapse was confirmed in three of the patients who had achieved CR (relapse rate, 10%). The 3-year estimated RFS rate was 89%. No patients experienced severe toxicity. CONCLUSIONS: Metformin inhibited disease relapse after MPA therapy. The combination of metformin and MPA in EC treatment should be studied further. TRIAL REGISTRATION NUMBER: UMIN 000002210.

The application of a newly developed linear stapler preloaded with tissue reinforcement for distal pancreatectomy in the management of ovarian cancer.

Advanced ovarian cancer may extend into the spleen, and even the pancreatic tail, in which a splenectomy associated with distal pancreatectomy is crucial for optimal cytoreduction. A new linear stapler preloaded with tissue reinforcement is currently introduced. We herein report the first three cases of successful application of this device for distal pancreatectomy performed during cytoreductive surgery for ovarian cancer.

The risk of post-molar gestational trophoblastic neoplasia is higher in heterozygous than in homozygous complete hydatidiform moles.

BACKGROUND: Complete hydatidiform mole (CHM) is a high-risk pregnancy for gestational trophoblastic neoplasia (GTN). Patients with CHM have a 10-30% chance of trophoblastic sequelae. CHM includes androgenic homozygous (monospermic) and androgenic heterozygous (dispermic) moles. It is controversial whether the risk of GTN is higher with heterozygous than with homozygous CHM. A prospective cohort study was conducted to assess risk of GTN in homozygous and heterozygous CHM using short tandem repeat (STR) polymorphisms, and a meta-analysis of previous reports. METHODS: Twenty-eight consecutive molar pregnancies were evacuated and followed by regular hCG measurements to detect GTN. Persistent GTN was diagnosed according to the International Federation of Gynecology and Obstetrics 2000 system. Cytogenesis of the mole was determined by STR polymorphisms of molar tissue and parental blood. A meta-analysis of the GTN rate from previous reports was conducted using Mantel-Haenszel methods. RESULTS: Of 28 molar pregnancies, 24 were homozygous and three were heterozygous CHM. The remaining mole was diandric triploidy (a partial hydatidiform mole). Of the 24 homozygous CHMs, six (25%) cases developed GTN and received chemotherapy. Meanwhile, all three cases (100%) of heterozygous mole developed GTN and needed chemotherapy. The GTN risk was higher in heterozygous (P = 0.029, Fisher's exact test) than homozygous moles. A systematic review revealed only five previous reports (with more than 15 cytogenetically diagnosed cases), and the pooled relative risk of persistent GTN for heterozygous mole was not significant (odds ratio, 2.0; 95% confidence interval, 0.98-4.07). CONCLUSIONS: Heterozygous CHM had a higher risk for GTN than homozygous CHM.

Serum YKL-40 as a marker for cervical adenocarcinoma.

BACKGROUND: The current study examined the clinical usefulness of YKL-40 in detection and prognosis of uterine cervical cancer. PATIENTS AND METHODS: Serum levels of YKL-40, cancer antigen 125 (CA 125), carbohydrate antigen 19-9 (CA19-9), and squamous cell carcinoma (SCC) antigen were determined by enzyme-linked immunosorbent assay in women with benign gynecologic disease (n=24), cervical malignancy (SCC, n=104; adenocarcinoma, n=37), and age-matched healthy controls (n=45). Immunohistochemical analysis for local YKL-40 expression was carried out on 28 adenocarcinomas. RESULTS: Receiver operating characteristic curve analysis showed that YKL-40 [area under the curve (AUC)=0.882] was significantly better at discriminating adenocarcinoma from healthy control than SCC antigen, CA 125, and CA19-9. For SCC, YKL-40 (AUC=0.898) carried out similarly to SCC antigen and was better than CA 125 and CA19-9. Using a cut-off YKL-40 value of 92.2 ng/ml, sensitivity of YKL-40 in stage I adenocarcinoma (68%) was higher than that of the other three markers (11%-21%). Tumor-associated macrophages showed immunoreactivity for YKL-40 in 2 of 28 adenocarcinoma tissue samples, but adenocarcinoma cells themselves were nonimmunoreactive in all samples. Multivariate Cox regression analysis revealed that elevated pretreatment YKL-40 levels predicted unfavorable prognosis, independent of International Federation of Gynecology and Obstetrics stage and age at diagnosis. CONCLUSIONS: Pretreatment serum YKL-40 level is a possible prognosticator of cervical adenocarcinoma.

Concurrent daily cisplatin and extended-field radiation therapy for carcinoma of the cervix.

The aim of this study was to assess acute toxicities of concurrent low-dose daily cisplatin and extended-field radiation therapy (EFRT) for carcinoma of the uterine cervix. Fifteen women with cervical cancer who were treated with concurrent daily low-dose cisplatin and EFRT were analyzed. Daily cisplatin dose was fixed to 8 mg/m(2), which was determined in the preceding phase I study using pelvic radiotherapy. Twelve patients underwent either combined external beam radiation therapy and intracavitary brachytherapy or external beam radiation therapy alone. Three other patients were treated with adjuvant chemoradiotherapy after surgery. A total dose of EFRT ranged from 40 to 45 Gy, with an additional boost to the gross tumor volume up to 50.4-55 Gy. A median total dose of cisplatin during entire radiation therapy course was 224 mg/m(2) (range, 200-240 mg/m(2)). In 14 of 15 patients (93%), daily cisplatin could be delivered continuously as planned without any modification. Administration of cisplatin had to be interrupted in only one patient for only 3 days. Fourteen patients developed grade 2 or worse leukopenia including five after treatment, grade 2 in four, grade 3 in eight, and grade 4 in two. Grade 3 thrombocytopenia was observed in three patients. Grade 2 or worse anemia was observed in 12. Three patients had grade 3 nonhematologic toxicities, diarrhea in two, and nausea/vomiting in one. Although moderate to severe hematologic toxicities are common, this study suggests that concurrent low-dose daily cisplatin and EFRT are feasible. A cumulative cisplatin dose of greater than 200 mg/m(2) during radiation therapy could be achieved by using daily cisplatin dose of 8 mg/m(2).

Detection of human papillomaviruses in cervical neoplasias using multiple sets of generic polymerase chain reaction primers.

OBJECTIVE: The aim of this study was to evaluate precisely the differences in the spectra of human papillomavirus (HPV) types detected by different generic primer pairs commonly used for detection of this extraordinarily heterogeneous virus. METHODS: Three sets of polymerase chain reaction (PCR) primers for the L1 open reading frame (ORF) and two sets for E6/E7 ORFs were used to detect HPVs in DNAs from 107 cervical tissues, including 77 cervical neoplasias. HPV types were determined by analysis of restriction fragment length polymorphisms (RFLPs) and nucleotide sequencing. RESULTS: A high overall detection rate of HPV in cervical neoplasias (76/77, 98.7%) was achieved by polymerase chain reaction (PCR) amplification with multiple sets of generic primers, while the detection rate for each individual primer pair varied from 48/77 (62%) to 70/77 (91%). Only in 34 of 77 cases (44%) were HPV DNAs positive for all sets of primer pairs. Further determination of HPV types by RFLPs and nucleotide sequencing showed inconsistencies between the PCR primer pairs used. CONCLUSION: Our study revealed that the HPV detection rate is critically affected by the choice of PCR primers, and that appropriate use of combinations of generic PCR primer sets followed by RFLP analyses is both necessary and sufficient for typing most HPVs in cervical lesions. More precise methods such as sequencing would be necessary in only a few cases.

Loop electrosurgical excision procedure (LEEP) during first trimester of pregnancy.

Loop electrosurgical excision procedure (LEEP) during pregnancy can be performed safely as in non-pregnant women and can replace traditional cone biopsy when performed in the first trimester.

Human papillomavirus-positive well-differentiated villoglandular adenocarcinoma of the uterine cervix: A case report and review of the literature.

OBJECTIVE: A case of well-differentiated villoglandular adenocarcinoma of the uterine cervix, which was positive for human papillomavirus type 18, was reported. METHODS: The patient was a 52-year-old multipara who was referred to our department because of an abnormal Papanicolaou smear. A 4.0-cm exophytic lesion involving the cervix was detected. She was staged as FIGO IIa and radical hysterectomy combined with bilateral pelvic lymphadenectomy was performed. In addition to histopathological examination of the resected tumor, immunohistochemical studies of estrogen and progesterone receptors were performed using monoclonal antibodies. Detection of human papillomavirus DNA was attempted by polymerase chain reaction using consensus primers. RESULTS: The tumor was a typical well-differentiated villoglandular adenocarcinoma involving the vaginal wall. Both estrogen and progesterone receptors were negative. Human papillomavirus type 18 DNA was detected in the resected tumor. CONCLUSION: 'This is the first report of a case of typical well-differentiated villoglandular adenocarcinoma which was positive for human papillomavirus.

GnRH agonist for intravenous leiomyomatosis with cardiac extension. A case report.

BACKGROUND: Intravenous leiomyomatosis with cardiac extension is an extremely rare disease. CASE: We recently treated a case of intravenous leiomyomatosis with extension from the inferior vena cava into the right atrium. Three operations--exploratory laparotomy, debulking of the pelvic mass and resection of the intracardiac leiomyoma--were performed. Since cells of the resected leiomyomatosis were estrogen receptor positive, we postoperatively administered GnRH agonist (leuprorelin acetate) for six months to prevent regrowth of the residual mass in the pelvis. The residual mass began to enlarge immediately after cessation of leuprorelin acetate. The same medication was readministered, and regrowth of the residual mass was completely inhibited for 15 months, until this writing. CONCLUSION: Intravenous leiomyomatosis seems to be hormone dependent, as in the case of uterine leiomyomas. In the absence of total resection, functioning ovarian tissue may remain. Therefore, long-term treatment with GnRH agonist may be useful in preventing recurrence of this disease.

Establishment and characterization of a new HPV-negative squamous cell carcinoma cell line (Yumoto) from the human uterine cervix.

A new cell line, Yumoto, derived from a squamous cell carcinoma of the uterine cervix, was established from serially transplanted tumor tissues in nude mice. Monolayer cultured cells were polygonal and formed pavement-like sheet. They showed a piling-up tendency and were devoid of contact inhibition. Electron micrographs demonstrated the presence of microvilli on the cell surface, abundant tonofilaments in the cytoplasm, and the connection with desmosomes. These electron micrographical characteristics of Yumoto cells were consistent with those of squamous cell origin. Yumoto cells were highly tumorigenic in BALB/c nude mice and produced a well-differentiated squamous cell carcinoma of keratinizing type which closely resembled to the original tumor tissues in nude mice. The presence of HPV DNA was examined using polymerase chain reaction and Southern blot analysis, but no known types of HPV DNA could be detected. Exons 2 through 11 of the p53 gene were analyzed by direct DNA sequencing, revealing a homozygous mutation at codon 281 in exon 8, GAC to CAC (Asp-->His). Furthermore, physical p53-gene deletion was demonstrated by dual-color fluorescence in situ hybridization. This cell line is useful for studying the carcinogenesis of cervical carcinoma and for investigating the biological characteristics of a HPV-negative and mutated p53 squamous cell carcinoma of the uterine cervix.

Primary transitional cell carcinoma of the fallopian tube: a case report and review of the literature.

Primary carcinoma of the fallopian tube is extremely rare and the preoperative diagnosis is often misdiagnosed as an ovarian carcinoma. We report a patient with primary carcinoma of the fallopian tube, strongly suspected preoperatively on the basis of characteristic clinical symptoms, elevated CA125 levels, and transvaginal sonography, computed tomography, and magnetic resonance imaging findings. The histology of fallopian tube carcinoma was demonstrated as transitional cell carcinoma. Extensive review of the literature showed that our case seemed to be the 14th case of primary transitional cell carcinoma of the fallopian tube.

[Reconsideration of evaluation criteria for physical fitness tests of a working population--comparing conventional and new evaluation criteria].

We set up new evaluation criteria values for grip strength, sit ups, trunk flexion, standing on one leg with eyes closed, whole body reaction and maximum oxygen uptake by age and by sex, by analysing data for about 50,000 people collected by the Japan Industrial Safety & Health Association. We thought that the conventional evaluation criteria values used in the physical fitness tests for a working population did not appropriately reflect the present conditions, and so we compared the new evaluation criteria values with the conventional evaluation criteria values. As a result, a very significant difference was noted in each test item. Then, by examining the quality of the data, change of the times, number of persons tested, and characteristics of the groups studied, all of which could have caused such differences, it was concluded that the proposed new criteria values would be appropriate for evaluation of the physical fitness of the current working population.