1 Akiramar

Rosario Giuseppe Dagata Essay

How do we define the essay? Ask a hundred writers and you’ll get a hundred answers—which is, of course, the whole idea. “You have to push yourself,” John D’Agata notes in A New History of the Essay, “push your peers, push your readers, push your critics, push your culture, push your forbears, push your instincts and beliefs and fears. You have to be willing to disrupt the history that you are already a part of. … That is what we owe to history: Risk. … And the courage to make the essay our own.” It is both a provocation and a coming to terms. What D’Agata is describing, after all, is the essay as essai (in Montaigne’s formulation): an attempt, a try, a framing of a question or a set of questions, an inquiry into consciousness or life. “So let’s lay it all out.” D’Agata writes. “I believe the goal of art is to break us all open, to make us all raw, to destabilize our understanding of ourselves and of our world that we might experience both anew, with fresh eyes, and with the possibility of recognizing something that we had not recognized before.”

A New History of the Essay is one of those projects: quixotic, ambitious, an attempt (that word again) to frame the genre by accretion and nuance. It’s been a decade-and-a-half in the making, a triad of anthologies, the last of which, The Making of the American Essay (Graywolf), has just been released. “I pitched an anthology to Graywolf when I was in my early twenties,” D’Agata—who runs the Nonfiction Writing Program at the University of Iowa—recalls by email, “at the same time they accepted my first book, Halls of Fame. The idea was for a single anthology that spanned all time and every culture. … Luckily, Fiona McCrae, the publisher, didn’t laugh me out of the press when I brought the idea to her. Instead, she basically said, ‘Ok … good idea. But you’re 23. … It might be safer to do a volume of essays that are a little more contemporary, a little more American and familiar to readers. And if that sells well, we can go back and do some other volumes.’” That initial collection, The Next American Essay, covered 30 years, beginning in the 1970s, and gathered work by, among others, Annie Dillard, Jamaica Kincaid, John McPhee, Joan Didion, and Sherman Alexie. It seems oddly fitting (in the sense that the essay is always circling, working back to front or even sideways) that, in regard to order of publication, the closing installment of the trilogy should have appeared first.

I’ve been wanting to discuss the essay with D’Agata since his book About a Mountain—a meditation on the relationship of fact and fantasy, built in part around nuclear waste disposal at Yucca Mountain, outside Las Vegas—came out in 2010. There, he entered what has become an ongoing controversy in nonfiction circles by admitting he’d reworked certain details, certain facts. “Although the narrative of this essay suggests that it takes place over a single summer,” D’Agata writes in his endnotes, “the span between my arrival in Las Vegas and my final departure was, in fact, much longer. I have conflated time in this way for dramatic effect only, but I have tried to indicate each instance of this below. At times, I have also changed subjects names or combined a number of subjects into a single composite ‘character.’” Two years later, he went even further in The Lifespan of a Fact, which reprints his Believer essay “What Happens There” with a Talmudic dialogue between the author and fact-checker Jim Fingal over the necessity, or desirability, of sticking strictly to the facts. “I’m not calling this ‘nonfiction,’” D’Agata argues late in that book, “and neither do I tend to call anything that I write ‘nonfiction,’ because I don’t accept that term as a useful description of anything that I value in literature. The only reason this is being labeled ‘nonfiction’ by your editors is because that is one of the two binary categories that editors allow in prose.” Let me say, so there is no mistaking my intent, that I agree with him, down to his dissatisfaction with the word “nonfiction”; as he writes on the very last page of The Making of the American Essay, “if fiction comes from fictio, the Latin word for “make,” then doesn’t that mean that non-fiction can only mean “not art,” prohibiting the genre from being able to do what every art medium does: make?”

What D’Agata has in mind, on one level, is to push the conversation, to throw a thought-bomb into the center of the room. That’s useful, crucial even, when it comes to essay writing, and it animates A New History of the Essay as well. At the same time, as he makes clear in our correspondence, it’s too straightforward a perspective, not nearly intricate enough. “On an aesthetic level,” D’Agata answers when I ask about it, “I don’t put a lot of stock in verifiability in nonfiction because for me there are more exciting ways to make nonfiction. But on a deeper level, on a (dare I say) spiritual level, I just don’t believe in the conceits of facts.” He continues: “I want an essay to surprise me. I want it to transport. I want to enter an essay in the here and now and then exit it in an entirely new place—a new place intellectually, emotionally, spiritually. I want to feel like I’ve been changed. So I’m looking for a transformative journey.” The essay, in other words, must work as art, not merely reportage; it must tell us something we don’t already know. The same is true of the genre as a whole, an idea D’Agata makes explicit in The Making of the American Essay and its precursors by essentially writing though the history of the form. Each essay is prefaced by a short text, more essay than explanation, offering aesthetic context, a framing mechanism. In one, introducing Gertrude Stein’s “If I Told Him: A Completed Portrait of Picasso,” he writes of the moment Ansel Adams learned to evoke emotion in a photograph. Another, which sets up Laura Riding’s “In a Café,” refers to Werner Heisenberg and his Uncertainty Principle; “Knowledge,” D’Agata observes there, “isn’t impossible, Heisenberg would insist. Knowing is.” If that seems a semantic distinction, involving the arrangement of letters and syllables … what’s vital is the middle territory it suggests, between perception and reflection, that the essay occupies.

For D’Agata—and for me also—this makes the question of accuracy, of verisimilitude, overstated at best and more fundamentally, beside the point. What’s important is imagination, the interplay between creativity and experience. It is this that makes the essay art. That has as much to do with how we think about the genre as it does with how we write within it; a central aspiration of A New History of the Essay is to stake out a lineage. The Making of the American Essay, for instance, includes an extract from Moby-Dick, configured as an essay. The Lost Origins of the Essay presents William Blake’s “The Marriage of Heaven and Hell” through a similar lens. Then, there are the deep sources, antecedents so ancient they predate genre, our inclination to categorize, to classify by form. The Lost Origins of the Essay incorporates Theophrastus of Eressos, Seneca, Sei Shonagon, T’ao Ch’ien; it begins with a list of rules for living (“The eyes of the slanderer always move like a spindle”; “[D]on’t ever buy a donkey that excessively brays, for this is the kind of animal that will knock you on your ass”) set down by the Sumerian king Ziusudra, dating from 2700 B.C. “Does the inclusion of these texts,” D’Agata emails, “mean that they’re essays? No. But my hope is that [their] inclusion … might encourage open-minded readers to question what an essay is. … What I cherish in any art form is the moment a project asks ‘what if?’ I think that there are a lot of fictions and poems that function essayistically, and I think that it’s not only fun to read them as such but also important to ask ourselves what that means.”

There’s more to it, of course, what we might classify as a tradition, although when it comes to a form as open as the essay, this both is and is not a contradiction in terms. When I met D’Agata, at a lunch this past November in Manhattan, he described visiting a town in Greece called Chaeronea, where he was shown a chair that had once, or so the legend went, belonged to Plutarch. The story is recounted in a reader’s note to The New History of the Essay, and the point (or one of them, at any rate) is that the chair couldn’t possibly have been his. And yet, what do we do with that myth, that supposition, that narrative, passed down across millennia, a thin tendril of connection between Plutarch’s time and ours? “I don’t know what history owes us,” D’Agata writes, “but … I have been thinking a lot about what we might owe to history.” When I ask him to elaborate, he responds, “What I love about history is that it tends to inspire in me a sense of camaraderie with something outside of myself. I love exploring the history of the essay because it invites me into an artistic heritage, an opportunity to feel like I am part of something that’s bigger than I am. We still don’t tend to teach the essay alongside poetry and fiction in English classes. You probably have to go to grad school before anyone’s going to seriously ask you to consider the literary qualities of an essay. And because of this, we leave school without the same appreciation for essays that we have for fiction or poetry. We are poorly trained essay readers. So I think the more we insist on claiming the legitimate essays that are in the essay’s history, the more likely it is that we’ll eventually start seeing those texts taught as essays, and thus start seeing readers more prepared to explore the contemporary essay with us.”

This is key, the notion that we are in it together, writers and readers, past and present, engaged in a conversation, a back-and-forth. This is why we read and write, and if that’s the case across the blurry bounds of genre, A New History of the Essay suggests it may be especially so in regard to this most fluid of forms. “I think,” D’Agata insists, “that it’s the writer’s responsibility to make sure that the literary heritage that they think they’re part of is known to the readership that they’re trying to communicate with. I think that’s fundamentally why these anthologies exist. It’s not why I started them, but I now think it’s what I was subconsciously thinking. It’s my way of saying, ‘These are my heroes. These are my kin. This is the context in which I want you to read my stuff.’”

1. Introduction

Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm of the serosal membranes lining the pleural cavity and has been linked with exposure to asbestos fibers [1].

MPM results in a very poor prognosis because of a limited response to standard treatments, and the median survival is approximately 6 to 12 months [1,2]. Many diagnostic biomarkers have been proposed for MPM, such as calretinin, ck5, podoplanin, mesothelin, osteopontin, hyaluronic acid, fibulin-3 and vascular endothelial growth factor [3], but unfortunately no reliable prognostic predictors are currently clinically applied.

The most important prognostic parameters for MPM include the histological subtype, sex and age at diagnosis [4]. Recent studies have highlighted the potential role of aquaporin-1 (AQP1) as an independent prognostic factor for improved survival in MPM patients exposed to asbestos [5,6]. AQP1 is a water channel protein found in cell membranes throughout the body and facilitates transcellular water transport [7,8]. In MPM cases, AQP1 has a role in cell proliferation, adhesion and motility, as well as in the modulation of pleural fluid volumes [9,10,11,12]. Furthermore, an increased expression of AQP1 evaluated by immunohistochemistry in asbestos-related MPM has been documented as a possible predictor of better prognosis. In detail, according to two recent studies on large series, high levels of immunohistochemically expressed AQP1, in over 50% of tumor cells, seemed to be linked with improved overall survival (OS) in these patients [5,6].

The majority of MPM cases are associated with exposure to asbestos fibers; however, other asbestos-like fibers have been considered agents to promoting MPM, such as erionite and fluoro-edenite (FE) fibers. [13,14,15,16,17,18,19,20,21,22,23]. The latter kind of fiber has raised the attention of the scientific community as a result of an increase in the incidence and mortality of MPM in Biancavilla, a small town on the southwest slope of Mt. Etna in Sicily (southern Italy), as revealed by an epidemiological survey conducted from 1988 to 1997 [24,25]. Environmental investigations showed the presence of FE fibers in the lava rocks excavated from a local stone quarry and used locally for about 50 years for house and road construction building purposes. In vitro, in vivo and epidemiological studies have demonstrated that FE fibers share size and morphological similarities with tremolite amphibolic asbestos fibers [13,14,15,16,17,18,19,20,21,22,23,24,25,26,27]. Therefore, FE fibers have been declared carcinogenic to humans by the International Agency for Research on Cancer (IARC; Lyon, France) [28].

In the present study, we investigated the immunohistochemical expression of AQP1 in a small but unique subset of MPM patients living in the Biancavilla area with documented evidence of environmental exposure to FE fibers. We also evaluated the correlation between AQP1 immunohistochemical expression and clinico-pathological parameters.

2. Results

The cohort of MPM FE-related patients was composed of six men and four women (mean age: 68.4 years; age range: 50–93 years). According to the World Health Organization (WHO) criteria, six cases were histologically classified as epithelioid, one was classified as sarcomatoid, and three were classified as biphasic subtypes [29]. In detail, two biphasic MPM cases from our series showed a slight predominance of the sarcomatoid elements (60% sarcomatoid, 40% epithelioid), while one case consisted predominantly of sarcomatous elements with scattered glandular elements. All clinico-pathological and immunohistochemical data are summarized in Table 1.

On parallel sections obtained from neoplastic tissue blocks, the immunohistochemical expression of AQP1 was documented by the linear (partial) and circumferential (complete) membranous staining not exclusively lining the apical cellular portion (Figure 1 and Figure 2).

Taking into consideration that only a score of ≥50% was considered as overexpression, six (60%) cases showed this AQP1 pattern; in this group, the Kaplan–Meier method showed a significant association of AQP1 overexpression with an increased OS, and the hazard ratio was 1.492 with a 95% confidence interval (CI) (0.432–5.153) (Figure 3; Table 2).

This difference in the median OS between high and low AQP1 expressors appeared statistically significant (p < 0.05).

Moreover, all MPM cases showed positive immunostains for calretinin, cytokeratin 5/6 and Wilms tumor protein (WT1), thus confirming the mesothelial histogenesis of FE-related MPM; by contrast, no immunoexpression was recorded for cytokeratin 7 or thyroid transcription factor (TTF1), consequently excluding a possible pulmonary origin of neoplasms.

No relationship emerged between AQP1 expression and other clinico-pathological variables.

3. Discussion

In the present study, we started a systematic analysis of a cohort of MPM patients living near the Biancavilla area, where the increased incidence and mortality from MPM have been attributed not to traditional asbestos fibers but to FE fibers.

In particular, we performed an immunohistochemical investigation on the AQP1 expression and distribution in MPM, also taking into consideration the suggested prognostic significance of AQP1 in asbestos-related MPM samples, as previously reported elsewhere [5,6,30].

In detail, AQP1 overexpression was revealed in 60% (n = 6) of MPM FE-induced cases, while the other 40% (n = 4) of cases exhibited a negative AQP1 expression or sometimes focal/non-uniform staining in less than 50% of the neoplastic mesothelial elements. This different AQP1 immunoreactivity appeared to be able to greatly influence the final outcome for MPM FE-induced patients; in fact, a significantly longer OS was found in the group with AQP1 overexpression, with delayed recurrences and death for the disease. By contrast, earlier recurrences and the worst prognoses were encountered in four patients who showed a low immunohistochemical expression of AQP1. In detail, a statistically significant association of AQP1 overexpression with increased survival was observed with a mean OS of 26.3 months for patients with ≥50% AQP1 expression versus a mean OS of only 8.9 months for patients with <50% AQP1 expression. This relationship between higher levels of AQP1 in MPM tissues and a better prognosis is quite surprising, as it appears to be in contrast to that reported in other tumors, including breast cancer, brain tumors, prostate adenocarcinoma, lung adenocarcinoma and carcinomas of the gastrointestinal tract, for which increased levels of AQP1 are associated with a poorer prognosis [12,31,32,33,34,35,36,37,38]. However, the role of AQP1 overexpression as an independent prognostic factor of a better prognosis has already been documented in MPM patients exposed to asbestos. Moreover, similar results to those observed for MPM have also been documented in receptor tyrosine-protein kinase erbB-2 (HER2)-positive early breast cancer, in patients with colorectal cancer and in biliary tract carcinoma, where AQP1 overexpression detected by immunohistochemistry was significantly associated with improved survival [39,40,41]. In the present study, AQP1 overexpression appeared as a promising prognostic tool for MPM patients; however, the relatively small number of MPM FE-induced patients followed indicates further validation is required to establish the definite prognostic value of AQP1 overexpression. Moreover, the principal limitation of the present study was the impossibility to retrieve the clinical stage for all studied patients. Therefore, our future perspective is to demonstrate the role of AQP1 as an independent prognostic marker also when it is corrected for disease stage.

We believe that in future studies, the clinical and prognostic implications of AQP1 expression should be integrated with other prognostic and predictive parameters. In this regard, the tumor immune microenvironment and the complex interrelations between tumor cells, mesenchymal stem cells and cells of the immune system have recently been found to play an important role in MPM tumorigenesis [42,43].

4. Materials and Methods

4.1. Sample Collection

Although the present research complied with the Helsinki Declaration, the non-interventional retrospective nature of our study did not require any informed consent by the local research ethics committee.

Adequate bioptic tissue from 10 patients who underwent video-assisted thoracoscopic surgery for MPM between 1996 and 2014 were retrospectively obtained from a larger series of 49 patients, for whom clinico-pathological reports and follow-up data were available.

The information for each patient came from the National Registry of Mesotheliomas (Renam). For each of the 10 analyzed subjects, the MPM diagnosis had been certified with cytological and histological exams.

All patients were residents in the town of Biancavilla or in nearby areas.

The histological diagnosis of MPM and histological subtypes were determined in accordance with the WHO criteria.

4.2. Laboratory Tests

Sections (4–5 μm in thickness) were cut from paraffin blocks using a microtome, mounted on sialinate-coated slides (Dako, Glostrup, Denmark) and stored at room temperature. The sections were stained with hematoxylin and eosin (H&E) and examined using a Zeiss Axioplan light microscope (Carl Zeiss, Oberkochen, Germany) for general morphological characterization and to highlight the presence or absence of structural alterations.

For diagnostic purposes, by immunohistochemistry, 4 μm sections of tissue samples from the same patients were stained using a Ventana Benchmark immunostainer (Ventana Medical Systems, Inc., Oro Valley, AZ, USA). In each case, a set of the following commercially obtained monoclonal antisera was applied: calretinin (SP65, Roche Diagnostics, Indianapolis, IN, USA; working dilution (wd) of 1:150), cytokeratin 7 (SP52, Roche Diagnostics; wd of 1:1000), cytokeratin 5/6 (D5/16B4, Roche Diagnostics; wd of 1:250), WT1 (6F-H2, Roche Diagnostics; wd of 1:250), and TTF1 (SP141, Roche Diagnostics; wd of 1:200).

Moreover, on parallel sections, AQP1 (B-11, Santa Cruz Biotechnology, Santa Cruz, CA, USA; wd of 1:100) was applied. In addition, as elsewhere suggested, the percentage of immunostained cells was assessed by semi-quantitative optical analysis according to a four-tiered system (0 = negative; <25% positive cells = focal staining; ≥25 to <50% positive cells = not uniform staining; ≥50% positive cells = diffuse staining); cases with over 50% immunoreactive neoplastic cells were considered as evidence of AQP1 overexpression, as reported elsewhere [30].

For the quantitative evaluation, the percentage of cells labeled by the antibodies was blindly assessed by two qualified anatomic pathologists (R.C. and G.T.). Only membrane labeling was considered specific, and this pattern of labeling was confirmed from 10 high-power (×400) fields (Figure 2A). In the case of dispute concerning interpretation, the case was reconsidered by a double-headed microscope to reach agreement. Positive and negative controls for AQP1 were used to test the specific reaction of the primary antibody used in this study at the protein level. Vascular endothelial cells and non-neoplastic mesothelial cells served as positive internal controls (Figure 2B). Negative controls, involving the omission of the primary antibody, were included.

Finally, representative photomicrographs were captured using a digital camera (AxioCam MRc5, Carl Zeiss).

4.3. Statistical Analysis

The OS was the primary endpoint for this study and was calculated from the date of diagnosis of the MPM FE-related patients and the date of death. The hazard ratio was calculated using the Mantel-Haenszel test. Cancer-specific survival analysis was performed using the Kaplan-Meier method, and for comparison of the survival curves, the Mantel-Cox log-rank test was used. A univariate model was evaluated for AQP1 expression; age, sex and histologic subtype were entered in the multivariate model. A p-value of less than 0.05 was considered statistically significant. Statistical analysis was performed using GraphPad Prism version 7 (GraphPad Software, Inc., La Jolla, CA, USA).

5. Conclusions

We contend that, together with the well-known suggested immunohistochemical mesothelial markers, a promising role should be attributed to AQP1, its overexpression being identified as a promising better prognostic predictor reliable also in cytopathology [38].

In conclusion, our study represents the first report that emphasizes the immunohistochemical expression of APQ1 occurring in MPM cases related to environmental exposure to FE fibers. We will continue our efforts in the already identified larger cohort to definitively establish the APQ1 prognostic significance.

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