WNT5A in tumor development and progression: A comprehensive review

Curious About Eating To Support Your Menstrual Cycle? Here's How To Do It

How in tune with your menstrual cycle are you? Thanks to growing awareness around how the female body works during the monthly hormonal process—and more ability to track changes in the body, be that via an Oura ring or an app like Flo—many of us have started to rethink how we live our lives in order to better promote mental and physical health during every phase. When it comes to nutrition, there are helpful things we should all know about how to eat to support ourselves.

What are the different phases of the menstrual cycle?

"While textbooks generally discuss a 28-day cycle, very few women actually experience this," says Renee McGregor, a leading sports nutritionist. "A normal menstrual cycle is defined as anything between 23 and 35 days." During each monthly cycle, there are three distinct phases that the body moves through, known as the follicular, ovulation, and luteal phases.

So, what happens in each of these phases? And how should we eat in each one?

How to eat during every phase of your menstrual cycle

A healthy, balanced diet—with plenty of fiber, lean protein, vegetables, and whole grains—is helpful at every stage of the menstrual cycle, and for all facets of general health. However, "quantities will change," says McGregor, while Rhian Stephenson, nutritionist and founder of Artah, says that "aligning our nutrition can help ease our symptoms of PMS, reduce pain, boost mood, and improve overall wellbeing. It helps us get the most out of our biology."

She recommends first tracking your PMS symptoms over a month, paying attention to how you feel, your energy levels, the food you crave, your sleep, and so on, in order to better understand the rhythm of your cycle, how it affects you personally, and how you can work with it for improved health and wellbeing.

Follicular phase

The follicular phase is marked by the first day of bleeding. It lasts around 14 days, and during the early days, our reproductive hormones are low, which is why often we feel relatively calm and optimistic. "In the mid to late follicular phase, follicle-stimulating hormone (or FSH) and estrogen slowly start to rise as we approach ovulation," says McGregor. Serotonin also rises—cue a happier state of mind, while a surge in testosterone boosts libido.

How to eat:

As hormones drop, it's a good time to increase your fat and protein intake to help support the brain, while also ensuring you are eating plenty of healthy fats, which are essential for hormone production. "Fiber is always important, but for those who are more estrogen dominant (and suffer from things like cyclical acne or tender breasts), eating plenty of fiber, and adding in fermented foods near the end of this phase, are particularly important," says Stephenson. If you're someone who likes to intermittently fast, this is a good time to do so, as blood sugar levels are more stable.

Ovulation

Ovulation happens between days 11 and 16, or thereabouts, as it varies from person to person. "Luteinising hormone (or LH), which triggers the release of an egg, rises, and estrogen also peaks," explains McGregor. "Some women may experience pain during this phase, while others will find their energy will soar." We may also feel at our best in terms of mood, energy levels, and confidence.

However, as ovulation occurs, our body temperature rises and we "start to see hormonal instability, meaning we can often feel a sharp change from one day to the next", says Stephenson. "Ovulation is an inflammatory process, and it's normal to feel pain, bloating, and tenderness once it has occurred."

How to eat:

Eat lighter whole grains, like quinoa or corn, to feel satiated, at this point in the cycle, we still don't need lots of carbohydrates. However, we should start to reduce any fasting practices. "Stick to nutrient-rich, anti-inflammatory foods like red peppers, spinach, tomatoes, leafy greens, raspberries, and strawberries," suggests Stephenson, adding that it's key to keep the microbiome healthy to prevent estrogen being reabsorbed in the gut.

Luteal

The luteal phase (from around day 15 onwards) is associated with high hormonal activity, including a sharp drop in estrogen and an equally sharp rise in progesterone. "When progesterone is dominant, we see a slight rise in our basal metabolic rate (BMR), and subsequently our carbohydrate requirements go up," explains McGregor. "At the same time, progesterone can cause fluctuating blood sugar levels."

How to eat:

This is a phase in which you should ensure you're eating enough carbohydrates and calories to fulfill a heightened metabolism. "From antioxidants to omega 3 fats, vitamins to minerals, you name it, the body uses more of everything in this phase," says Stephenson. "Because of this, inflammatory conditions often get worse. We also have less control over our blood sugar and changing hormones lead to sugar cravings. Eating more sugary foods only worsens PMS symptoms, so the key is increasing carbs that work for the body, like naturally sweet root vegetables, such as sweet potato, and complex carbohydrates and grains, like brown rice, which are metabolized slowly by the body."

You can increase your calorie intake by around 200 kcal a day during this time, plus both experts recommend B vitamins—in particular, folate, B6, and B12—to reduce premenstrual symptoms. Foods like asparagus, spinach, nuts and seeds, and avocado are all good sources. When it comes to carbohydrates, whole grains, like brown rice and buckwheat, are brilliant, plus they're good sources of fiber too. "Studies have shown that calcium and vitamin D help combat symptoms of PMS, so include tahini—which is an incredible source—sardines, almonds, and organic tofu," recommends Stephenson. "If you eat dairy, lean towards goats and sheep milk varieties, or fermented yogurt-based dairy."

It's also worth noting that during the week or so before your period starts, the body is less able to cope with "dietary sources of inflammation," which include alcohol, refined sugar, and ultra-processed foods, so it's a good time to steer clear.

Challenging Cancer Stereotypes While Living With Follicular Lymphoma

Living with follicular lymphoma, I challenge common misconceptions about cancer, highlighting the unique and varied experiences of patients with cancer.

Karen Cohn is a retired middle school special education teacher who was diagnosed with follicular lymphoma in July 2020. Catch up on all of Karen's blogs here!

There are many preconceptions about cancer, even among patients with cancer. I have follicular lymphoma, a form of blood cancer that is considered highly treatable, but also chronic and incurable. Blood cancer is different than many other forms of cancer, in that there is not usually a single tumor, because it spreads in and through the blood, so even early stages can be in multiple locations — something even many people with other types of cancer aren't aware of. I met a woman with liver cancer, which had been treated, in part, with surgery, and she asked what type of surgery I'd had for my treatment; she was shocked to learn that I hadn't had any.

This entry was triggered not by that, but by an article in the New York Times, about a doctor who teaches medicine at Stanford University. When he was diagnosed with cancer, he chose to continue working, and to discuss the process of dealing with terminal lung cancer (he was given two years to live) with his students, rather than retiring immediately. He was placed on a treatment regimen, which included chemotherapy, which, in his case (as well as many others) caused mouth sores. His response? "Day in the life of a cancer patient," as he said in a video diary he began after his diagnosis, according to the Times.

Here's the thing about that: it's not something every patient with cancer experiences. I have no idea how many patients with cancer do experience such sores; I am happy to say that I wasn't one of them, much to my dentist's pleased surprise.

The chemotherapy regimen I underwent is mild, as such things go, and I didn't lose my hair — well, not all of it; it thinned a little around the hairline, but it wasn't particularly noticeable — which is normal for this particular form of chemotherapy. I only noticed because I was looking for it, and because extra hair shed when I combed my hair in the shower. But an amazing number of people commented on my keeping my hair, and a few even asked how I got such a wonderful wig; everyone who knew I had been given chemotherapy just assumed I would have gone bald.

A friend whose daughter had undergone treatment for osteosarcoma (bone cancer) bought me extra trash cans and scented liners because she knew, from her daughter's experience, that I would be vomiting a lot. But I wasn't. I was given a different chemotherapy medication, which, as I said, was milder, and between that and an anti-nausea medication, I was never nauseous.

Even an advocate for a blood cancer organization seemed shocked that I wasn't undergoing maintenance treatment (ongoing immunotherapy treatments intended to keep cancer from recurring, which some patients with blood cancer don't do at all, some do for a limited period of time, and some do indefinitely), and this is a person who advocates for patients with blood cancer with health care providers and lobbies for coverage with legislators.

I was off work during treatment; it was the second half of 2020. My oncologist wasn't sure what would happen if I caught COVID during treatment, and since I was a middle school teacher, the risks were high. When I returned to work, most people were surprised that I looked, well, normal — I had not gained or lost enough weight to look obese or emaciated, which was what most people were apparently expecting.

My point, I suppose, is that there's no "typical" patient with cancer, something that not even medical doctors teaching other medical doctors know. If you know someone who has been diagnosed with cancer, take them as they are, just like you would anyone else; please don't lump them into a stereotype of what a patient with cancer should be, because you could be right, but there's a better than reasonable chance you'll be wrong, no matter what you think you know.

For more news on cancer updates, research and education, don't forget to subscribe to CURE®'s newsletters here.

Obinutuzumab For The Treatment Of Non-Hodgkin Lymphomas

Indolent non-Hodgkin lymphoma and chronic lymphocytic leukaemia

Non-Hodgkin lymphomas can be classified according to the speed at which they progress. Those that grow and spread slowly are described as 'indolent', one of the most common types of which is follicular lymphoma. About one-fifth of new cases of non-Hodgkin lymphoma are diagnosed as follicular lymphoma1. Follicular lymphoma usually appears as painless, slowly growing lymph nodes. In the early stages of disease there are typically no symptoms, but at advanced stages the patient may experience symptoms such as fever, night sweats, weight loss and general lack of energy. The disease is typically characterised by a series of relapses and retreatment. Often, with each relapse, the disease becomes increasingly resistant to chemotherapy2.

Chronic lymphocytic leukaemia is the most common type of adult leukaemia in the Western world. Most patients are diagnosed when a high number of blood lymphocytes are found after a patient has a full blood count for an unrelated reason. In common with follicular lymphoma, chronic lymphocytic leukaemia is slow to progress. Many patients do not have symptoms for years, but if the treating physician notices a sharp increase in the number of lymphocytes and a drop in the number of red blood cells, they may begin treatment.

These chronic diseases contrast with the aggressive non-Hodgkin lymphoma subtype, diffuse large B-cell lymphoma, which can be fatal within weeks or months of diagnosis if not treated. Diffuse large B-cell lymphoma and treatment advances for diffuse large B-cell lymphoma are described further in this issue of Nature Outlook: Lymphoma.

Immunotherapies for non-Hodgkin lymphoma and chronic lymphocytic leukaemia

Immunotherapies are often described as 'biological' or 'targeted' therapies that stimulate the body's immune system to act against cancer cells. In the search for an immunotherapy for B-cell malignancies, the membrane protein CD20 was considered a prime target. CD20 is found on the surface of all normal B cells and on 95% of cancerous B cells.

Rituximab, developed in partnership by Roche and Biogen Idec, was the first anti-CD20 monoclonal antibody to be approved for the treatment of non-Hodgkin lymphomas. It works by specifically targeting the CD20 protein and kills B cells in three different ways 1) antibody-dependent cellular cytotoxicity –'effector' immune cells such as natural killer cells and macrophages are recruited to kill the B cells, including the cancerous B cells; 2) complement-dependent cytotoxicity – the proteins of the 'complement' system are recruited, which damage the B-cell membrane leading to cell death; and 3) direct cell death – as rituximab binds to the B cell through the CD20 receptor, the signal causes the B cell to die3. These mechanisms are shown in more detail in Figure 1.

Figure 1: Differences in the proposed mechanisms of action of rituximab and obinutuzumab. Rituximab is a type I antibody that functions by the stabilisation of CD20 on lipid rafts, resulting in strong complement-dependent cytotoxicity. Obinutuzumab is a glycoengineered type II antibody that leaves CD20 distributed across the surface of the B cell and has much lower complement-dependent cytotoxicity, but greater antibody-dependent cellular cytotoxicity, antibody-dependent phagocytosis and direct cell death.

Rituximab in combination with chemotherapy was found to be effective at destroying both cancerous and healthy B cells; when the rituximab treatment is completed, the body replaces the normal B cells. In 1997, rituximab received approval for use by the United States Food and Drug Administration (US FDA) for the treatment of patients with relapsed low-grade non-Hodgkin lymphomas. It was the first therapeutic antibody to be approved for chronic lymphocytic leukaemia and non-Hodgkin lymphoma. Compared with the previously available chemotherapy treatments, rituximab improved the survival outlook for these patients. One study showed that after a median observation period of 18 months, patients with advanced stage follicular lymphoma who received rituximab in combination with chemotherapy were significantly less likely to experience treatment failure than patients who received chemotherapy alone4.

The unmet medical need for follicular lymphoma and chronic lymphocytic leukaemia

Although rituximab helps many patients with non-Hodgkin lymphoma and chronic lymphocytic leukaemia, and was a major step forward in the treatment of the disease, it has some limitations. The level and duration of the response to rituximab may decrease over time. Eventually, the majority of patients receiving rituximab relapse and some even develop resistance to the drug. In addition, some patients do not respond to initial rituximab treatment, or their disease continues to get worse while receiving rituximab5. Furthermore, while patients with indolent diseases survive for a comparatively long time, on average between six and ten years with treatment, they usually cannot be cured if they present in the clinic in the advanced stages of disease. Also, at some stage their disease may become more aggressive. Consequently, Roche has continued to develop new treatments to improve upon rituximab for these patient populations.

Obinutuzumab, a humanised, glycoengineered, type II, monoclonal antibody

Roche wanted to create an antibody that would overcome some of the limitations of rituximab and be more effective than rituximab at treating B-cell malignancies. Roche used a process known as glycoengineering to design obinutuzumab. Glycoengineering involves controlling the type of sugar molecules in the Fc region of the antibody. The Fc region of the antibody recruits immune cells to kill the target cell, which is bound by the antibody. Laboratory testing of obinutuzumab showed that compared with rituximab, the Fc region of obinutuzumab is more effective at recruiting effector immune cells (antibody-dependent cellular cytotoxicity and phagocytosis) and thus better at triggering the death of cancerous cells (Fig. 1). Obinutuzumab was the first medicinal product using glycoengineering technology to be approved in the US and the European Union (EU)6. Obinutuzumab is a type II antibody, unlike rituximab, which is a type I antibody. These classifications are based on the way the antibodies bind to CD20. When rituximab binds to CD20, it reorganises the CD20 molecules on the cancerous B cells into lipid rafts, which indirectly triggers cell death by a mechanism known as complement-dependent cytotoxicity (Fig. 1). In contrast, the type II antibody, obinutuzumab, is not as effective at inducing complement-dependent cytotoxicity but is much more effective than rituximab at inducing direct cell death. This direct action of obinutuzumab on B-cell death, together with its effective induction of antibody dependent cellular cytotoxicity and antibody-dependent phagocytosis, may represent an important advantage, as it has the potential to reduce the risk of drug resistance seen with rituximab.

Figure 2: Reduction in the risk of disease worsening and death in four key clinical trials of obinutuzumab. The GALLIUM trial compared obinutuzumab plus chemotherapy combinations with rituximab plus chemotherapy in patients with previously untreated follicular lymphoma (Ref 9). The CLL11 trial compared obinutuzumab plus chemotherapy (chlorambucil), with rituximab plus chlorambucil in patients with chronic lymphocytic leukaemia. GADOLIN compared obinutuzumab plus chemotherapy (bendamustine) with bendamustine alone in patients with indolent non-Hodgkin lymphoma who did not respond to rituximab (Ref 8). GOYA compared obinutuzumab plus chemotherapy combinations with rituximab plus chemotherapy in patients with previously untreated advanced-stage diffuse large B-cell lymphoma (Ref 10).

Clinical trials of obinutuzumab

The superior effects of obinutuzumab seen in the laboratory have been confirmed in clinical trials and, in 2013, the drug was the first drug to be awarded Breakthrough Therapy Designation by the US FDA. Obinutuzumab was compared with rituximab in stage 2 of the CLL11 clinical trial of patients with chronic lymphocytic leukaemia and other co-existing conditions; both groups also received chlorambucil chemotherapy7. The use of obinutuzumab in the CLL11 trial led to a 51% decrease in the risk of disease worsening or death compared with rituximab. The trial also showed that patients who received obinutuzumab survived for longer than those who received rituximab; the risk of death was 24% lower in the obinutuzumab group compared with the rituximab group (Fig. 2). The side effect profiles of rituximab and obinutuzumab were similar, although the number of patients experiencing side effects, including reactions during or following drug infusions, and a decrease in some blood cell counts (neutrophils), was higher in those treated with obinutuzumab compared with rituximab.

A phase III study, called the GADOLIN trial, looked at the risk of disease worsening or death in patients with indolent non-Hodgkin lymphoma who did not respond to, or who relapsed during or within 6 months after a previous rituximab treatment regimen. These patients received either obinutuzumab plus chemotherapy (bendamustine) or bendamustine only. Patients who received the obinutuzumab regimen were 43% less likely to experience disease worsening or death than those who received chemotherapy only. This trial also showed that 75% of patients in the group who received obinutuzumab survived to the end of the study, compared with only 65% of the patients receiving chemotherapy alone; this represented a 33% lower risk of death in the group of patients who received obinutuzumab (Fig. 2)8. The side effects experienced by patients in the GADOLIN study were similar for both treatment groups. The findings from GADOLIN led to the US approval of obinutuzumab in combination with bendamustine chemotherapy, followed by obinutuzumab alone, as a new treatment regimen for patients with follicular lymphoma who relapse after rituximab treatment, or who do not respond to rituximab. Shortly after, obinutuzumab in combination with bendamustine was approved in the EU for patients with follicular lymphoma who do not respond to rituximab or who relapse within six months of rituximab treatment. Roche also investigated the use of obinutuzumab for indolent non-Hodgkin lymphoma patients who have not previously received treatment. The GALLIUM clinical trial assessed the efficacy of obinutuzumab plus chemotherapy compared with rituximab plus chemotherapy in patients with previously untreated follicular lymphoma. In this trial, the risk of disease worsening or death was 32% lower in patients who received obinutuzumab compared with those who received rituximab9. Obinutuzumab was more effective than rituximab but the group receiving obinutuzumab had a different profile of side effects. Importantly, the improvement in patient quality of life was similar with obinutuzumab and rituximab, despite the different side effects9. The outcomes of the GALLIUM trial led to the approval, in the US, EU and many other countries, of obinutuzumab in combination with chemotherapy for the treatment of patients with previously untreated advanced follicular lymphoma.

Disappointingly, the results of the GOYA trial of obinutuzumab in patients with the aggressive form of non-Hodgkin lymphoma, diffuse large B-cell lymphoma, revealed that outcomes with obinutuzumab were not better than with rituximab when combined with chemotherapy10. Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma making up about 30% of all lymphomas. It is typically fatal if left untreated and so more effective drugs for patients with diffuse large B-cell lymphoma are desperately needed. The search for such treatments by Roche has uncovered a new antibody-drug conjugate, polatuzumab vedotin, described in this edition of Nature Outlook: Lymphoma.

Future directions

Roche continues to look at ways of advancing the treatment of lymphomas. One approach is to combine obinutuzumab with different drugs, including chemotherapy-free treatment options. A programme of early phase clinical studies, known as InHarmony, is testing obinutuzumab combinations with various different drugs that have different mechanisms of action in different groups of patients with lymphoma (either those receiving their first treatment or those who have relapsed following treatment). Such combinations include an immunomodulatory agent (lenalidomide), a checkpoint inhibitor (atezolizumab), a Bcl2 inhibitor (venetoclax) or an antibody-drug conjugate (polatuzumab vedotin). An ongoing study (CLL14) of patients with previously untreated chronic lymphocytic leukaemia is comparing the efficacy of obinutuzumab in combination with the drugs venetoclax or chlorambucil. Roche is dedicated to improving the lives of patients with non-Hodgkin lymphoma and chronic lymphocytic leukaemia. A number of additional approaches to the treatment of B-cell malignancies are in the pipeline, including the T cell bispecific antibodies, mosunetuzumab11 and CD20-TCB12. Our aim is to optimise the use of available treatments while continuing to search for new, more effective treatments for these life-limiting diseases.

Acknowledgement

Third-party medical writing assistance, under the direction of the authors, was provided by Angela Rogers of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.

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