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The Ancient Indians were the first to use pens around 5000 BCE. While these writing implements were primitive, typically consisting of hollowed out reeds that could hold a small amount of ink, which was generally soot in water with a plant gum binder, they were used for thousands of years and are still used today in certain parts of Pakistan. Around 500 BCE, pens started to be constructed from the wing feathers of larger birds, such as geese or swans. These pens, known as quill pens, were widely used until steel-nib pens were developed in the 1800s. Today, the most commonly used pen is the retractable ballpoint pen, the type often distributed by exhibitors at medical conventions or by local businesses. Being so widely available, and often free, pens are largely considered dispensable these days. While it is hard to imagine pens evolving much further, tech companies have envisioned pens with digital capabilities for decades. This year has been particularly exciting for the digital-pen tech sector, with many touting unique advancements yet reasonable price tags, making them more appealing to consumers. Digital pens are also finding a place in the healthcare sector, where they will no doubt increasingly leave their mark.

There are two types of digital pens: those that come with tablet PCs and function as an input device and the stand-alone digital pen, which has been around since the late 1990s when Anoto (

), a Swedish company, pioneered a paper that would allow a pen with a built-in camera to track itself. Stand-alone digital pens have come a long way since then. Let’s look at three of the available options and their features. 

This October, Livescribe released the Livescribe 4GB Pulse Smartpen (this pen was included in our Holiday Buying Guide last month), which contains “Pulse,” a small computer that captures handwritten notes while simultaneously recording audio, allowing them to be linked together. The user can tap on a note with the Livescribe Smartpen and can hear the conversation play back from the exact moment the note was written. One reviewer on Amazon.com commented that “the recordings are great, even in a large room,” whereas another said “audio quality is superb in small classroom settings; however, open wide to a large lecture hall and forget it.” Notes can be uploaded to a computer for storage, allowing keyword searches to be conducted and the notes to be shared with others. Another reviewer commented, “Another cool feature is the ability to upload your notes to a special location so that they may be shared with others—I’ve already tried doing this [as a test] with someone I know who is not very technologically savvy and, again, the results were very cool!” The Livescribe 4GB Smartpen holds approximately 400 hours of recorded audio and provides enough storage for apps to be added to the pen. Livescribe launched its Applications Store in November, which features several entertainment, education, and productivity tools, ranging from free to $99.99. The pen has a 4-star rating (out of 5) on 

The Logitech io2 digital pen resembles and feels like a regular ballpoint pen; there are no keys to press and no display. The pen is activated by removing the cap and deactivated by replacing the cap. The user writes on digital paper, as on regular paper. The pen has an ink cartridge so written or drawn notes are visible; however, the pen records all strokes with its optical sensor, and once the pen is placed back in its cradle, the notes can be downloaded to a PC. The io2 can store up to 40 pages of handwritten content, with each page defined as 29 lines of handwritten text, before the user needs to dock the pen into its cradle to offload the data. The io2 comes with free software that learns the user’s handwriting, including tables, shapes, and charts, allowing them to be turned into digital text that can be edited and used in any application. The pen has a 3.5-star (out of 5) rating on Amazon. One user commented, “The reason I like this so well is that I don’t have to take my laptop to meetings, and when I get an idea, I can just write it down as I always did.” Like the Livescribe pen, the Logitech pen also requires the use of special paper, which can be pricey. The io2 retails for $129.99 at 

Unlike the Livescribe and Logitech digital pens, the Mobile Digital Scribe captures notes or drawings written on any surface, eliminating the need for special paper, and stores them in its receiver. The user simply writes notes on regular paper with the Mobile Digital Scribe, which uses ordinary ink refills, and then offloads them onto a laptop at a time that is convenient. Notes can be exported in JPEG format, allowing them to be shared with others via e-mail or instant messaging. The pen comes with handwriting recognition software (OCR software), which turns handwritten text into digital text. The Mobile Digital Scribe has a 3.5-star (out of 5) rating on 

 and retails for $49.99. Unlike other digital pens, this pen works with Mac OS in addition to PCs. One drawback is that the receiver must be clipped to the paper that is being written on. One Amazon reviewer commented, “I agree with the reviewer who complained about the small spring-loaded clips which are meant to secure the ‘receiver’ to one’s paper. Securing the ‘receiver clip’ to the paper is important because even a slight movement of the paper in relation to the receiver can mess things up.”

Medicine is moving into a digital age, with a great push toward replacing paper records with electronic health records (EHRs). Digital pens may eventually serve as an integral component of EHRs, and several companies are offering digital pens as EHR components or as a workflow solution that can be integrated with an existing EHR or practice management system. Digital pens are also being used in certain medical settings and can be useful to both physicians and patients. Let’s examine some of the ways digital pens are being used in medicine.

Digital pens have largely been applied clinically in Europe. During MEDICA 2009, which took place in Düsseldorf, Germany, from November 18 to 21, a new telemedicine solution called DiabCareOnline from Germany’s Ontaris was highlighted. This solution used a blood glucose meter, patient diary, Anoto digital pen, and a mobile phone to enable faster communication of patient data. Patients monitored their blood glucose levels as before and recorded them in their diaries using the Anoto digital pen. The data were then transmitted via a mobile phone to the patient’s EHR and compared with the patient’s specific blood glucose targets. Anoto officials noted that this method allowed health issues to be addressed much more quickly and lowered the cost of care because much of the data analysis was handled remotely, which also allowed patients to spend more time away from the doctor’s office.

Digital pens have also been used to assess pain. In 2008, an article by Swedish researchers published in the International Journal of Medical Informatics (

) reported on the use of a pain diary, digital pen, and mobile Internet technology to assess pain in 12 palliative home care patients between December 2002 and September 2003. On a Visual Analogue Scale (VAS) for pain, patients reported an initial pain level of 35 mm or greater on a scale of 0 to 100 mm. Patients were instructed to record their pain intensity and the number of consumed extra doses of analgesics three times daily. Additional data were collected from interviews with patients and their families, questionnaires, medical records, and the system log. Overall, patients found the pain diary and digital pen easy to use for pain assessment, and the researchers noted that contact between patients and their caregivers improved, leading to an increased sense of security among patients. In addition, an assessment of the patients’ medical records showed a quick response to variations in their health status by means of changes in medical treatment.

It is not difficult to envision digital pens eventually being used to monitor side effects experienced by patients enrolled in clinical trials or to assess pain or side effects in those receiving cancer treatments. In many cases, side effects are the No. 1 reason for discontinuing treatment. If clinicians become aware of side effects earlier, strategies to minimize or eliminate them can be implemented sooner, which may allow patients to continue to receive treatment. While no trials in patients with cancer are currently applying digital-pen technology, one observational study being conducted in the United States is assessing the use of this technology to develop individual education plans (IEPs) for people with autism spectrum disorders (

). The researchers plan to use the pens to collect behavior data, chart progress, create forms, and facilitate communication within the IEP team. The investigators hypothesize that a digital pen- based system will facilitate educating children on the spectrum, while enhancing communication between schools and families and saving time and money in the process by eliminating cumbersome paper-and-pencil methods of developing IEPs.

In France, digital pen technology has been used to reduce the amount of time it takes for patients to receive mammogram results (

www.medicalnewstoday.com/articles/123750.php

), which has also cut down on the time other women must wait to receive breast cancer screenings. Although women who had mammograms that were positive for breast cancer received notice quickly, those with negative results had to wait 3 or 4 weeks to receive notifi cation because French law requires negative screenings to undergo a second expert review. By using digital-pen technology, the expert reviewers had access to the examining radiologist’s notes while assessing the mammograms, and facilities were able to process the results of the examinations more quickly. Through the use of digital-pen technology, screening centers in France have been able to meet the legal requirement of sending out results of breast examinations within 2 weeks.

Although healthcare is increasingly becoming digitized, many key processes remain ideally suited to paper. Several companies offer digital-pen services that allow physicians to continue to use paper forms, but also enable these forms to integrate instantly and seamlessly into existing EHR software. This allows healthcare professionals to populate these systems with timely data, which has been a challenge for many. Because using a digital pen is just like using a standard pen, there is no new technology for users to get used to. The time it takes to transfer clinical and other patient data to the EHR is also greatly reduced, and the risk of incorporating any errors is minimized. It is estimated that data re-entry can add 2 or 3 hours to the workload daily, reducing time that could be spend with patients.

Convention halls can be huge and tiresome to navigate, especially when you start toting all the paper and other items that get picked up along the way from the medical society, exhibitors, and others. Because digital pens are so compact and lightweight, they can be carried more easily to convention halls and meetings than laptops, which could remain at the hotel or in the office. The notes could then be off-loaded upon returning to the hotel or at a time that is convenient. If the user prefers to record sessions, Livescribe offers digitals pens that also serve as an audio recorder—the 4GB model (described earlier) and a 2GB model that holds 200 hours of recorded audio&mdash;which would allow any notes to be linked with the audio. If a particularly important session is recorded, the fi le could be shared with colleagues who may not be in attendance or who may have had to attend a different session.

While digital-pen technology has not taken off yet among the masses, there is little doubt that it eventually will, especially as the technology continues to improve and its cost decreases. The healthcare sector is especially well-suited to making use of this technology, especially as incentives are offered to migrate to EHRs. While populating EHRs may be cumbersome and time- consuming, requiring considerable data entry, digital pens may help bridge the gap between paper and electronic records by converting paper documentation into digital information. Patients may eventually complete their medical history and other forms using a digital pen, and healthcare providers may use digital pens to make notes in patient records, record encounter

Digital pens have also shown promise in improving patient care. European studies have shown that digital-pen technology may help treatment by making healthcare providers aware of important patient information in a timely fashion, such as blood glucose levels or pain levels, allowing them to act on this information more quickly. While no studies have been conducted assessing the use of digital pens to improve the care of patients with cancer, it is reasonable to conclude that this technology could have a positive impact in this population as well. Technology will continue to progress, and as it does, this platform’s mark will become more pronounced.                            

Articles

The Ancient Indians were the fi rst to use pens around 5000 BCE. While these writing implements were primitive, typically consisting of hollowed out reeds that could hold a small amount of ink, which was generally soot in water with a plant gum binder, they were used for thousands of years and are still used today in certain parts of Pakistan.

Digital Ink: Leaving a Mark on Medicine

Once a human malignancy metastasizes, currently available cytotoxic chemotherapy is usually palliative. While conventional chemotherapy regimens are associated with objective tumor regression, this only occurs in a minority of patients. Transient disease stabilization is common, but disease progression and ultimately death secondary to malignancy are expected. In most malignancies, conventional chemotherapy has reached a plateau in terms of response rate, progression-free survival, and most important, overall survival. While modest gains in response rate are achieved by combining a greater number of cytotoxic agents, increased toxicity is seen without improvement in survival. Recent discoveries in cellular and tumor biology have led to the development of novel targeted therapies that hold the promise of more selective anticancer treatment. One such molecular target is the Hedgehog signal transduction network.

The Hedgehog signal transduction pathway is named after a gene discovered by 1995 Nobel laureates Edward B. Lewis and Christiane Nüsslein- Volhard, who were screening for developmental genes causing body segmentation in 

(fruit fly). An experimental mutation in the Hedgehog gene caused fruit flies to develop as spikey balls reminiscent of a hedgehog, rather than with classic anterior-posterior segmentation. The Hedgehog signaling pathway plays a critical role in embryonic development, differentiation, and tissue polarity. Aberrant activation of this pathway occurs frequently in human cancer, whereas inactivation is associated with developmental disorders.

Hedgehog signaling is initiated by the binding of Hedgehog ligand to 

, a 12-transmembrane protein receptor. This ligand-receptor family includes three known ligands, Sonic Hedgehog, Indian Hedgehog, and Desert Hedgehog, and two highly homologous receptors, 

. The Hedgehog pathway is repressed under normal conditions. In the absence of Hedgehog ligand, 

, a 7-transmembrane protein receptor that is a key downstream mediator of Hedgehog signaling. Downstream of 

are the effector molecules of Hedgehog signaling: the Gli proteins (Gli1, Gli2, and Gli3), which function as zinc finger activators, repressors of transcription, or both. When 

 is inhibited, the Gli proteins are sequestered in the cytoplasm and bound to microtubules in a complex with the Fused (Fu) and Suppressor of Fused (SuFu) proteins; however, when Hedgehog binds 

 is relieved and the Gli proteins are released to enter the nucleus and induce transcription of Hedgehog target genes. There are a variety of downstream protein targets of Hedgehog signaling, including cyclins B1 and D1, p21, BCL-2, IL1R, and p53; these proteins are associated with mitosis, apoptosis, or resistance to therapy.

Considerable additional insight into the role of the Hedgehog pathway in vertebrate development and human cancers has come from the discovery that mutations of the 

 gene are associated with a rare hereditary form of basal cell carcinoma (BCC): the Gorlin syndrome, also known as the basal cell nevus syndrome.

The most common manifestation of this disorder is the early development of multiple BCCs, usually on sun-exposed areas. Affected persons are also at risk for medulloblastomas, usually by age 3; palmar and/or plantar cutaneous pits; odontogenic cysts and other skeletal abnormalities; genitourinary anomalies, usually calcified ovarian fibromas; and a predisposition to unusual neoplasms such as sarcomas, cardiac fi bromas, and meningiomas.

are loss- of-function nonsense mutations that lead to a constitutive activation of 

 gene is frequently absent (loss of heterozygosity), while the other copy contains mutations, most of which are predicted to interrupt the function of 

 null mutation exhibit a phenotype that resembles the basal cell nevus syndrome, including the development of BCCs, medulloblastomas, and rhabdomyosarcomas. These observations indicate that 

 may function as a tumor suppressor. Activation of the Hedgehog signal transduction pathway due to loss-of-function mutations of 

 in human BCCs disrupts his feedback regulation, leading to uncontrolled 

—mediated inhibition, which leads to an outcome similar to 

 inactivation. Endogenous activation of the Hedgehog pathway, through loss-of-function mutations of 

 or loss-of-function of SuFu, is found in BCCs, trichoepitheliomas, medulloblastomas, and subsets of prostate cancer.

Since 2003, a growing body of data has indicated that the Hedgehog pathway is involved in the development, growth, and metastatic potential of a variety of cancers, including those of the lung, gastrointestinal tract, pancreas, and prostate. Unlike genetic mutations of 

 seen in BCCs and medulloblastomas, these tumors often appear to have elevated Hedgehog ligand expression. In some preclinical systems, such as BCC models, inhibition of Hedgehog signaling is associated with objective antitumor responses; in others, such as pancreatic cancer murine xenograft models, there is little effect against the primary tumor site, but there is a marked reduction in the number and sites of metastatic foci.

There is also evidence that Hedgehog signaling is potentially important in maintaining the tumor stem cell compartment.

For example, in the murine pancreatic cancer model, inhibition of Hedgehog signal transduction by the plant alkaloid cyclopamine reduced the number of putative pancreatic carcinoma stem cells and markedly reduced the number of subsequent metastatic tumor foci, although in that system there was little effect on the primary tumor itself.

In light of the poor outcome with current treatment for advanced cancer, new agents exploiting novel mechanisms must be evaluated. One such agent is GDC-0449, an orally bioavailable inhibitor of Hedgehog pathway signal transduction, for which the results of a phase I clinical trial have recently been published.

 Of the 68 patients enrolled, 33 subjects with locally advanced or metastatic BCC were divided into three cohorts and given GDC- 0449 daily doses of 150 mg (n = 17), 270 mg (n = 15), and 540 mg (n = 1); these 33 patients formed the basis of the report, and no data were provided on non-BCC participants. The first dose was administered on day 1, followed by a second dose on day 8, with daily dosing onwards. This unique schedule allowed the collection of single- and multiple-dose pharmacokinetic data in the same patients. The half-life of the drug was 10 to 14 days. The steady-state serum levels were the same in all three dose cohorts, which indicates no need to increase the daily dose above 150 mg with this schedule. Skin punch biopsies and hair follicle assessments were used for pharmacodynamic analysis. Down-modulation of the Gli1 transcription factor was observed in all skin punch biopsy samples after treatment with the drug. GDC-0449 was extremely well tolerated, and no dose-related toxicities were observed. Adverse events considered to be possibly or probably drug-related included grade 3 fatigue in four patients; grade 1-2 dysguesia in three patients; and grade 3 hyponatremia, muscle spasm, and atrial fibrillation in one patient each. One episode of grade 4 hyponatremia was thought to be unrelated to the study drug.

Of the patients with BCCs, partial response was seen in 18, with stable disease observed in 11 and disease progression noted in the remaining four. Median progression-free survival was longer than 8.8 months at the time of publication. One additional patient who was referred for participation in the phase I trial was included in a separate report by Rudin and colleagues.12 This patient was a 26-year- old man with widely metastatic and refractory medulloblastoma that demonstrated biochemical evidence of Hedgehog pathway activity. He was treated off protocol because of pancytopenia, presumed secondary to bone marrow infiltration. The patient experienced a marked clinical partial response to GDC-0449 at a total daily dose of 540 mg by the second month, evidenced by relief of symptoms and by physical and radiographic examination; however, 1 month later, radiographic evaluation showed disease progression, and he was taken off therapy. The patient died 2 months later. While the response was brief, this case report highlights a fundamental principle in the development of Hedgehog and other targeted therapies: cancers selected for target activation are more likely to be susceptible to target inhibition. The key challenge is identification of valid measurements of pathway dependence.

Multiple phase II studies involving GDC-0449 are now recruiting. Examples include GDC-0449 versus placebo in combination with standard chemotherapy (5-fl uorouracil, folinic acid, oxaliplatin, and bevacizumab) for first-line treatment of metastatic colorectal cancer, and first-line therapy for small- cell lung cancer in combination with etoposide and cisplatin. In addition, studies are being planned in advanced BCC, as well as maintenance therapy after a second or third remission from conventional chemotherapy in patients with ovarian adenocarcinomas. 

While GDC-0449 has demonstrated clinical safety and potential activity, additional agents targeting the Hedgehog signaling pathway are beginning to enter clinical trials. Some agents are potentially limited in their applicability. For example, Hedgehog-binding antibodies, similar to the vascular endothelial growth factor—binding bevacizumab (Avastin), will be ineffective if Hedgehog pathway activation results not from overexpression of ligand, but instead from an abnormality of Patched, Smoothened, or effector molecules further downstream. An additional agent, such as forskolin, a protein kinase A inhibitor, would be active in blocking activity downstream but would be associated with significant potential adverse effects due to the ubiquitous nature of protein kinase A signaling.

 However, in addition to cyclopamine, which is too toxic for human use, a variety of naturally occurring compounds have demonstrated the ability to inhibit signal transduction through the Hedgehog pathway.

Other agents, such as IPI-926 and XL-139 (BMS-833923), are also now in phase I clinical trials as single agents and in combination with standard cytotoxic drugs, and will likely rapidly progress into phase II evaluation in the absence of major toxicities.

Putting Cancer Treatments in Perspective 

Cytotoxic chemotherapy has produced substantial palliation in a majority of advanced adult malignancies and, in the setting of adjuvant therapy, has undoubtedly contributed to curing some cancers. The level of benefit with currently available agents, however, has apparently reached a plateau that has not yielded dramatically to variations in dose, schedule, combination, or number of concurrent drugs. Recent appreciation of the molecular pathways upon which malignant cells depend has allowed the development of novel treatment strategies that have produced clinical benefit for a substantial number of patients. A note of caution is in order, however: as with most targeted therapies, particularly the small-molecule signal transduction inhibitors, it is unlikely that a single agent will provide substantial clinical benefit for a majority of patients with a single disease, or across a broad spectrum of diseases. This is a result largely of the genetic heterogeneity of most malignancies, such that only a small fraction truly depends upon a single signal transduction pathway. Examples include the Philadelphia chromosome in chronic myelogenous leukemia, EGFR-exon 19— or EGFR-exon 21–mutated non-small cell lung cancer, and Hedgehog-dependent BCC. While dramatic results can be seen in small patient populations in relatively uncommon settings (eg, imatinib in chronic myelogenous leukemia), such responses will be unlikely in unselected patients with more common malignancies such as those of the colon, breast, prostate, or lung. As for most other targeted small-molecule inhibitors, Hedgehog signal inhibitors are likely to be effective in cancers selected for evidence of pathway activation. This is an unsurprising manifestation of the paradigm established by the first targeted therapy, estrogen manipulation in breast cancer. At present, it would be unthinkable to offer tamoxifen or an aromatase inhibitor to a woman whose breast cancer showed no evidence of either the estrogen or progesterone receptor.

If the patient population most likely to benefit from Hedgehog inhibitor therapy could be identified, then the development of such drugs would provide hope, not empty hype. Further studies will likely identify predictors of clinical benefit and determine who among patients with more common cancers may benefit from Hedgehog signaling blockade or other targeted therapies. The size of candidate populations may number only in the thousands, but the unmet need is great, and the benefit to that minority is likely to be very large. The era of finding blockbusters has largely passed, and clinical trials of targeted agents are ushering in a new era of truly individualized therapies. 

Julie E. Bauman, MD, and Dennie V. Jones, Jr, MD, practice in the Department of Internal Medicine/ Division of Hematology and oncology, University of New Mexico Cancer Center, Albuquerque, New Mexico. 

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Once a human malignancy metastasizes, currently available cytotoxic chemotherapy is usually palliative. While conventional chemotherapy regimens are associated with objective tumor regression, this only occurs in a minority of patients. 

December 2009 | Oncology Live®

Digital Ink: Leaving a Mark on Medicine

Hedgehog Signal Inhibition Hope or Hype?