Similar Histologic Type Research Articles

Comparative analyses define differences between BHD-associated renal tumour and sporadic chromophobe renal cell carcinoma.

Birt-Hogg-Dubé (BHD) syndrome, caused by germline alteration of folliculin (FLCN) gene, develops hybrid oncocytic/chromophobe tumour (HOCT) and chromophobe renal cell carcinoma (ChRCC), whereas sporadic ChRCC does not harbor FLCN alteration. To date, molecular characteristics of these similar histological types of tumours have been incompletely elucidated. To elucidate renal tumourigenesis of BHD-associated renal tumours and sporadic renal tumours, we conducted whole genome sequencing (WGS) and RNA-sequencing (RNA-seq) of sixteen BHD-associated renal tumours from nine unrelated BHD patients, twenty-one sporadic ChRCCs and seven sporadic oncocytomas. We then compared somatic mutation profiles with FLCN variants and RNA expression profiles between BHD-associated renal tumours and sporadic renal tumours. RNA-seq analysis revealed that BHD-associated renal tumours and sporadic renal tumours have totally different expression profiles. Sporadic ChRCCs were clustered into two distinct clusters characterized by L1CAM and FOXI1 expressions, molecular markers for renal tubule subclasses. Increased mitochondrial DNA (mtDNA) copy number with fewer variants was observed in BHD-associated renal tumours compared to sporadic ChRCCs. Cell-of-origin analysis using WGS data demonstrated that BHD-associated renal tumours and sporadic ChRCCs may arise from different cells of origin and second hit FLCN alterations may occur in early third decade of life in BHD patients. These data further our understanding of renal tumourigenesis of these two different types of renal tumours with similar histology. This study was supported by JSPS KAKENHI Grants, RIKEN internal grant, and the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research.

2303 Comparison of Laparoscopy and Laparotomy in Primary Cytoreductive Surgery of Advanced Epithelial Ovarian Cancer

Study Objective The aim of this study was to assess the surgical and oncologic outcome of laparoscopic primary cytoreductive surgery on advanced epithelial ovarian cancer in comparison with conventional laparotomy surgery. Design Retrospective cohort study. Setting University hospital in Korea. Patients or Participants Patients with FIGO stage up to III ovarian cancer undergoing laparoscopic primary cytoreductive surgery from January 2011 to March 2019 were matched to controls treated with laparotomic cytoreduction during the same period. Interventions Laparoscopic and laparotomic optimal cytoreduction. Measurements and Main Results The surgical and long-term outcome with advanced ovarian cancer were compared. The laparoscopic group (n=30) and laparotomic group (n=24) had similar age, BMI, stages, histologic type and final stage. There were no significant differences in operating time (P = 0.08) and blood loss (P = 0.34). The laparoscopic group exhibited significantly shorter hospital stay (P = 0.002) and time to start to treat adjuvant chemotherapy (P Conclusion Laparoscopic and laparotomic primary cytoreduction were similar in surgical and oncologic outcome. Laparoscopic primary cytoreduction in highly selected patients with advanced ovarian cancer was feasible and not to inferior in laparotomic surgery. Prospective randomized trials are required to evaluate the overall oncologic outcomes.

Gender Differences in the Recurrence Timing of Patients Undergoing Resection for Non-Small Cell Lung Cancer

Objective:This study was designed to visually represent postoperative recurrence patterns using event dynamics and to assess sex-based differences in the timing of recurrence for non-small cell lung cancer.Methods:We studied 829 patients (538 men, 291 women) with NSCLC who underwent complete pulmonary resection in 9 hospitals. Event dynamics with the use of life-table methods were evaluated, and only first events (distant metastases or local recurrence) were considered. The effects of sex, histological type, pathological stage, and smoking history were studied.Result:The resulting smoothed hazard rate curves indicated that the recurrence risk pattern definitely correlated with sex, with a sharp peak in the first year in men and a broad peak during the first 2 to 3 years in women. These findings were also confirmed by analyses according to pathological stage, histological type, and smoking history.Conclusion:The peak times of recurrence differed considerably between men and women. The delayed time of peak recurrence in women, associated with a longer disease-free interval within subsets of patients with similar disease stage, histological type, and smoking status, might account for the better survival in women.

Feasibility and outcome of primary laparoscopic cytoreductive surgery for advanced epithelial ovarian cancer: a comparison to laparotomic surgery in retrospective cohorts.

ObjectivesTo assess the feasibility and outcome of primary laparoscopic cytoreductive surgery on advanced epithelial ovarian cancer in comparison with conventional open surgery.Materials and MethodsPatients undergoing primary laparoscopic cytoreductive surgery (LCS) from March 2007 to December 2016 were matched to controls treated with laparotomic cytoreduction during the same period. Procedural data and outcomes were analyzed.ResultsThe LCS group (n = 64) and laparotomic group (n = 68) had similar age, BMI, stages, histologic type and grading. The LCS group exhibited significantly less operating time (P < 0.001), less intraoperative blood loss (P < 0.001), and shorter time to recover postoperatively (P = 0.002). No statistical difference was observed for the number of pelvic and para-aortic lymph nodes dissected (P = 0.326 and P = 0.151). Significant difference was observed in satisfaction of the cytoreduction (95.3% vs. 76.5%, P = 0.008). No significant difference were observed either in intra-operative or in post-operative complications between the two groups (P = 0.250). Three patients in the LCS group experienced intra-operative complications (4.7%) and were all treated laparoscopically. The conversion rate was 3.1%. No significant differences were observed in the progression-free survival and overall survival between the two groups during the medium follow-up of 18 months (P = 0.236 and P = 0.216). The 2-year and 3-year progression-free survival was 67.9%, 55.5% in LCS group and 53.8%, 33.3% respectively in the control group. The 2-year and 3-year overall survival was 95.8%, 88.7% respectively in the LCS group and 89.0%, 83.7% in the control group.ConclusionsPrimary laparoscopic cytoreductive surgery in some strictly selected advanced stages of EOC patients was feasible and safe, resulting in oncologic outcomes not inferior to those in open surgery.

Synchronous and Metachronous Malignant Epithelial and Lymphoid Tumors: a Clinicopathologic Study of 10 Patients from a Major Tertiary Care Center in Pakistan

Case reports and case series documenting unfortunate patients with more than one malignant neoplasm are rare but well established. While majority of such patients have two malignancies, cases with three or even four malignant neoplasms in the same patient have been published in literature. A number of factors influencing carcinogenesis have been implicated in such cases including exposure to large amounts of radiation, chemotherapy for the original malignancy; prolonged history of heavy smoking and exposure to other environmental carcinogens; aging; and underlying genetic alterations. Concomitant multiple malignant neoplasms may be synchronous-two or more malignant neoplasms histologically distinct from each other, arising in the same site and detected simultaneously (for example during the same hospital admission) or detected one after the other in sequence in a period less than 6 months; or metachronous-two or more malignant neoplasms of similar or distinct histologic type detected at different times (after an interval of greater than 6 months) in different anatomic sites. Any combination of malignant tumors can occur in the same patient for example carcinomas with other carcinomas, carcinomas with Non-Hodgkin or Hodgkin lymphomas, carcinomas with mesotheliomas, carcinomas with sarcomas etc. We have reported several cases with multiple malignancies during our practice, and these cases were composed of the different combinations described above. The aim of the present study is to document 10 such cases of combined carcinoma and Non Hodgkin lymphoma in the same patient which were diagnosed in our section.

Advances in Diagnosis and Treatment of Multiple Primary Lung Cancer

多原发性肺癌的发病率和检出率逐年升高。目前临床上诊断多原发性肺癌(multiple primary lung cancer, MPLC)主要参照Martini-Melamed标准和美国胸科医师协会(American College of Chest Physicians, ACCP)标准, 综合考虑临床表现、影像学特征、组织学类型和分子遗传学特征。组织学类型不同的MPLC诊断相对容易, 而组织学类型相同的MPLC诊断仍相当困难。DNA倍体分析、基因突变检测、微卫星多态性分析等分子生物学技术为MPLC的正确诊断提供了新手段, 可评估各病灶的克隆性关系, 帮助鉴别MPLC与转移。MPLC的首选治疗方案为根治性手术, 术式应考虑患者肺功能储备等因素, 选择肺叶切除、肺段切除或楔形切除; 对于不能根治性切除的病灶, 可综合化疗、放疗、立体定向放疗(stereotactic ablative radiotherapy, SABR)、射频消融(radiofrequency ablation, RFA)、分子靶向治疗等。

Abstract 5118: In-vivo non-invasive mitochondrial evaluation of 3D human skin

Abstract Alterations in metabolism are considered one of the hallmarks of cancer and have been associated with changes in mitochondrial organization. The latter is typically studied in two-dimensional cell cultures, using exogenous stains, and qualitative or at best semi-quantitative approaches. We have recently developed a method that relies on the automated analysis of high resolution intrinsic NADH two-photon excited fluorescence (TPEF) images of three-dimensional specimens to assess quantitatively mitochondrial clustering levels. The purpose of this study was to assess whether this approach could be extended to the analysis of endogenous TPEF images acquired in vivo from human subjects. In-vivo depth-resolved TPEF and SHG images were acquired in vivo using a MPTflex clinical tomograph (Jenlab) at 790nm excitation. The TPEF signal was detected over 410nm-650nm, whereas SHG signal was detected in the 385nm-405nm range. In this proof of principle study a patient with a basal cell carcinoma lesion and a healthy volunteer were imaged. All in vivo measurements were conducted according to an approved institutional protocol. Image processing was performed in ImJ and Matlab. A series of analytical steps were implemented to exclude from the analysis the nuclei and interstitial space and also the collagen and melanin-associated fluorescence. After the cytoplasmic isolation, we proceeded with an automated, thresholding and digital object cloning method we have previously described. The power spectral density of the corresponding two-dimensional fourier transform of each processed image was fit to a simple inverse power law decay expression to extract a parameter indicative of the levels of mitochondrial clustering, β. Increased β in our study represents more clustered mitochondrial formations. The detailed depth-dependent analysis demonstrates distinct patterns of the clustering for the healthy and diseased tissue examined. An increase in mitochondrial clustering from the superficial to the basal layer is detected for the healthy sample, an outcome in accordance to previously results observed in fresh biopsies from healthy cervical epithelia. Since both the cervical and the skin epithelium are of similar histological type our finding is not startling but rather encouraging. The mitochondrial clustering values of the BCC lesion on the other hand, are depth-invariant, which implies an undifferentiated cellular phenotype, finding consistent with both the cancerous nature of the lesion and previously published in vitro and ex-vivo studies. In conclusion, we demonstrate that characterization of mitochondrial organization is feasible within three dimensional tissues of human subjects. This approach offers the potential to observe dynamically subtle changes in mitochondrial dynamics that occur during cancer development or in response to treatment, which would enrich our understanding of tissue metabolism and could further enhance current diagnostic approaches. Citation Format: Dimitra Pouli, Mihaela Balu, Bruce Tromberg, Irene Georgakoudi. In-vivo non-invasive mitochondrial evaluation of 3D human skin. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5118. doi:10.1158/1538-7445.AM2015-5118

Abstract P2-10-07: Ep-ICD overexpression associates with poor prognosis in invasive ductal carcinoma

Abstract Background: Despite improvements in treatment strategies recurrence rates are still high among breast cancer patients. This may be attributed to heterogeneous nature of breast cancers representing varied morphologic and biological features, behavior, and response to therapy. Even among breast tumors of similar histologic type and grade, prognosis varies. Currently, breast cancer prognosis assessment methods have limited accuracy, are expensive, and in 20-30% of cases lead to over-treatment with adverse effects. None of the currently known prognostic factors has the ability to predict accurately which breast cancer patients are at high risk of recurrence. Thus, there is an increasing need for identification and validation of prognostic markers for assessment of risk for disease recurrence in breast cancer patients. Epithelial cell adhesion molecule (EpCAM) is a glycosylated, 30- to 40-kDa type I membrane protein, expressed in several human epithelial tissues and overexpressed in cancers, as well as in progenitors, normal and cancer stem cells, and is implicated in epithelial mesenchymal transition (EMT). Regulated intra-membrane proteolysis (RIP) of EpCAM by tumor-necrosis-factor alpha converting enzyme (TACE) results in shedding of its extracellular domain (EpEx) and release of intracellular domain, Ep-ICD, into the cytoplasm. Ep-ICD can signal into the cell nucleus by engagement of components of the Wnt pathway proteins including four and one half LIM domains protein 2 (FHL2), β-catenin and Lef, leading to activation of its oncogenic activity. Objective. Evaluate the prognostic significance of Ep-ICD overexpression in invasive ductal carcinoma (IDC). Methodology: Formalin fixed paraffin embedded (FFPE) tissue sections obtained from IDCs (n = 180) and normal breast tissues (n = 45) were used for immunostaining for Ep-ICD using specific monoclonal antibody. A semi-quantitative visual scoring of the immunostaining results for Ep-ICD based on percentage of tumor cells stained and intensity of scoring was used to compare the expression in breast cancers and normal tissues. Statistical analysis was carried out to determine the association of Ep-ICD expression with clinical outcome. Results: Among the 180 IDCs analyzed, nuclear Ep-ICD was observed in 75 tissues (41.7%) while cytoplasmic positivity was observed in 145 tissues (80.6%). In comparison, nuclear Ep-ICD localization was observed only in 11 normal tissues (23.9%) and cytoplasmic positivity was observed in 39 normal tissues (86.7%). The nuclear / cytoplasmic Ep-ICD expression has been correlated with at least 5 years follow-up data of 180 breast cancer patients after primary treatment. Kaplan Meier survival analysis showed significantly reduced 5 year disease free survival in IDC patients showing nuclear positivity (p &amp;lt; 0.001) or cytoplasmic positivity (p = 0.048). In Cox multivariate regression analysis, nuclear Ep-ICD overexpression emerged as an independent indicator of poor prognosis in IDCs (p = 0.008, H.R. = 81.18). Conclusion: Among invasive ductal carcinomas of the breast, nuclear Ep-ICD overexpression predicts reduced 5-year disease free survival. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-10-07.

Role of contemporary pathological diagnostics in the personalized treatment of cancer

Due to the developments of pathology in the past decades (immunohistochemistry and molecular pathology) classification of cancers changed fundamentally, laying a ground for personalized management of cancer patients. Our picture of cancer is more complex today, identifying the genetic basis of the morphological variants. On the other hand, this picture has a much higher resolution enabling us to subclassify similar histological cancer types based on molecular markers. This redefined classification of cancers helps us to better predict the possible biological behavior of the disease and/or the therapeutic sensitivity, opening the way toward a more personalized treatment of this disease. The redefined molecular classification of cancer may affect the universal application of treatment protocols. To achieve this goal molecular diagnostics must be an integral and reimbursed part of the routine pathological diagnostics. On the other hand, it is time to extend the multidisciplinary team with molecular pathologist to improve the decision making process of the management of cancer patients.

Evaluation of inadequate, indeterminate, false-negative and false-positive cases in cytological examination for breast cancer according to histological type

BackgroundWe previously investigated the current status of breast cytology cancer screening at seven institutes in our area of southern Fukuoka Prefecture, and found some differences in diagnostic accuracy among the institutions. In the present study, we evaluated the cases involved and noted possible reasons for their original cytological classification as inadequate, indeterminate, false-negative and false-positive according to histological type.MethodsWe evaluated the histological findings in 5693 individuals who underwent cytological examination for breast cancer (including inadequate, indeterminate, false-negative and false-positive cases), to determine the most common histological types and/or features in these settings and the usefulness/limitations of cytological examination for the diagnosis of breast cancer.ResultsAmong 1152 cytologically inadequate cases, histology revealed that 75/173 (43.6%) cases were benign, including mastopathy (fibrocystic disease) in 38.6%, fibroadenoma in 24.0% and papilloma in 5.3%. Ninety-five of 173 (54.9%) cases were histologically malignant, with scirrhous growing type, invasive ductal carcinoma (SIDC) being significantly more frequent (49.5%) than papillotubular growing type (Papi-tub) (P < 0.0001), solid-tubular growing type (P = 0.0001) and ductal carcinoma in situ (DCIS) (P = 0.0001). Among 458 indeterminate cases, 54/139 (38.8%) were histologically benign (mastopathy, 30.0%; fibroadenoma, 27.8%; papilloma, 26.0%) and 73/139 (52.5%) were malignant, with SIDC being the most frequent malignant tumor (37.0%). Among 52 false-negative cases, SIDC was significantly more frequent (42.3%) than DCIS (P = 0.0049) and Papi-tub (P = 0.001). There were three false-positive cases, with one each of fibroadenoma, epidermal cyst and papilloma.ConclusionsThe inadequate, indeterminate, false-negative and false-positive cases showed similar histological types, notably SIDC for malignant tumors, and mastopathy, fibroadenoma and papilloma for benign cases. We need to pay particular attention to the collection and assessment of aspirates for these histological types of breast disease. In particular, several inadequate, indeterminate and false-negative cases with samples collected by aspiration were diagnosed as SIDC. These findings should encourage the use of needle biopsy rather than aspiration when this histological type is identified on imaging. Namely, good communication between clinicians and pathological staff, and triple assessment (i.e., clinical, pathological and radiological assessment), are important for accurate diagnosis of aspiration samples.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7349809170055423

Concurrent breast stroma sarcoma and breast carcinoma: a case report

IntroductionBreast cancer is one of the most important health problems in the world and affects a great number of women over the entire globe. This group of tumors rarely presents as bilateral disease and, when it does happen, normally occurs within the same histological type. We report a rare case of concurrent bilateral breast cancer with two different histology types, a breast carcinoma and a breast sarcoma, in a 42-year-old woman referred to our hospital.Case presentationA 42-year-old Caucasian woman admitted to our institute in August 1999, presented with a nodule in the left breast of 3.0 × 2.5 cm, and, in the right breast, one of 1.0 cm, suspected of malignancy and with a clinically negative armpit. Biopsies had revealed invasive mammary carcinoma (right breast) and sarcoma (left breast). She was submitted to bilateral modified radical mastectomy. A histological study showed an invasive mammary carcinoma degree II lobular pleomorphic type with invasion of seven of the 19 excised axillary nodes in the right breast and, in the left breast, a sarcoma of the mammary stroma, for which the immunohistochemistry study was negative for epithelial biomarkers and positive for vimentin. Later, she was submitted for chemotherapy (six cycles of 75 mg/m2 5-fluorouracil, epirubicin and cyclophosphamide) followed by radiotherapy of the thoracic wall and axillary nodes on the left. Hormone receptors were positive in the tumor of the right breast, and tamoxifen, 20 mg, was prescribed on a daily basis (five years) followed by letrozole, 2.5 mg, also daily (five years). She presented no sign of negative evolution in the last consultation.ConclusionThe risk of development of bilateral breast cancer is about 1% each year within a similar histological type, but it is higher in tumors with lobular histology. In this case, the patient presented, simultaneously, two histologically distinct tumors, thus evidencing a rare situation.

TNM Stage Is the Most Important Determinant of Survival in Metachronous Lung Cancer

Distinguishing a metachronous lung cancer from a metastatic or recurrent lesion in patients with a prior history of non-small cell lung cancer is a challenging task. Previous studies have suggested histologic type and disease-free interval as criteria for diagnosing metachronous lung cancer. These factors may not be as relevant now that current imaging allows for earlier detection of tumors and with the rising incidence of adenocarcinoma. The purpose of this study was to reexamine the factors that determine outcomes in patients with a second primary lung cancer. A retrospective review of a prospective lung cancer database was performed to identify patients with metachronous lung cancer. Metachronous lung cancer was defined as any non-small cell lung cancer occurring after a prior resection regardless of disease-free interval or histologic type. The Kaplan-Meier method was used for survival analysis. The Mantel-Cox method was used to compare overall survival. Cox regression was used for multivariate analysis. Fifty-eight patients had metachronous lung cancer. Overall survival at 5 years was 66% (stage IA, 74%; IB, 59%; all other stages, 0%; p = 0.01). Seventy-two percent (42 of 58 patients) had similar histologic type. There was no difference in overall survival based on similar versus different histologic type (65% versus 73%; p = 0.77). Median disease-free interval was 42 months (range, 8 to 312 months). Disease-free interval was not a significant predictor of overall survival (p = 0.24). The extent of resection included wedge (36%, 21 of 58 patients), segmentectomy (24%, 14 of 58 patients), and lobectomy (40%, 23 of 58 patients), with no difference in overall survival (58% versus 60% versus 75%, respectively; p = 0.32). These data suggest that early tumor stage is the only significant determinant of survival after surgical treatment of metachronous lung cancer. Neither histologic type nor disease-free interval was of prognostic value. Limited resections may be adequate treatment.

Different papillomaviruses have different repertoires of transcription factor binding sites: convergence and divergence in the upstream regulatory region

BackgroundPapillomaviruses (PVs) infect stratified squamous epithelia in warm-blooded vertebrates and have undergone a complex evolutionary process. The control of the expression of the early ORFs in PVs depends on the binding of cellular and viral transcription factors to the upstream regulatory region (URR) of the virus. It is believed that there is a core of transcription factor binding sites (TFBS) common to all PVs, with additional individual differences, although most of the available information focuses only on a handful of viruses.ResultsWe have studied the URR of sixty-one PVs, covering twenty different hosts. We have predicted the TFBS present in the URR and analysed these results by principal component analysis and genetic algorithms. The number and nature of TFBS in the URR might be much broader than thus far described, and different PVs have different repertoires of TFBS.ConclusionThere are common fingerprints in the URR in PVs that infect primates, although the ancestors of these viruses diverged a long time ago. Additionally, there are obvious differences between the URR of alpha and beta PVs, despite these PVs infect similar histological cell types in the same host, i.e. human. A thorough analysis of the TFBS in the URR might provide crucial information about the differential biology of cancer-associated PVs.

A Correlative Study of Gliomas Using In Vivo Bromodeoxyuridine Labeling Index and Computer-aided Malignancy Grading

An in vivo bromodeoxyuridine (BrdU) labeling index (LI) was estimated in 43 cases of astrocytic tumors and mixed gliomas by one hour intra-operative intravenous infusion at a dose of 200 mg/m2and correlated with (a) histological grading using a computer aided malignancy classifier TESTAST-268; and (b) histological typing using WHO classification. The lowest BrdU LI was seen in pilocytic and gemistocytic astrocytomas followed by astrocytomas, anaplastic astrocytomas and glioblastoma multiforme in that order. Mixed oligoastrocytomas followed the pattern of their astrocytic counterparts. Tumors of similar histological type showed different BrdU LI values especially amongst astrocytomas and glioblastomas. A statistically significant difference in the BrdU LI was also noted between the higher TESTAST grades of astrocytomas (T III and IV) versus the lower TESTAST grades (T II). Unlike earlier reports in literature, in the present study the category of BrdU LI of5 contained only anaplastic astrocytoma and glioblastoma multiforme (TESTAST grades III and IV). Maximum spread of cases was seen in the BrdU LI category of 1–5, not only in terms of histological types but also TESTAST grades. Thus there appeared to be a positive trend of increasing BrdU LI values both with histological types and increasing TESTAST grades. Further, an interesting observation was that by using a combination of TESTAST grades and BrdU LI, the histologically homogenous glioblastoma group could be further subdivided into 4 categories which showed a trend towards prognostic correlation. Thus, this study though preliminary with number of cases being small in some groups, highlights the possible usefulness of combined histological typing, TESTAST grading and in vivo BrdU LI for prognostication of gliomas especially glioblastoma multiforme. Copyright 1999 W.B. Saunders Company Ltd on behalf of the Arányi Lajos Foundation

The role of autologous tumor cells in preventing lymphokine-activated killer cell inductionin vitro

Peripheral blood lymphocytes (PBL), when cultured in vitro in the presence of autologous irradiated tumor and interleukin-2 (IL-2), become more restricted in the spectrum of their cytotoxicity. The cells continue to exhibit cytotoxicity for autologous tumor cells and major histocompatibility complex (MHC)-concordant allogeneic tumor cells of similar histologic type but not for the natural killer target cell line, K562. Furthermore, the addition of autologous tumor at different time points after the initiation with IL-2 alone of conventional lymphokine-activated killer cell cultures modifies both the specificity and the degree of cytotoxicity of these lymphocytes for tumor targets. By varying the culture conditions it may be possible to generate killer cells that will exhibit similarly enhanced and more restricted antitumor effects in vivo.

Identification of transcripts encoding a parathyroid hormone-like peptide in messenger RNAs from a variety of human and animal tumors associated with humoral hypercalcemia of malignancy.

The syndrome of humoral hypercalcemia of malignancy (HHM) appears to be mediated in many instances by a parathyroid hormone-like peptide, which has recently been purified, sequenced, and cloned. Using a probe representing the coding region of the human PTH-like peptide, we examined by Northern analysis poly (A)+ RNA from a variety of human and animal tumors associated with HHM. Hybridizing transcripts were identified in mRNA from each of 12 human and each of four animal HHM-associated tumors, with a complex hybridization pattern observed in the human mRNAs and a relatively simple pattern observed in the animal mRNAs. Poly (A)+ RNA prepared from tumors of similar histological types unassociated with HHM failed to hybridize with the probe. Messenger RNA-dependent biological activity from the animal tumors was entirely eliminated in a hybridization-arrest experiment using a complementary oligonucleotide spanning the region of homology between human PTH and the PTH-like peptide. These findings indicate that the PTH-like peptide is associated with the syndrome of HHM in a wide spectrum of tumor types from a variety of mammalian species and that the PTH-like sequence in the proximal amino terminus of the peptide is highly conserved.

Successful pregnancy in primary glomerular disease

The course of 66 pregnancies was studied in 48 women with primary glomerular diseases. In all cases diagnoses were established by biopsy before pregnancy. They were: membranoproliferative glomerulonephritis in 16 patients, focal glomeruloesclerosis in 13, IgA nephropathy in 10, membranous nephropathy in seven and focal glomerulonephritis in two women. The clinical status of the nephropathy before conception was that 43 had only mild renal dysfunction, five had moderate renal insufficiency, serum creatinine (1.3 to 1.9 mg%), eight women had hypertension (150/100 mm Hg) and eight had nephrotic range proteinuria. Their clinical course was compared with a control group of 36 women with primary glomerular disease who did not become pregnant, and were matched for similar age, histological type, and status of nephropathy (renal function, blood pressure and proteinuria). After one year and at the end of the five year follow-up period, the incidence of hypertension, proteinuria, and renal failure was similar in the two groups. The fetal survival rate was 92%; 51 pregnancies ended in full-term delivery, with a mean birthweight of 3,242 +/- 320 g. There were seven pre-term deliveries (2,170 +/- 135 g), three small for gestational-age (2,340 +/- 135 g), two stillbirths and three spontaneous abortions. These patients had more pre-term deliveries (10.6%) and perinatal mortality (31%) than a normal population (5.5% and 9.6%, respectively). Blood pressure increased during pregnancy in 13 women; in 10 it was reversible, and in four it persisted after delivery. Ten gravidas developed increased proteinuria (reversible in six of them) and two others developed permanent impairment of renal function.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum Haptoglobin Levels in Mice with 7,12-Dimethylbenz[a]anthracene-induced Tumors

Serum haptoglobin (Hp) levels were determined periodically in mice treated with the carcinogen 7, 12-dimethylbenz[a]anthracene (DMBA). The magnitude and duration of the Hp response to tumors induced by DMBA were dependent on the tumor type; lymphocytic lymphomas elicted a minimal response, whereas mice bearing mammary carcinomas and stomach squamous cell carcinomas had high Hp levels which remained elevated throughout most of the period of tumor development. In the majority of mice with mammary carcinomas, the initial rise in serum Hp coincided fairly closely with the first appearance of palpable masses. Some variation in the magnitude of the Hp response was observed between individual mice bearing chemically-induced tumors of similar histological types.

In Vitro Reactivity of Splenic Lymphocytes from Normal and UV-Irradiated Mice Against Syngeneic UV-Induced Tumors

Abstract Skin tumors induced in mice by chronic ultraviolet (UV) irradiation are highly antigenic and are frequently immunologically rejected upon transplantation to normal syngeneic recipients. In this study we characterized this immune response with an in vitro microcytotoxicity test. Cytotoxic activity was present in the spleen cells of mice given a single injection of syngeneic UV-induced fibrosarcoma cells. After removal of adherent spleen cells, the remaining splenic lymphocytes were specifically cytotoxic for the immunizing tumor and showed no cross-reactivity with other syngeneic UV-induced or methylcholanthrene-induced tumors of similar histologic type. The level of cell-mediated reactivity against UV-induced tumors was quite high compared to that obtained with syngeneic tumors induced by methylcholanthrene, and the cytotoxicity was attributable to a population of θ antigen-bearing lymphocytes. With this in vitro test, we compared the response of normal mice, which reject a syngeneic tumor challenge, with that of UV-irradiated mice, in which the syngeneic UV-induced tumors grow progressively. After tumor cell inoculation, lymphocytes from the unirradiated (regressor) mice showed a high degree of cytotoxicity that reached a maximum level 8 days after injection. In contrast, no reactivity could be detected in the spleens of tumor-challenged UV-irradiated (progressor) mice.

Mediation of immune responses to tumor antigens in vitro by immune RNA.

It was shown that normal nonimmune C3H mouse spleen cells became specifically cytotoxic to chemically-induced syngeneic C3H tumor cells by incubation with xenogeneic I-RNA extracted from the lymphoid organs of specifically immunized guinea pigs. This response was specific for the tumor used to immunize the I-RNA donor. In a totally syngeneic system, we showed that syngeneic I-RNA extracted from the spleens of tumor-bearing rats mediated cytotoxic immune reactions which were directed specifically against the tumor-associated antigens of syngeneic rat tumor target cells. Active antitumor I-RNA synthesis in the lymphoid organs of I-RNA donor animals reached a maximum between days 14 and 21, depending on the route of administration and the nature of the immunizing tumor. Active I-RNA preparations were insensitive to treatment with deoxyribonuclease or pronase, but were inactivated by ribonuclease treatment; thereby indicating that the active moiety was one or more species of RNA. The active fractions of the I-RNA preparations had sedimentation values in sucrose density gradients of 12-16S, and comprised only a small fraction of the total RNA present in the lymphoid cells. Active antitumor I-RNA appeared to be localized in the cytoplasm of sensitized lymphoid cells, rather than in the nucleus. Lymphocytes from normal human donors as well as from cancer patients, when incubated with xenogeneic or allogeneic I-RNA, became specifically cytotoxic for human tumor cells in vitro. Crossreactivity among tumors of the same histologic type was observed, but not crossreactivity with tumors of other histologic types. Xenogeneic I-RNA extracted from the lymphoid organs of donor animals immunized either iwth tumor cells or normal tissues, following incubation with normal allogeneic lymphocytes, mediated cytotoxic immune reactions which were directed both against tumor-associated antigens and normal transplantation antigens. However, when autologous lymphocytes were used as effector cells, only immune reactions directed against tumor-associated antigens were observed. Allogeneic I-RNA extracted from peripheral blood lymphocytes of human cancer patients mediated specific cytotoxic immune reactions that were directed against common tumor-associated antigens shared by human tumors of similar histologic type. I-RNA's directed against "self" normal cell surface antigens appear to be recognized as self by lymphocytes, and immune responses against these self antigens are not elicited. On the other hand, I-RNA's directed against "nonself" tumor-associated antigens induce lymphocytes to effect specific antitumor immune responses. Our data are consistent with the hypothesis that I-RNA is an information-containing ribonucleic acid molecule capable of mediating immune reactions in vitro which are specific for the tumor-associated antigens of the tumor used to immunize the I-RNA donor.