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\begin{document}

\title{Pulmonary Micronodules Less Than 5 mm Detected At Presentation In
Patients With Osteosarcoma Do Not Effect 5 Year Overall Survival}



\author[1]{Reid Davison}%
\author[1]{Fadi Hamati}%
\author[2]{Paul Kent}%
\affil[1]{Rush Medical College of Rush University}%
\affil[2]{Rush University Medical Center}%


\vspace{-1em}



  
  \date{May 14, 2024}


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\selectlanguage{english}
\begin{abstract}
Within the last 25 years, high-resolution CT scans have revealed
pulmonary micronodules (nodules \textless{} 10 mm) not previously seen.
For osteosarcoma (OST), staging criteria, prognosis estimates, and
surgical recommendations have not yet changed to reflect this reality,
however, the frequent identification of micronodules on presentation
leaves clinicians in a difficult position regarding the need to biopsy,
resect, or follow the lesions and whether to consider the patient
metastatic or non-metastatic. We retrospectively collected data on all
newly diagnosed OST patients, age less than 50, treated at Rush
University Hospital over 25 years without pulmonary nodules
\textgreater{} 10mm to study the relationship between size and location
of micronodules discovered at the time of diagnosis and its relationship
to 5 year overall survival. Kaplan-Meier curves comparing 5 year overall
survival of patients with their largest nodules on presentation at each
size interval showed there was no difference in 5 year overall survival
in patients with any size nodule \textless{} 5 mm compared to patients
with no nodules. In addition, our study showed a survival advantage for
those who presented with 0 or 1 nodule (90\%) compared to [?] 2 nodules
(53\%). Additionally, patients who develop nodules after presentation
but within a year of diagnosis with any number of new micronodules had a
lower 5 year overall survival (93\% vs 63\%). Our data suggest surgery
may not be necessary for singular nodules \textless{} 5 mm identified on
presentation, and that these patients behave more like ``localized''
patients than metastatic patients.%
\end{abstract}%



\sloppy


\textbf{Pulmonary Micronodules Less Than 5 mm Detected At Presentation
In Patients With Osteosarcoma Do Not Effect 5 Year Overall Survival}

Davison, Reid MSE\textsuperscript{1}; Hamati, Fadi\textsuperscript{1};
Kent, Paul MD\textsuperscript{1,2}

\textsuperscript{1}Rush University School of Medicine

\textsuperscript{2}Pediatric Oncology, Rush University Medical Center

Corresponding author:

Reid Davison

1119 S Loomis St, Apartment 201

Chicago IL, 60607

(248)-622-0988

Reid\_m\_davison@rush.edu

\textbf{Word Count:}

Abstract: 247

Main text: 3380

Number of Tables: 1, Figures: 5, Supporting Information files: 0

Short running title: Lung Micronodules in Patients with Osteosarcoma

Keywords: Osteosarcoma, sarcoma, neoplasm metastasis, solitary pulmonary
nodule, survival, prognosis

Abbreviations:\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Abbreviation & Term\tabularnewline
\midrule
\endhead
OST & Osteosarcoma\tabularnewline
OS & Overall survival\tabularnewline
COG & Children's Oncology Group\tabularnewline
NCCN & National Comprehensive Cancer Network\tabularnewline
IRB & Institutional Review Board\tabularnewline
\bottomrule
\end{longtable}

\begin{enumerate}
\tightlist
\item
  Davison, Reid, Hamadi, Fadi, Kent, Paul, Fewer Than Two Pulmonary
  Nodules Identified On Presentation In Patients With Osteosarcoma Have
  No Effect On 5 Year Overall Survival, Connective Tissue Oncology
  Society, November 2020.
\item
  Davison, Reid, Hamadi, Fadi, Kent, Paul, Pulmonary Micronodules Less
  Than 5 mm Detected On CT At Presentation In Patients With Osteosarcoma
  Do Not Effect 5 Year Overall Survival, Connective Tissue Oncology
  Society, November 2020.
\end{enumerate}

\textbf{ABSTRACT}

\textbf{Background}

Within the last 25 years, high-resolution CT scans have revealed
pulmonary micronodules (nodules \textless{} 10 mm) not previously seen.
For osteosarcoma (OST), staging criteria, prognosis estimates, and
surgical recommendations have not yet changed to reflect this reality,
however, the frequent identification of micronodules on presentation
leaves clinicians in a difficult position regarding the need to biopsy,
resect, or follow the lesions and whether to consider the patient
metastatic or non-metastatic.

\textbf{Procedure}

We retrospectively collected data on all newly diagnosed OST patients,
age less than 50, treated at Rush University Hospital over 25 years
without pulmonary nodules \emph{\textgreater{}} 10mm to study the
relationship between size and location of micronodules discovered at the
time of diagnosis and its relationship to 5 year overall survival.

\textbf{Results}

Kaplan-Meier curves comparing 5 year overall survival of patients with
their largest nodules on presentation at each size interval showed there
was no difference in 5 year overall survival in patients with any size
nodule \textless{} 5 mm compared to patients with no nodules. In
addition, our study showed a survival advantage for those who presented
with 0 or 1 nodule (90\%) compared to [?] 2 nodules (53\%). Additionally,
patients who develop nodules after presentation but within a year of
diagnosis with any number of new micronodules had a lower 5 year overall
survival (93\% vs 63\%).

\textbf{Conclusions}

Our data suggest surgery may not be necessary for singular nodules
\textless{} 5 mm identified on presentation, and that these patients
behave more like ``localized'' patients than metastatic patients.

\textbf{Introduction}

Osteosarcoma (OST) is one of the most common non-hematopoietic bone
sarcomas with an annual incidence of 800 to 900 new cases in the United
Stated, with about half of these cases involving children and teens,
however people of any age can be affected\textsuperscript{1-4}. The
5-year overall survival rate of patients with OST ranges from 28\% to
70\%.\textsuperscript{5,6} This variation has been attributed to several
factors including metastasis at diagnosis, age, tumor location, tumor
size, and percent necrosis at primary surgery. The biggest improvements
are from adjuvant chemotherapy for OST patients classified as
``localized'' at diagnosis. Because the lungs are the most common site
for metastases, all patients with biopsy positive OST receive an initial
lung CT. However, it has not been well established how the discovery of
lung micronodules at the time of diagnosis effects the 5-year overall
survival or the management of patients with OST, since the dichotomy
between ``localized'' and ``metastatic'' has become blurred. Since 1996
the Children's Oncology Group (COG) and the National Comprehensive
Cancer Network (NCCN) have had an inconsistent and unvalidated
definition of ``pulmonary metastasis'' for subcentimeter lesions based
on initial CT imaging for OST.\textsuperscript{7} In patients newly
diagnosed with OST, the dichotomous classification of the disease as
``localized'' or ``metastatic'' has implications with respect to
surgical intervention, clinical trial participation, and prognosis.

The widespread adoption of high resolution CT scans in the last 25 years
has revealed pulmonary micronodules (defined as nodules \textless{} 10
mm) not previously appreciated\textsuperscript{8} and even experienced
radiologist have not been in agreement reading
micronodules.\textsuperscript{9} This category of nodules is important
as many consider lung nodules \textless{} 10mm as `non-measurable' and
cannot be used as `target lesions''.\textsuperscript{10} These lesions
may increase, decrease, or disappear without resolving the question of
their etiology, which may include transient atelectasis, recent
infection, or simply different degrees of sensitivity by the CT scanner
or the radiologist,\textsuperscript{10} in addition to metastatic
disease. However the frequent identification of nodules on presentation
leaves clinicians in a difficult position regarding the need to biopsy,
resect, or follow the lesions, and whether to consider the patient
metastatic or non-metastatic for purposes of study enrollment and
prognosis counselling.\textsuperscript{10} Osteosarcoma was selected as
our population of choice because surgery or biopsy, and not radiation or
chemotherapy, as in other sarcomas, is seen as the only curative
intervention for detectable lung lesions. In fact, open bilateral
surgical thoracic exploration is still recommended in many protocols.
The assumed, but unproven assertion is that surgical resection of tiny
lung nodules benefits the patient.

Staging criteria, prognosis estimates, and surgical recommendations have
not yet changed to reflect the increase in incidence of detecting lung
nodules. The ``New Response Evaluation Criteria in Solid Tumours:
Revised RECIST guideline (version 1.1)'' considers lung nodules
\textless{} 10mm as `non-measurable,' and many clinical trials require
RECIST criteria, ie, lesions \textgreater{}10mm for
enrollment.\textsuperscript{10} At the COG Annual Meeting in 2008, the
COG identified ``small pulmonary nodules'' as an area requiring
additional research; to date, however, the literature remains scant.
Additionally, the relationship between percent necrosis of the primary
tumor after 2 rounds of chemotherapy, which is an important prognostic
indicator for patients with OST,\textsuperscript{11-14} and lung nodule
management has yet to be examined.

The few studies that address this issue do not include all patients
under the age of 50 years, do not limit it to initial CT findings (which
is important because development of new lesions after initial
presentation is associated with progressive disease), do not limit it to
osteosarcoma (an important consideration since surgery is seen as
necessary for curative intent in OST, unlike many other sarcomas), nor
studied the effect of surgery versus observation of micronodules on
overall survival.\textsuperscript{15,16} For example, Kusam et al,
retrospectively studied 27 OST and 8 Ewings sarcoma patients, less than
25 years of age, who had biopsies of lung nodules presenting at any
time, and found that nodules \textgreater{} 5 mm predicted malignancy,
and up to 1/3 of those \textless{} 5mm when found in connection to large
nodules (\textgreater{} 5mm) were malignant but only two patients
with\emph{only} \textless{} 5mm nodules found to be malignant after
biopsy.\textsuperscript{17} We do not know if these micronodules were
present at diagnosis, therefore affecting management, or appeared later,
nor if the surgery effected survival. Ghosh, et al, retrospectively
studied 104 mostly adult OST patients with ``indeterminant nodules''
(defined as radiologist unable to call them ``benign,'' or
``metastatic,'' and non-calcified \textless{} 10mm), found survival for
``indeterminant'' nodules similar to those classified as ``without
metastasis,''\textsuperscript{18} but we do not know who had surgery and
which micronodules were not counted because they were initially read as
``benign'' or ``malignant'' or ``calcified.''

We sought to address some of these shortcoming using our own extensive
database of over 500 patients with osteosarcoma. Our institution has
maintained a combined adult and pediatric oncology sarcoma program for
40 years, with a longstanding combined weekly sarcoma tumor board, a
tradition of treating all OST patients under 50 uniformly according to
standard COG (or current pediatric) protocols, and a large number of
patients who did not get surgery for micronodules.

\textbf{Methods}

Under an IRB approved protocol (IRB number 16071805), we retrospectively
collected data on all newly diagnosed OST patients, age less than 50,
treated at Rush University Hospital over 25 years from 1995-2020 who had
an initial CT chest within two months of diagnosis. Subjects were
excluded if they had a history of other prior cancer treatment, any lung
nodule \emph{\textgreater{}} 10mm, other metastatic disease, or had
surgery on a lobe of the lung involved with any nodule on presentation.
Diagnosis date was defined as the date of biopsy proven OST. All
patients underwent similar treatment protocols following Children's
Oncology Group or National Comprehensive Cancer Network's standard of
care, which entailed the surgical excision of the primary tumor with
adjuvant and neoadjuvant chemotherapeutic treatment, consisting of
Methotrexate, cis-platinum, and doxorubicin.

Patient demographics (sex, age at diagnosis, primary tumor location,
type of primary resection surgery, percent necrosis, and dates last
known alive and dates of death were collected by reviewing electronic
medical records and patient charts. Initial CT scan reports within the
first month of diagnosis were identified and reviewed for number of
nodules, diameters of the nodules, as well as location and laterality of
the nodules. Micronodules were identified by reviewers if they were
under 10 mm in size and not explicitly labeled as benign by the
reporting radiologist. Huvos scores were calculated based on previously
defined criteria for categorizing percent necrosis of a patients'
primary tumor after 2 rounds of chemotherapy.\textsuperscript{19}

Over the 25-year inclusion period, corresponding to the era of
consistent high resolution CT scanning, patients who fit these criteria
were divided into cohorts based on the number of nodules on the initial
CT scan, the largest nodules on presentation, the number of lung lobes
involved, and the timing of nodule occurrence within the first year. In
addition an ``additive micronodule cohorts,'' based on RECIST 1.1 for
Solid tumors\textsuperscript{10} ``sum of target lesions at baseline''
paradigm, were constructed, where, for example, a patient with 3 mm and
4 mm nodules would be represented as 7 mm. Kaplan-Meier survival curves
for years of survival for these groups were also constructed and
compared between the cohorts. Data was analyzed using R-Studio version
(RStudio: Integrated Development for R. RStudio, PBC, Boston, MA), and
an alpha value of 0.05 was considered significant. Tarone-Ware tests
analyses were conducted to compare the 5-year survival between various
patient cohorts, and T-tests, chi squared tests, and 1- and 2-way ANOVA
analyses were conducted to compare patient characteristics between
groups.

\textbf{Results}

Over 25 years, there were 97 patients (mean age = 20, range = 6-49, 46F,
51M) that fit our inclusion and exclusion criteria, with 44 (45\%)
patients having nodules on presentation and 53 did not. Of the 78
patients who we had conformation at 5 years if they were alive or dead,
61 were still alive (78\%). Figure 1 is a Kaplan Meier curve comparing
the 5-year overall survival (OS) of patients with no nodules on
presentation and patients with at least 1 nodule \textless{} 10 mm on
presentation (p = 0.307). Of all patients fitting inclusion criteria
only, 26 (mean age = 20, range 7-47, 9F, 17M) total patients had either
a wedge resection, lobectomy, or radiofrequency ablation, with a
confirmed 5 year life expectancy of 64\% (14/22), and of those 26
patients, 8 had surgeries at any time involving the same lobe as the
nodule(s) on presentation and therefore these 8 were excluded from the
study. Of these 8 patients, however, only 1 patient had a lung surgery
immediately after identifying nodules (6 nodules, largest 8 mm) on CT at
presentation. Additionally, 2 of these 8 patients had surgeries on the
lobe(s) involved with nodules on presentation due to other new nodules
and not the original stable nodule. Of the remaining 18 patients who
underwent at least 1 lung surgery, 10 of them had nodules on
presentation and 8 did not. Of these 10 patient who had nodules on
presentation, none had a lung surgery within the first year.

On presentation, 4 patients had a 1 mm nodule, 18 patients had a 2 mm
nodule, 11 had a 3 mm nodule, 5 had a 4 mm nodule, 3 had a 5 mm nodule,
2 had a 6 mm nodule, and 1 had an 8 mm nodule. On presentation, 24
patients had 1 nodule, 14 patients had 2 nodules, and 6 had
\textgreater{}2 nodules.

\textbf{5 Year Overall Survival and Size of Lung Nodule \textless{} 10
mm on Presentation}

The 5-year OS, calculated using only patients who were confirmed alive
or dead at 5 years, for patients with no nodules on presentation was
83\% (34/41), and it was 82\% (14/17), 73\% (11/15), and 40\% (2/5), for
patients in the 1-2mm, 3-4mm, and 5-9mm groups, respectively. A
Kaplan-Meier curve comparing 5 year OS of patients with their largest
nodules on presentation at each size interval showed there was no
difference in 5 year OS in patients with any size nodule \textless{} 5
mm compared to patients with no nodules (figure 2a). Also those who
presented with nodules 5 - 9 mm had a significantly shorter 5 year OS
than those who had no nodules or 1-2 mm nodules on presentation (figure
2a). The mean number of nodules on presentation for the 1-2 mm, 3-4 mm,
and 5-9 mm groups were 1.5 (SD = 1.1), 2.4 (SD = 2.1), 1.7 (SD = 0.82),
respectively. ANOVA with Bonferroni multiple comparison indicated that
these three groups had similar number of nodules on presentation. There
was no difference in percent necrosis, between groups (p = 0.91).

Additional analysis of additive micronodules size showed that 5-year OS
rates for 0 mm total, 1-2 mm total, 3-4 mm total, and 5-20 mm total were
83\% (34/41), 91\% (10/11), 80\% (8/10), 53\% (8/15), respectively.
Kaplan-Meier curves indicated that there was no difference in 5 year OS
between any of the groups, however, the p values when comparing patients
with any additive nodule size 5-20 mm to 0 nodules and 1-2 mm nodules
were 0.067 and 0.070, respectively (figure 2b).

\textbf{5 Year Overall Survival and Number of Lung Nodules \textless{}
10 mm on Presentation}

The 5-year OS for patients with no nodules on presentation was 83\%
(34/41) and for patients with 1 and [?] 2 nodules had a 90\% (18/20) and
53\% (9/17) 5 year OS, respectively. A Kaplan-Meier curve indicates a
similar 5 year OS between patients with 0 and 1 nodule on presentation,
but patients with 0 and 1 nodules both have a significantly longer 5
year OS than patients with multiple ([?] 2 nodules), (figure 3a). There
was no difference in percent necrosis of the patient's primary tumor
among these groups (p = 0.61). The mean largest size nodule on
presentation for the 1 and 2 nodule groups were 2.7 mm (SD = 1.7) and
3.2 mm (SD = 1.2), respectively. A T test on the mean largest size
nodule between these two groups shows no difference in largest size
nodule (p = 0.22). However, when only including patient with a largest
nodule of [?] 4 mm, there was no significant difference between patients
with no nodules and patients with multiple nodules on presentation
(figure 3b, p = 0.090). Lastly, when only patents with Huvos scores of
3-4 were included, there was no difference in 5 year OS between patients
with no nodules \textless{} 10 mm on presentation and patients with
multiple nodules \textless{} 10 mm on presentation (Figure 3b, p =
0.18).

\textbf{5 Year Overall Survival and Number of Lobes with Lung Nodules
\textless{} 10 mm on Presentation}

Next, the number of lobes involved on presentation was analyzed. The
mean size of the largest nodule in patients with one and multiple lobes
involved were 2.6 mm (SD =1.6) and 3.4 mm (SD = 1.2), respectively.
These two means were not significantly different (p = 0.10). The mean
number of nodules in patients with one and multiple lobes involved were
1.1 (SD = 0.3) and 3.1 (SD = 1.9), respectively. These two means for
number of lobes were significantly different (p = 0.00049). Figure 4
indicates that patients with 2 or more lobes involved have worse 5 year
OS than those who presented with 0 or 1 lobe involvement. Of the
patients who were confirmed alive or dead at 5 years, 5 year survival
rates for 0 nodules, 1 lobe, and multiple lobes were 83\% (34/41), 87\%
(20/23), and 50\% (7/14), respectively.

\textbf{5 Year Overall Survival and Presence of Lung Nodules \textless{}
10 mm within 1 Year of Diagnosis}

The development of nodules within the first year after diagnosis was
analyzed. There were 44 patients (mean age = 20, 17F 27M) who had
nodules identified on presentation (defined by nodules detected within
the first 2 months), 19 patients (mean age = 21, 11F, 8M) who developed
nodules from 2 months to 1 year after presentation, and 34 patients
(mean age = 19, 18F 16M) who did not develop nodules within the first
year. Of the patients who developed their first nodules after 2 months,
12 had their first nodules while on chemotherapy and 7 developed their
first nodules after finishing chemotherapy. Figure 5a compares 5 year OS
between patients who did not have nodules [?] 10 mm within a year after
presentation, patients who had at least 1 nodule [?] 10 mm within the
first 2 months, and patients who did not have nodules in the first 2
months but had at least 1 nodule [?] 10 mm identified within the first
year after diagnosis. Of the patients who were confirmed to be alive or
dead at 5 years, the 5 year life expectancies were 96\% (24/25), 73\%
(27/37), and 63\% (10/16), respectively. There was no difference between
percent necrosis in patients' primary tumor for patients in these three
groups (p = 1.00) and there was no relationship between Huvos score and
patients in these three groups (p \textgreater{} 0.73). Kaplan Meier
curve comparing these three groups indicated that the 5 year OS for
patients with no nodules within the first year is significantly
different than patients with nodules \textless{}10 mm on presentation in
addition to patients with their first nodules \textless{} 10 mm from 2
months -- 1 year (p values = 0.017, 0.0027, respectively). When only
patients with Huvos scores between 3-4 were included, there was no
difference in 5 year survival between patients with no nodules
\textless{} 10 mm within the first year of diagnosis, patients with
nodules \textless{} 10 mm on presentation, and patients with no nodules
on presentation but developed at least 1 nodule between 2 months and 1
year (Figure 5b).

Lastly, the impact demographic categories have on micronodules
\textless{} 10 mm on presentation and within the first year were
examined on patients who did not undergo pulmonary intervention on the
lobe involved (Table 1). Patients 19 and older were more likely to have
nodules on presentation than patients 18 and younger. Otherwise, there
were no differences found on presence, size, or number of nodules on
presentation between all demographic groups investigated.

\textbf{Discussion}

The 5-year all-cause survival rate of patients with osteosarcoma has
been shown to range from 28\% to 70\%.\textsuperscript{1,2} This
variation has been attributed to traits such as metastasis at diagnosis,
age, tumor location, tumor size, and percent necrosis at primary
surgery. However, it has not been well established how the discovery of
lung micronodules at the time of diagnosis effects the 5-year overall
survival and management. Our retrospective, single institution study of
97 patients demonstrated a 78\% 5-year overall survival rate, which is
in agreement with historical ``localized'' OST 5 year survival
rates.\textsuperscript{20,21}

According to COG guidelines for OST, standard practice has been to
remove all visible nodules, however, these recommendations have existed
for 25 years, before high resolution CT clearly showed micronodules. In
our study the 5 year OS was no different for those who presented with
any number of nodules less than 5 mm in size, without surgical resection
on the nodule found on presentation, compared to having no nodules. At
presentation, for patients with an additive nodule size less than 5 mm,
there was also no difference in 5-year overall survival in patients
without surgical removal of nodules compared to patients with no
nodules. Our data suggest surgery (or biopsy) may not be necessary for
several small micronodules identified on presentation.

Patients with multiple nodules and lobes on presentation were shown to
have a decrease in 5 year OS compared to patients with 0 or 1 nodule or
lobe, however, when only patients with nodules \textless{} 4 mm were
included there was no difference between patients with multiple nodules
and no nodules on presentation. Patients with new micronodules after
presentation but before one year had a significantly lower 5-year
overall survival (63\%), between that of historical controls for
`localized' and for ``metastatic.'' Additionally, for patients with
Huvos scores of 3 or 4, the 5 year OS for a patient with osteosarcoma
did not significantly decrease with number of nodules \textless{} 10 mm
on presentation or discovering a nodule \textless{} 10 mm at any time
before 1 year, however, these comparisons involved a relatively small
number of patients and therefore further investigation are needed to
determine the role Huvos scores plays in lung nodule management.

There are a few limitations that need to be addressed. There were
generally less patients in the larger size and number of nodule groups,
and conclusions would be strengthened if patient numbers particularly in
these groups were increased. Additionally, our conformation of patients
being alive or dead was dependent on the presence of hospital records
indicating patient follow up, which could lead to longer recorded
survival times for those with continual follow up, however, this should
have been relatively similar between groups analyzed.

Other investigators have argued that pulmonary nodules \textless{} 5mm
in OST warrant biopsy/resection because of the 20-30\% incidence of
malignancy found on histologic review.\textsuperscript{17} However, just
because we can detect OST micro-metastasis, does it mean that it must be
removed? The concept of micrometastasis to the lungs has been well
established since Link et al, in 1986,\textsuperscript{22} long before
the availability of high resolution scanning, showed the tremendous
benefit of adjuvant chemotherapy in OST patients with ``negative'' lung
CT scans, proving that chemotherapy can and will eradicate sufficiently
small lung nodules in most patients that now, and in the future, we are
able to ``see.'' As imaging continues to increase sensitivity,
understanding the relevance of possibly clinically insignificant
subcentimeter nodules is critical to avoid excess treatment and possible
morbidity and anxiety for patients. It may be necessary to define an
``intermediate group'' between ``localized'' and ``metastatic'' with an
intermediate 5-year survival that has ``contaminated'' studies on
``localized'' or ``metastatic'' OST based on imprecise classification
paradigms. This may be based on (1) a solitary nodule less than
\textless{} 5mm (2) uni-lobar involvement (3) a new subcentimer
nodule(s) identified on presentation verses after presentation. This
group may benefit from different treatment, such as maintenance, and may
make it clear if a ``low risk'' group (no nodules or any number of 1mm
nodules and nothing developing in the first year) exists that could
benefit from less treatment. We hope that prospective COG studies that
include observation versus biopsy of micronodules can be performed to
help answer these questions.

\textbf{Conflict of Interest statement}

The authors of this manuscript certify that, to the best of their
knowledge, they have no affiliations with or involvement in any
organization or entity with any financial interest, have not received
and financial support from any pharmaceutical company or other
commercial source, or have any non-financial interest (such as personal
or professional relationships, affiliations, knowledge or beliefs) in
the subject matter or materials discussed in this manuscript.

\textbf{Acknowledgements}

The authors would like to thank all faculty, nurses, students, hospital
staff, and patient family members at Rush University for their efforts
in providing care to the patients who were a part of this study.

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\end{enumerate}

\textbf{Legends}

FIGURE 1 Kaplan Meier curve demonstrating survival probability vs years.
Groups are separated by presence of a nodule \textless{} 10 mm on
presentation and those who did not have any nodules on presentation.

FIGURE 2 Kaplan Meier curves demonstrating survival probability vs
years. Groups are separated by a) size of largest nodule \textless{} 10
mm or b) sum of nodules \textless{} 10 mm on presentation.

FIGURE 3 Kaplan Meier curves demonstrating survival probability vs
years. Groups are separated by a) number of nodules \textless{} 10 mm on
presentation b) number of nodules in patients with nodules [?] 4mm, or c)
number of nodules in patients with Huvos scores between 3-4

FIGURE 4 Kaplan Meier curves demonstrating survival probability vs
years. Groups are separated by number of lobes with lung nodules
\textless{} 10 mm on presentation.

FIGURE 5 Kaplan Meier Curves demonstrating survival probability vs
years. Groups are separated by number of nodules \textless{} 10 mm on
presentation

TABLE 1 Compares the nodule status of patients based on demographics. P
values generated using t tests and chi squared tests.\selectlanguage{english}
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