Deletion of Slc6a14 reduces cancer growth and metastatic spread and improves survival in KPC mouse model of spontaneous pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is lethal. There is a dire need for better therapeutic targets. Cancer cells have increased demand for sugars, amino acids, and lipids and therefore up-regulate various nutrient transporters to meet this demand. In PDAC, SLC6A14 (an amino acid transporter (AAT)) is up-regulated, affecting overall patient survival. Previously we have shown using in vitro cell culture models and in vivo xenograft mouse models that pharmacological inhibition of SLC6A14 with α-methyl-l-tryptophan (α-MLT) attenuates PDAC growth. Mechanistically, blockade of SLC6A14-mediated amino acid transport with α-MLT leads to amino acid deprivation, eventually inhibiting mTORC1 signaling pathway, in tumor cells. Here, we report on the effect of Slc6a14 deletion on various parameters of PDAC in KPC mice, a model for spontaneous PDAC. Pancreatic tumors in KPC mice show evidence of Slc6a14 up-regulation. Deletion of Slc6a14 in this mouse attenuates PDAC growth, decreases the metastatic spread of the tumor, reduces ascites fluid accumulation, and improves overall survival. At the molecular level, we show lower proliferation index and reduced desmoplastic reaction following Slc6a14 deletion. Furthermore, we find that deletion of Slc6a14 does not lead to compensatory up-regulation in any of the other amino transporters. In fact, some of the AATs are actually down-regulated in response to Slc6a14 deletion, most likely related to altered mTORC1 signaling. Taken together, these results underscore the positive role SLC6A14 plays in PDAC growth and metastasis. Therefore, SLC6A14 is a viable drug target for the treatment of PDAC and also for any other cancer that overexpresses this transporter.

SLC6A14 deficiency is linked to obesity, fatty liver, and metabolic syndrome but only under conditions of a high-fat diet.

SLC6A14 is a Na+/Cl--coupled transporter for neutral/cationic amino acids, expressed in ileum and colon. A single-nucleotide polymorphism (SNP), rs2011162 (-22,510C > G), in SLC6A14 coding for the 3'-untranslated region (3'-UTR) is associated with obesity in humans. But the impact of this polymorphism on the transporter expression and its connection to obesity are not known. Our objective was to address these issues. The impact of rs2011162 (-22,510C > G) on SLC6A14 expression was monitored using a luciferase reporter. The link between Slc6a14 and obesity was investigated in wild type and Slc6a14-/- mice when fed a normal diet or a high-fat diet. The obesity-associated 3'-UTR polymorphism reduced SLC6A14 expression. With a high-fat diet, Slc6a14-/- mice gained more weight than wild type mice. With normal diet, there was no difference between the two genotypes. The gain in body weight with the high-fat diet in Slc6a14-/- mice was accompanied with metabolic syndrome. With the high-fat diet, Slc6a14-/- mice showed increased food intake, developed fatty liver, and altered plasma amino acid profile. The high-fat diet-associated hepatic steatosis in Slc6a14-/- mice showed male preponderance. We conclude that the 3'-UTR SNP in SLC6A14 associated with obesity decreases the expression of SLC6A14 and that the deficiency of SLC6A14 is linked to obesity. This is supported by the findings that Slc6a14-/- mice develop obesity, fatty liver, and metabolic syndrome. This connection is evident only with a high-fat diet. Therefore, dietary/pharmacologic interventions that induce SLC6A14 expression in the intestinal tract might have potential for obesity prevention.1.

Hereditary hemochromatosis promotes colitis and colon cancer and causes bacterial dysbiosis in mice.

Hereditary hemochromatosis (HH), an iron-overload disease, is a prevalent genetic disorder. As excess iron causes a multitude of metabolic disturbances, we postulated that iron overload in HH disrupts colonic homeostasis and colon-microbiome interaction and exacerbates the development and progression of colonic inflammation and colon cancer. To test this hypothesis, we examined the progression and severity of colitis and colon cancer in a mouse model of HH (Hfe-/-), and evaluated the potential contributing factors. We found that experimentally induced colitis and colon cancer progressed more robustly in Hfe-/- mice than in wild-type mice. The underlying causes were multifactorial. Hfe-/- colons were leakier with lower proliferation capacity of crypt cells, which impaired wound healing and amplified inflammation-driven tissue injury. The host/microflora axis was also disrupted. Sequencing of fecal 16S RNA revealed profound changes in the colonic microbiome in Hfe-/- mice in favor of the pathogenic bacteria belonging to phyla Proteobacteria and TM7. There was an increased number of bacteria adhered onto the mucosal surface of the colonic epithelium in Hfe-/- mice than in wild-type mice. Furthermore, the expression of innate antimicrobial peptides, the first-line of defense against bacteria, was lower in Hfe-/- mouse colon than in wild-type mouse colon; the release of pro-inflammatory cytokines upon inflammatory stimuli was also greater in Hfe-/- mouse colon than in wild-type mouse colon. These data provide evidence that excess iron accumulation in colonic tissue as happens in HH promotes colitis and colon cancer, accompanied with bacterial dysbiosis and loss of function of the intestinal/colonic barrier.

DFseq: Distribution-Free Method to Detect Differential Gene Expression for RNA-Sequencing Data.

Many current RNA-sequencing data analysis methods compare expressions one gene at a time, taking little consideration of the correlations among genes. In this study, we propose a method to convert such an one-dimensional comparison approach into a two-dimensional evaluation of the ratio of standard deviations (SD) of two constructed random variables. This method allows the identification of differentially expressed genes while controlling a preset significance level conditional on the read count mean-variance relationship. Meanwhile, correlations among genes are naturally accommodated due to the clustering of genes with similar distribution in the proposed σ-σ plot. The proposed distribution-free method is designated as DFseq, because it does not depend on a parametric distribution to fit read count. As a result, compared with parametric methods, DFseq can effectively handle genes with a bimodal-like distribution and/or genes with excessive 0 read counts, as well as genes with outlying observations. Besides, DFseq is an ideal platform for comparing performance of different differential gene expression detection methods.

Operative Management of T1b Gallbladder Carcinoma with Concurrent Hepatic Anastomosing Hemangioma.

We report a case of stage T1b gallbladder carcinoma with concurrent hepatic anastomosing hemangioma managed by operative resection. We review the work-up and surgical management of this patient. We also discuss the relevant literature of both gallbladder cancer and hepatic anastomosing hemangioma, a recently described and rare variant of capillary hemangioma.

Isolated Asymptomatic Metastatic Melanoma to the Colon: A Case Report.

Metastatic melanoma is generally rare, and the colon is a very rare metastatic site. We report a case of asymptomatic, isolated metastatic melanoma to the colon. Asymptomatic patients are usually not expected to have metastatic lesions in the colon. Ninety-five percent of large bowel metastases are identified during a postmortem examination. Our patient was found to have metastatic melanoma to the colon during a follow-up colonoscopy done for the surveillance of colon polyps. An awareness that patients with melanoma may possibly develop colon metastases is needed.

The Peridural Membrane of the Human Spine is Well Innervated.

There is evidence that low back pain may originate from a peridural membrane (PDM) at the inferior and medial aspect of neural foramen of the lumbar spine. The objective of this investigation was to determine if this membrane contains neural elements suggestive of sensory innervation with nociceptive function. Spines of four embalmed and three non-embalmed human cadavers were dissected using a sagittal approach to the neural foramen. Seventeen samples of the peridural membrane overlying the neural foramen were collected for immunohistochemistry (IHC) examination by light microscopy and transmission electron microscopy (TEM). Chromagin tagged antibodies to protein gene product 9.5 (PGP9.5) and S-100, and fluorescent antibodies to substance P and calcitonin gene related peptide (CGRP) were used to label neural structures in tissue sections cut from paraffin embedded blocks. This approach allows good visualization of all neural elements, small sensory, and nociceptive nerve fibers in particular. Neural elements were found in all samples. Marked presence of small nerve fibers was observed in 12 of 15 samples. IHC and TEM evaluation revealed myelinated as well as unmyelinated fibers in the peridural membrane. CGRP and substance P immunoreactive fibers indicative of nociceptive function were abundant. These findings confirm and expand evidence that the peridural membrane in human is well innervated and contains sensory nociceptive nerve fibers suggestive of a nociceptive function of the membrane.

Countries with high circumcision prevalence have lower prostate cancer mortality.

The present study determined the relationship of male circumcision (MC) prevalence with prostatic carcinoma mortality rate in the 85 countries globally for which data on each were available. MC prevalence in different countries were obtained from a WHO report and allocated to WHO categories of 81%-100%, 20%-80%, and 0%-19%. Prostatic carcinoma mortality data were from Globoscan, gross national income per capita as well as male life expectancy were from a World Bank report, and percentages of Jews and Muslims by country were from the Pew Research Institute and the North American Jewish Data Bank. Negative binomial regression was used to estimate prostatic carcinoma mortality rate ratios. Compared to countries with 81%-100% MC prevalence, prostatic carcinoma mortality rate was higher in those with MC prevalence of 0%-19% (adjusted OR [adjOR] =1.82; 95% CI 1.14, 2.91) and 20%-80% (adjOR = 1.80; 95% CI, 1.16, 2.78). Higher Muslim percentage (adjOR = 0.92 [95% CI 0.87, 0.98] for each 10% increase) and longer life expectancy (adjOR = 0.82 [95% CI 0.72, 0.93] for each 5 additional years) were associated with lower prostatic carcinoma mortality. Higher gross national income per capita (adjOR = 1.10 [95% CI 1.01, 1.20] for double this parameter) correlated with higher mortality. Compared with American countries, prostatic carcinoma mortality rate was similar in Eastern Mediterranean countries (adjOR = 1.02; 95% CI 0.58, 1.76), but was lower in European (adjOR = 0.60; 95% CI 0.50, 0.74) and Western Pacific countries (adjOR = 0.54, 95% CI 0.37, 0.78). Thus, prostate cancer mortality is significantly lower in countries in which MC prevalence exceeds 80%.

Hormone Replacement Therapy, Likely Neither Angel Nor Demon.

PURPOSE: A decline in breast cancer incidence has been attributed to the reduction in hormone replacement therapy (HRT) prescriptions since the publication of the landmark WHIT paper in 2003. Concurrently, a relationship between HRT and cerebrovascular disease incidence has also been suggested. No generalized analysis of HRT prescription rates and breast cancer incidence rates that included more than seven years of data. We hypothesized that detailed analysis of SEER data would clarify the relationship between HRT use and breast cancer incidence. Given the large decline in HRT prescription rates uncovered, analyses of potential complications were also conducted, with the understanding that a small effect or one limited to a subpopulation, such as a single race, might not be detected. METHODS: Incidence rates (per 100,000 women) and standard errors for ductal and lobular breast carcinomas, and endometrioid /endometrial carcinomas in women over 50 years were obtained from the Surveillance, Epidemiology, and End Results (SEER) database 1992-2012. From the Medical Expenditure Panel Survey 1996-2012 weighted counts and standard errors of hormone replacement therapy (HRT) prescriptions for women over 50 years were obtained. Using the National Hospital Discharge Survey (NHDS), 1996-2010 weighted counts and standard errors of femoral neck fractures, total hip replacements, acute myocardial infarctions, and cerebral infarctions were obtained for 50+ year men and women. Weighted counts and standard errors were divided by US census figures and multiplied by 100,000. Joinpoint regression was used to analyze rates. MAIN RESULTS: Beginning 2001, HRT prescription rates dropped dramatically, 2001-2012 AAPC -14.9 (95% CI -17.4, -12.4). Breast cancer rates, which began to decline in 1999, increased after 2003; 2012 rates were similar to those seen in 2001 for both ductal, AAPC 0.1 (-0.4, 0.6) and lobular, AAPC 0.5 (-0.4, 1.5), carcinoma. Endometrial carcinoma rates increased, 2001-2012 AAPC 3.5 (3.1, 3.8), arguing against a negative effect of HRT discontinuation of endometrial carcinoma. Tests for parallelism failed to detect APC differences among genders for femoral neck fractures (P = 0.24), for total hip replacements (P = 0.11), for myocardial infarctions (P = 0.10), or for cerebral infarctions (P = 0.19), precluding any assignment of general effect on these disorders by HRT. CONCLUSIONS: Using SEER data, we demonstrated that changes in breast cancer rates cannot be explained by HRT prescription rate changes.

Implications on clinical management of the small renal mass in patients 80 years of age and older based on a retrospective review of the SEER database.

PURPOSE: Incidental detection of small renal masses has increased in recent years with increased use of various imaging modalities, and a substantial number of diagnoses are made in the elderly population. Minimally invasive surgical procedures have previously been established as options with excellent long-term oncological results, but surveillance strategies have more recently been introduced as alternatives for surgical intervention. This study reviews the outcomes for elderly patients treated with observation or surgery for small renal masses in order to better elucidate optimal management strategies. METHODS: A total of 4647 patients from the SEER database met criteria for inclusion in this study. Cumulative incidences of RCC-specific mortality and non-RCC-related mortality were estimated, and frequency distributions by tumor size and surgical status were calculated. RESULTS: No difference in RCC-related mortality was observed among all treatment groups, including surveillance, for tumors 1-30 mm in size. RCC-related mortality was significantly lower for surgically treated patients for all other tumor size groups. Mortality unrelated to RCC was significantly higher in patients undergoing surveillance compared to those undergoing surgical intervention for tumor sizes 1-30 or 1-40 mm. CONCLUSIONS: A small renal mass in patients of 80+ years of age is best defined as up to 3 cm in size. For these patients, observation appears be a valid, if not preferential strategy. Patients 80+ years of age with renal masses greater than 3 cm still appear to benefit from surgical intervention.

Odds of death after glioblastoma diagnosis in the United States by chemotherapeutic era.

Bevacizumab (BZM) and temozolomide (TMZ) have been shown to be beneficial in the treatment of patients with glioblastoma. We sought evidence for the benefit of BZM in the general patient population at large. The Surveillance, Epidemiology, and End Results SEER database was queried for patients diagnosed with glioblastoma between 2000 and 2009, divided into a pre-TMZ era (January 2000-June 2003), a transitional era (July 2003-March 2005), a TMZ era (April 2005-October 2007), and a BZM-TMZ era (November 2007-December 2009). Binomial logit regression analyzed odds of death, taking into account age at diagnosis, tumor size, gender, race, marital status, radiotherapy, and extensive surgery. Compared with the pre-TMZ era, odds of death were decreased in the TMZ era by 12% (97.5% CI [confidence interval] 3-20%) 6 months after diagnosis and 36% (30-42%) a year after diagnosis; corresponding values for BZM-TMZ were 31% (24-37%) and 50% (45-55%). For era comparisons, decreases in odds of death were larger at 12 than 6 months; the opposite was true for extensive surgery and radiotherapy (P < 0.025, Wald χ(2) test, for each analysis). For both 6 and 12 month comparisons, odds of death in the BZM-TMZ era were lower than in the TMZ era (P < 0.025, Wald χ(2) test, for each analysis). The results provide evidence that TMZ positively impacted survival of glioblastoma patients and that the addition of BZM further improved survival, this lends support to the addition of BZM to the chemotherapeutic armamentarium. Evaluation of odds of death is an attractive alternative to Cox regression when proportional hazards assumptions are violated and follow-up is good.

Outcomes for patients who are diagnosed with breast and endometrial cancer.

The present study sought to determine the survival outcomes for women diagnosed with breast and endometrial cancer. Using SEER data, a population-based cohort study of women diagnosed with breast and endometrial cancer was conducted. Kaplan-Meier survival curves were created for disease-specific survival rates. A total of 2,027 women diagnosed with breast and endometrial cancer were identified. Of these, 1,296 (63.9%) developed breast cancer first and 731 (36.1%) developed endometrial cancer first. Regional lymph node involvement was significantly more common with a breast cancer diagnosis [522 (25.8%) women] compared with an endometrial cancer diagnosis [87 (4.3%) women] (P<0.05). Factors associated with decreased survival included a high tumor grade in endometrial cancer, nodal positivity and estrogen receptor-negative breast cancer (P<0.05 for each). There were 83 (4.1%) mortalities due to breast cancer, 63 (3.1%) mortalities due to endometrial cancer and 178 (8.8%) mortalities due to other causes (P<0.05). In conclusion, for women diagnosed with breast and endometrial cancer, the cumulative risk of mortality at five years following the second cancer diagnosis is nearly four times more likely to be due to breast cancer than endometrial cancer.

PSA screening and deaths from prostate cancer after diagnosis--a population based analysis.

BACKGROUND: The United States Preventative Health Task Force recently recommended prostate specific antigen (PSA) screening be abandoned, believing the results of prior studies failed to show benefits that outweighed risks. Prior analyses did not include a complete 10 year follow-up in their analyses. METHODS: SEER rate sessions were used to obtain for U.S. White and Black men age-adjusted incidence rates for prostate cancer, in total and by loco-regional and distant (D2) spread for 1983-2009, as well as for prostate cancer diagnoses with associated prostate cancer deaths within 10 years of diagnosis (incidence based mortality rates) for 1983-1999. The SEER-Stat Program was used to tabulate rate estimates and calculate standard errors. The Joinpoint Regression Program was used to provide estimates and 95% confidence intervals (CI) of annual percent changes (APC) and times at which APC changed (joinpoints), as well as to test for parallelism to see if APC's differed between groups of rates. RESULTS: All analyses showed a 1991-1993 joinpoint, consistent with an impact of PSA screening. Between 1991 and 1999, incidence based mortality rates showed a decline for Whites of 10.9% (CI 9.2%-12.7%) and for Blacks of 11.6% (CI 9.7%-13.4%); incidence based mortality and D2 spread rate curves were similar (P > 0.05, test for parallelism). CONCLUSION: Incidence based mortality declined by about 10% per year between 1991 and 1999 in a fashion similar to that of D2 spread, but not loco-regional spread or overall, incidence.

Endoscopic thyroidectomy: the development in a Chinese center.

BACKGROUND: Endoscopic thyroidectomy (ET) precludes the long cervical incision of the open procedure. Although endoscopy is an essential tool taught to almost every surgeon, its effective use with regard to thyroidectomy requires understanding its limitations pertaining to trauma and cancer, as well as an understanding of the advantages and disadvantages of the different endoscopic approaches. The development of an ET center in China is discussed here. METHODS: Overall, 235 patients who had undergone attempted ET in Qilu Hospital of Shandong University in China from August 2001 to September 2010 were evaluated. RESULTS: Of the 11 men and 224 women on whom the procedure had been attempted, all but seven successfully underwent ET, 145 (63.6%) via a modified anterior chest approach, and 83 (36.4%) via a breast approach. Age ranged from 17 to 52 years, with a mean of 34.5 years. Surgery was limited, in the case of masses, to lesions smaller than 6 cm ultrasonographically. All patients were followed for at least 3 months. The 24 and 48 hours Visual Analog Scale postoperative measurements were low. Complications included four cases of cutaneous emphysema, five seromas, four episodes of anterior chest discomfort, three transient laryngeal nerve palsies, and four episodes of hypocalcemia. The seven procedures that had been converted to an open procedure comprised two patients discovered at frozen section to have poorly differentiated thyroid carcinoma, two with tumors larger than 5 cm, and three with thyroiditis. CONCLUSIONS: ET is readily learned, provided the surgeon is competent at both laparoscopic technique and open thyroidectomy. Procedural advantages of an endoscopic approach include superior cosmesis and decreased invasiveness.

Prognosis of metastatic carcinoma of the lung in the bevacizumab era: comparison between the major histologic types of lung cancer.

BACKGROUND: In October 2006, bevacizumab was approved for treatment for patients with metastatic non-small-cell lung cancer other than squamous carcinoma. Our hypothesis was that the change in survival after approval of bevacizumab for metastatic adenocarcinoma would show differences from that of small-cell carcinoma and squamous carcinoma. METHODS: Data was obtained from the National Cancer Institute Surveillance Epidemiology and End Results (SEER) registry for patients with lung cancer diagnosed between January 2004 and November 2007. In addition to known characteristics predicting survival differences (histotype, age, gender, and race) we compared 1-year survival experience in those diagnosed before (January 2004-September 2006) and after (October 2006-November 2007) introduction of bevacizumab. RESULTS: Of 24,575 patients meeting criteria, 16,081 (65.4%) died within 1 y. Adjusted for age, gender, and race, patients with squamous carcinoma showed a 13% decline (95% CI 7%-20%) in survival times. By contrast, the 1% increment for adenocarcinoma and the 1% decrement for small cell carcinoma might well have been due to chance (P > 0.05 for each analysis). CONCLUSIONS: Life expectancy for metastatic adenocarcinoma (for which bevacizumab is approved) and metastatic small-cell carcinoma (bevacizumab not approved) did not change statistically. On the other hand, life expectancy for patients with metastatic squamous carcinoma (bevacizumab not approved) of the lung has declined since the approval of bevacizumab. This likely reflects increased classification of tumors previously diagnosed as poorly differentiated non-small-cell carcinoma as poorly differentiated squamous carcinoma. Hence, life expectancy of metastatic adeno, squamous, and small-cell-lung cancer has not improved after introduction of bevacizumab.

Outcomes for patients who develop both breast and colorectal cancer.

BACKGROUND: Patients diagnosed with both breast and colorectal cancer are not uncommon and will likely be seen more often as the population ages and treatment modalities improve. Survival outcomes for such patients have not been previously reported. METHODS: The 1988-2007 Surveillance, Epidemiology, and End Results data were used to identify women diagnosed with both breast and colorectal cancer. Disease-specific survival rates were compared. RESULTS: We identified 4,835 women who were diagnosed with both breast and colorectal cancer. Of these, 2,844 (58.8%) were diagnosed with breast cancer first and 1,807 (37.4%) were diagnosed with colorectal cancer first; 184 (3.8%) had synchronous cancers. At 5 years following the second cancer diagnosis, 163 (3.4%) died of breast cancer and 477 (9.9%) died of colorectal cancer (P < 0.05). Comparing primary site groups between years 1 and 5 after the second cancer diagnosis showed that the relative risk of death from breast cancer declined by 46%, though it did not reach statistical significance (P = 0.24), while it significantly increased by 46% for colorectal cancer death (P = 0.0004). These findings persisted regardless of patient age, stage at diagnosis, or breast tumor histology. CONCLUSION: For women diagnosed with both breast and colorectal cancer, the cumulative risk of death at 5 years following the second cancer diagnosis is 3 times more likely to be due to colorectal cancer than to breast cancer. Colorectal cancer specific mortality increases with time, while breast cancer specific mortality decreases with time. Consideration should be given to these findings when discussing prognosis and making treatment decisions.

A cost-benefit analysis of bariatric surgery on the South Plains region of Texas.

The regional economic burdens of obesity have not been fully quantified. This study incorporated bariatric surgery demographics collected from a large university hospital with regional economic and employment data to evaluate the cost of obesity for the South Plains region of Texas. Data were collected from patients who underwent laparoscopic gastric bypass and laparoscopic banding between September 2003 and September 2005 at Texas Tech University Health Sciences Center. A regional economic model estimated the economic impact of lost productivity due to obesity. Comparisons of lost work days in the year before and after surgery were used to estimate the potential benefit of bariatric surgery to the South Plains economy. Total output impacts of obesity, over $364 million, were 3.3% of total personal income; total labor income impacts neared $60 million: the losses corresponded to $2,389 lost output and $390 lost labor income per household. Obesity cost the South Plains over 1,977 jobs and decreased indirect business tax revenues by over $13 million. The net benefit of bariatric surgery was estimated at $9.9 billion for a discount rate of 3%, $5.0 billion for a discount rate of 5%, and $1.3 billion for a discount rate of 10%. Potential benefits to the South Plains economy of performing bariatric surgery more than outweigh its costs.

Nottingham grades of lobular carcinoma lack the prognostic implications they bear for ductal carcinoma.

BACKGROUND: Invasive lobular cancer (L) differs clinically and morphologically from invasive ductal cancer (D); differences notwithstanding, Nottingham grades are provided in both. This study compared 22,719 lobular carcinomas with 201,517 ductal carcinomas, dividing them into the grades: well differentiated (W), moderately differentiated (M), poorly differentiated (P), and ungraded to see if differences between comparable grades of lobular and ductal cancer were uniform, consistent with the notion the grading system provides similar information for both cancer subtypes. METHODS: The Surveillance, Epidemiology and End Results (SEER) database was used to limn relationships among grades, as respects proportions of patients with T3 tumors and nodal metastases, as well as cancer-specific survival. Taken into account were age, estrogen and progesterone receptor status, and the administration of radiotherapy. RESULTS: More lobular than ductal carcinomas were T3; grades were not homogenous, with the incidence rate ratio (IRR) comparing lobular and ductal carcinomas being 8.2 for well differentiated, 4.1 for moderately differentiated, and 2.48 for poorly differentiated. With respect to nodal metastases, the 1.16 W L:W D IRR (P < 0.05) was not explicable by chance, but both the 0.97 M L:M D IRR (P > 0.05) and the 0.96 P L:P D IRR (P > 0.05) could have been due to chance. As respects survival, neither the 1.4 P L:P D time ratio (TR) (P < 0.05) nor the 1.23 M L:M D TR (P < 0.05) could have been explained by chance; the 1.05 W L: W D (P > 0.05) might have been due to chance. CONCLUSION: Grades of lobular carcinoma imply different meanings than do grades of ductal carcinoma. Studies of breast cancer should not assume commonality with respect to grade.